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Smoking and Airway Inflammation in Patients With Mild Asthma
Abstract
Cigarette smoking is common in asthmatic patients, and we investigated the impact of cigarette smoking on airway inflammation in asthma.
Single-center observational study of airway inflammation in asthmatic and healthy smokers and nonsmokers.
Asthma research unit in a university hospital.
Sixty-seven asthmatic and 30 nonasthmatic subjects classified as smokers or nonsmokers. Asthmatics had chronic, stable asthma and were not receiving inhaled or oral steroids at the time of the study.
We examined induced-sputum cell counts and levels of interleukin (IL)-8 and eosinophilic cationic protein (ECP). Bronchial hyperreactivity was assessed using methacholine challenge.
Asthmatic smokers had higher total sputum cell counts than nonsmoking asthmatics and both smoking and nonsmoking healthy subjects. Smoking was associated with sputum neutrophilia in both asthmatics and nonasthmatics (median, 47% and 41%, respectively) compared with nonsmokers (median, 23% and 22%, respectively), and sputum IL-8 was increased in smokers compared with nonsmokers, both in subjects with asthma (median, 945 pg/mL vs 660 pg/mL, respectively) and in healthy subjects (median, 1,310 pg/mL vs 561 pg/mL, respectively). Sputum eosinophils and ECP levels were higher in both nonsmoking and smoking asthmatics than in healthy nonsmokers. In smoking asthmatics, lung function (FEV(1) percent predicted) was negatively related to both sputum IL-8 (r = - 0.52) and sputum neutrophil proportion (r = - 0.38), and sputum IL-8 correlated positively with smoking pack-years (r = 0.57) and percent neutrophil count (r = 0.51).
In addition to the eosinophilic airway inflammation observed in patients with asthma, smoking induces neutrophilic airway inflammation; a relationship is apparent between smoking history, airway inflammation, and lung function in smoking asthmatics.
... Studies exploring the airway inflammation of asthmatics have commonly been conducted on non-smoking asthmatics to avoid the effect of CS on the pathogenic mechanism of asthma (239,240). Therefore, the impact of CS on airway inflammation is not very well understood (236). ...
... The non-T2 endotype of asthma is associated with neutrophilic airway inflammation as well as increased Th17 cytokines (20,83). Cigarette smoke (CS) has been linked with non-T2 airway inflammation in asthma compared with asthmatic patients who have never smoked (236,269). We have shown in chapter 3 that CSE may shift the airway inflammation in asthma from T2 ...
... to non-T2. CS is a significant inflammatory factor in the airways and has been shown to promote non-T2 airway inflammation in asthmatic smokers (219,236). Th17 cytokines also play a crucial role in non-T2 airway response and the development of severe forms of asthma, which known to be insensitive to glucocorticoids treatment (270). Glucocorticoids are the main treatment for chronic inflammatory diseases including asthma (192). ...
... Bacterial dysbiosis [102][103][104] and oxidative stress from pollutants 102,105,106 can contribute to non-atopic asthma through over recruitment of neutrophils and destruction of airway epithelium. Cigarette smoke is associated with lung function decline, increased airway neutrophils 102,105,[107][108][109][110] and an increase in IL-8 108 . Studies show significant neutrophil reduction 6 weeks post smoking cessation 107 . ...
... Bacterial dysbiosis [102][103][104] and oxidative stress from pollutants 102,105,106 can contribute to non-atopic asthma through over recruitment of neutrophils and destruction of airway epithelium. Cigarette smoke is associated with lung function decline, increased airway neutrophils 102,105,[107][108][109][110] and an increase in IL-8 108 . Studies show significant neutrophil reduction 6 weeks post smoking cessation 107 . ...
... Airway neutrophil numbers can also increase in response to exacerbation 92 and cigarette smoke exposure 102,105,108,109,365 . Therefore, in order to understand a stable airway granulocyte concentration, analysis must occur in the absence of infection and cigarette smoke exposure. ...
Up to 1 in 120 of the UK population suffer with severe asthma, a heterogeneous inflammatory disease with persistent symptoms, an average of 4 exacerbations per year and poor response to treatment. Sputum sampling provides a relatively non-invasive measure of airway inflammation, focussing on the proportions of granulocytes (eosinophils and neutrophils) in the sputum. Patients are considered eosinophilic, neutrophilic, mixed granular or paucigranular according to their cell profile. Eosinophilic patients (≥2-3% eosinophils) are considered type-2 (T2) inflammation high but there is also a T2-low population whose disease is poorly understood and fewer treatments are available. Sputum neutrophils have been implicated as a marker of non-T2 disease and patients with high sputum neutrophils have a greater propensity for hospitalisation than pure T2-high patients. Neutrophilia is less well defined than eosinophilia and the definition can range from ≥40% up to ≥76% neutrophils making identification and treatment of this population difficult.
The aim of this thesis was to explore two hypotheses: 1) New approaches to endotyping asthma by characterising sputum inflammatory profiles can be established that better correlate with markers of disease severity and activity than current methods; 2) The use of protein markers of cellular activation will improve the value of sputum measurements in phenotyping asthma.
The Wessex Severe Asthma Cohort (WSAC) is a cohort of severe asthma, mild/moderate asthma and healthy controls. Volunteers in WSAC underwent extensive clinical characterisation including sputum induction in order to investigate the heterogeneity of severe asthma. Class comparison techniques were used to compare clinical measures of disease severity, sputum eosinophilic vs non-eosinophilic phenotypes and sputum supernatant protein concentrations. Unbiased clustering analysis of sputum supernatant proteins was used to identify specific sputum protein fingerprints of disease endotypes.
As expected, severe asthma patients in the WSAC had poorer disease control, poorer lung function, more exacerbations and had higher psychological comorbidities than patients with mild/moderate asthma. Both sputum eosinophils and neutrophils correlated with poorer lung function, but sputum neutrophils also correlated with poor asthma control. However, an optimal definition of what constituted a neutrophilic phenotype using previously published definitions was not identified. Further analysis of sputum proteins revealed that markers associated with neutrophil recruitment and activation had a greater number of significant correlations with clinical measures than neutrophil proportions alone. When multiple sputum proteins were analysed in class comparison analysis only IL-5 was associated with a granulocytic phenotype (eosinophilia). Unbiased cluster analysis exclusively driven by sputum protein concentrations revealed 4 clusters of patients. The largest cluster contained patients with a high eosinophil burden and represented 40% of the population. The remaining 3 clusters each represented 20% of the population. A pauci inflammatory cluster was identified which may indicate over treatment. The remaining two clusters both each had high IL-1 and high TNF, however one cluster had low IL-1Ra and high IL-8 whereas the other had high IL-4, these may be potential treatable targets for these clusters of patients. Current clinical measures provided no insight into the underlying disease mechanisms.
Work in this thesis supports the hypothesis that sputum inflammatory profiles correlate better with disease activity than sputum granulocytes alone. Sputum inflammometry in the absence of granulocyte bias identified 4 clusters of patients with distinct biological differences highlighting potential protein targets for therapeutic intervention. Thus, further sputum protein profiling is needed to enable a precision medicine approach to treat those severe asthma patients who do not respond to current therapies.
... MGA (5.2%), and NA (4.3%). ICS treatment, older age, and smoking could increase sputum neutrophilic inflammation in patients with asthma [29][30][31][32]. The average age of patients with NA was the highest among the four asthma inflammatory phenotype groups in this study, and the prevalence of NA was higher among older patients. ...
... This confirmed previously published observations that sputum neutrophils in asthma increase with age [30]. In addition, smoking has also been shown to increase sputum neutrophilia [32]. In our study, smoking and overweight/obese patients exhibited a larger proportion of NA. ...
... Moreover, our results were also distinctly different from a report from Beijing, China, which showed that the proportions of the four inflammatory phenotypes were 34.9% for NA, 34.9% for EA, 23.8% for MGA, and 6.3% for PA [7]. It is interesting that the proportion of NA was only 4.3% in our study, despite the fact that patients with asthma in our study had a higher average age (51 ± 14 vs 47 ± 17.6) and included a larger proportion of smokers (40.65 vs 19.6%), both factors that should have increased the proportion of NA [30,32]. This may be related to the specific conditions in Northeast China. ...
Background
The inflammatory phenotypes of asthma predict the treatment response and prognosis. The phenotype distributions differ depending on the geographical region. This study aimed to assess the distribution of different inflammatory phenotypes among asthma patients in Jilin Province, China.
Methods
A total of 255 patients with asthma were recruited from Jilin Province, China for this cross-sectional study. Each patient underwent sputum induction following clinical assessment and peripheral blood collection. Inflammatory phenotypes were classified according to the inflammatory cell counts in the sputum.
Results
Paucigranulocytic asthma (PGA) was the most common inflammatory phenotype (52.2%), followed by eosinophilic asthma (EA, 38.3%), mixed granulocytic asthma (MGA, 5.2%), and neutrophilic asthma (NA, 4.3%). NA was more common among patients over 45 years old and those who were treated with higher doses of inhaled corticosteroids (ICS), but was less common following antibiotics treatment ( p < 0.05). The proportion of patients with EA decreased as the ICS treatment dose and time increased ( p = 0.038). Patients with uncontrolled asthma had higher numbers of sputum eosinophils and neutrophils ( p < 0.05). Patients with severe asthma had a higher percentage of sputum neutrophils ( p < 0.05). A greater proportion of patients with NA had severe asthma (60%) compared to those with EA (18.2%) ( p = 0.016).
Conclusions
The most common asthma inflammatory cell phenotype in Jilin Province, China is PGA, followed by EA, MGA, and NA. The low prevalence of NA in Jilin Province compared to other countries and also other regions in China might be due to excessive antibiotic use and irregular ICS treatment in this region.
... In addition, most studies included patients with a history of smoking or ICS use, [15][16][17][18][19][20] which might affect the expressions of the inflammatory biomarkers. [21][22][23][24] What's more, there is no research on the NLR in distinguishing between COPD and ACO. ...
... However, all of them are affected by factors such as therapeutic drugs and smoking. [21][22][23][24] Therefore, the present study was conducted to further evaluate the accuracy of FeNO, EOS, and NLR in ACO diagnosis after excluding the influence of ICS and smoking use. Congruent with some previous studies, [15][16][17][18][19][20] our results confirmed the higher levels of FeNO and EOS in ACO patients than in COPD patients, especially in those without ICS use or with a smoking history. ...
... 6,7 What's more, steroid responsiveness, airway inflammation, and airway remodeling that occur in asthma and COPD are associated with cigarette smoking. 24 Patients with asthma who smoke have larger numbers of neutrophils and eosinophils. 24,29,30 Therefore, the FeNO and EOS levels were higher in the ACO patients, and increased FeNO and EOS levels in ACO patients also manifest that ACO has an eosinophil airway inflammatory response similar to asthma. ...
Purpose
To evaluate the accuracy of inflammatory biomarkers in differentiating patients with asthma–COPD overlap (ACO) from those with COPD alone.
Methods
Clinical data of 134 patients with COPD and 48 patients with ACO admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 2016 to June 2019 were retrospectively analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the best cut-off values of fractional exhaled nitric oxide (FeNO), blood eosinophil counts (EOS), and neutrophil to lymphocyte ratio (NLR) for differentiating between ACO and COPD alone. Spearman correlation analysis was conducted to evaluate the relationships between these inflammatory biomarkers and the forced expiratory volume in one second/prediction (FEV1%pred).
Results
FeNO and EOS in the ACO patients were significantly higher than those in the COPD patients (FeNO: median 37.50 vs 24.50 ppb, P < 0.001; EOS: median 0.20 vs 0.10 ×10⁹/L, P = 0.004). FeNO was positively correlated with FEV1%pred (r = 0.314, P = 0.030), while NLR was negatively correlated with FEV1%pred (r = −0.372, P = 0.009) in patients with ACO. In addition, a positive correlation between FeNO and EOS was also found in ACO, especially in patients without history of inhaled corticosteroids (ICS) use (r = 0.682, P < 0.001). The optimal cut-off value of FeNO was 31.5 ppb (AUC = 0.758, 95% CI = 0.631–0.886) in patients with smoking history, with 70.0% sensitivity and 89.9% specificity for differentiating ACO from COPD. In patients without history of ICS use, the best cut-off value of FeNO was 39.5 ppb (AUC = 0.740, 95% CI = 0.610–0.870), with 58.3% sensitivity and 84.9% specificity. Among patients without history of ICS use and smoking, 27.5 ppb was optimal cut-off level for FeNO (AUC = 0.744, 95% CI = 0.579–0.908) to diagnose ACO, with 81.8% sensitivity and 60.7% specificity, and the sensitivity was improved to 91.7% when FeNO was combined with EOS.
Conclusion
The inflammatory biomarkers FeNO and EOS can be used as indicators for differentiating between ACO and COPD alone.
... The risk of osteoporosis increases with higher cigarette consumption [27]. Smokers with asthma experience worse asthma control with accelerated decline in lung function and increased severity of airflow obstruction compared to non-smoking asthmatic patients [32][33][34]. There also seems to be an association between asthma severity and smoke prevalence [35]. ...
... There also seems to be an association between asthma severity and smoke prevalence [35]. Mechanisms for the adverse effects of smoking in asthma include altered airway inflammation with a predominance of activated macrophages and neutrophils as in early COPD [32,33] and corticosteroid insensitivity [34]. Neutrophil numbers in airways are known to correlate to rate of decline in lung function [36] and as neutrophils are not normally responsive to corticosteroid treatment [32,33], persistent exposure to cigarette smoke in patients with asthma may necessitate the use of SG as acute and chronic add-on therapy [5]. ...
... Mechanisms for the adverse effects of smoking in asthma include altered airway inflammation with a predominance of activated macrophages and neutrophils as in early COPD [32,33] and corticosteroid insensitivity [34]. Neutrophil numbers in airways are known to correlate to rate of decline in lung function [36] and as neutrophils are not normally responsive to corticosteroid treatment [32,33], persistent exposure to cigarette smoke in patients with asthma may necessitate the use of SG as acute and chronic add-on therapy [5]. ...
It is well-known that use of continuous systemic corticosteroids (SG) affects bone metabolism, bone mineral density (BMD), and ultimately increases the risk of osteoporosis. In patients with asthma, on the other hand, the effects of long-term high-dose inhaled corticosteroids (ICS) on BMD and risk of osteoporotic fractures is controversial. The reasons for this inconsistency could be explained by the fact that only few long-term studies investigating the effect of ICS in patients with asthma exist. The studies are characterized by different study designs and duration of ICS exposure, small study populations, and differences between the used ICS. The aim of this article is to unravel which factors, if any, that contribute to an increased risk of osteoporosis in patients with asthma and to summarize the evidence regarding adverse effects of ICS on bone metabolism, BMD and osteoporotic fractures in patients with asthma.
... Cigarette smoking is associated with the development of airflow obstruction over time through the narrowing the airways . The mechanism is as follows: cigarette smoking alters the airway , the number of white blood cells responsible to heal injuries and infections (Chalmers et al., 2001;Telenga et al., 2013;Thomson et al., 2004 and can cause airway inflammation (Boulet et al., 2006;Chalmers et al., 2001;Thomson et al., 2004;Wu et al., 2017). Cigarette smoking induces oxidative stress (Takahashi et al., 2018;Thomson et al., 2004) which releases proinflammatory signaling activating white blood cells responsible for combating infections and healing injuries increasing their numbers and inducing tissue damage to the epithelium and other structures of the respiratory system leading to asthma. ...
... Cigarette smoking is associated with the development of airflow obstruction over time through the narrowing the airways . The mechanism is as follows: cigarette smoking alters the airway , the number of white blood cells responsible to heal injuries and infections (Chalmers et al., 2001;Telenga et al., 2013;Thomson et al., 2004 and can cause airway inflammation (Boulet et al., 2006;Chalmers et al., 2001;Thomson et al., 2004;Wu et al., 2017). Cigarette smoking induces oxidative stress (Takahashi et al., 2018;Thomson et al., 2004) which releases proinflammatory signaling activating white blood cells responsible for combating infections and healing injuries increasing their numbers and inducing tissue damage to the epithelium and other structures of the respiratory system leading to asthma. ...
Background: In the United States (US), cigarette smoking and weight status have been considered the main public health concerns in recent years due to a higher incidence of all-cause
mortality and respiratory diseases such as asthma and COPD among those with past 30 day smoking or have an underweight or obesity weight status than those who do not smoke cigarettes or have a weight status of normal weight or overweight. The health burden associated with cigarette smoking and weight status in the US adult population has not been consistent across sociodemographic factors such as sex/gender, socioeconomic status (SES), and race/ethnicity. The association among cigarette smoking, weight status and all-cause mortality; cigarette smoking, weight status and asthma; and cigarette smoking, weight status and COPD are not entirely understood, or how disparities may contribute to these associations. Each of this dissertation’s three aims addresses a specific research question about the associations among cigarette smoking and weight status with all-cause mortality, asthma, and COPD as well as which factors may contribute to health disparities of these associations. The first aim sought to determine whether weight status was a mediator between cigarette smoking and all-cause mortality among adults with past 30 days smoking in the US. The second aim sought to determine whether weight status is a mediator between cigarette smoking and asthma, and cigarette smoking and COPD. The third aim sought to determine which factors were a source of health disparities in the associations among cigarette smoking and weight status with all-cause mortality, asthma, or COPD.
Methods: The study population included adults in the US with past 30 day smoking, with nationally representative samples for the National Health and Nutrition Examination Survey (NHANES). For all three aims, cigarette smoking, asthma, and COPD were self-reported, while weight status was measured on-sites and all-cause mortality was collected through death records.
The first and second studies included causal mediation analyses with weight status as the mediator of the associations between cigarette smoking and all-cause mortality, cigarette smoking and asthma and cigarette smoking and COPD using the NHANES dataset from 2003- 2018 and 2013-2018, respectively. For the third study Structural Equation Models (SEM) were
implemented to determine which factors related to health disparities may contribute to the associations among cigarette smoking, weight status, all-cause mortality, asthma, or COPD using the NHANES 2003-2018 dataset (for all-cause mortality) and the NHANES 2013-2018 (for asthma and COPD).
Results: In the mediation analysis between cigarette smoking and all-cause mortality with weight status as a mediator, the total effect (TE) for the model with only physiological factors was -1.94
(95% CI=-2.67, -0.04; p<0.001), with an average direct effect (DE) of -1.82 (95% CI=-2.51, - 0.56; p<0.001) and an average indirect effect (IE) of -0.118 (95% CI= -0.19, -0.03; p =0.004).
The TE for the model adjusted for physiological and sociodemographic factors was -1.54 (95% CI = -2.20, 0.01; p = 0.048), an average DE of -1.49 (95% CI -2.18, -0.01; p = 0.048) and an average IE of -0.049 (95% CI = -0.052, 0.02; p = 0.518). For the mediation analysis between cigarette smoking and asthma and cigarette smoking and COPD having as mediator weight status, it was obtained that for asthma, the TE was 0.0009; p=0.016, with an average DE 0.0009; p=0.016 and an average IE of 0.00003; p=0.232. For COPD, the TE was 0.00166; p<0.001. The average DE was 0.00174; p<0.001; the average IE was -0.00008; p=0.46. The Prevalence Ratio (PR) of having asthma and COPD was 1.03 (95% CI=1.00, 1.06; p<0.1032) and 1.04 (95% CI: 1.03, 1.05; p<0.001), respectively. For the third aim, sex/gender was a significant factor in the associations among cigarette smoking, weight status and all-cause mortality; cigarette smoking, weight status and asthma and cigarette smoking, weight status, and COPD. Race/ethnicity was only significant in the association of cigarette smoking, weight status, and all-cause mortality, and cigarette smoking, weight status, and COPD among Hispanic Mexican and Non-Hispanic White individuals.
Conclusions: Findings from this dissertation showed that weight status was not a mediator between cigarette smoking and all-cause mortality; cigarette smoking and asthma, or cigarette
smoking and COPD when considering physiological and sociodemographic factors. The findings also indicated that sex/gender contribute to health disparities of these associations. Smoking cessation and harm reduction interventions to reduce the incidence of all-cause mortality, asthma, and COPD due to cigarette smoking should be tailored by sex/gender.
... The pro-inflammatory IL-17A mRNA has been detected in higher levels in the nasal tissues of smoking asthmatics than nonsmoking counterparts [51]. Higher sputum eosinophils, eosinophilic cationic protein (ECP), neutrophils and IL-8 levels were observed in asthmatic smokers compared to asthmatic nonsmokers, which were associated with FEV1 and neutrophil count [52]. Comparatively greater levels of sputum IL-1β, IL-5 and Interleukin 18 receptor 1 (IL-18R1) have been reported in current/former smoking severe asthmatics compared to healthy 5 of 20 controls [53]. ...
... Nonsmokers with BA have significantly elevated sputum and blood eosinophil counts [44]. Compared to healthy nonsmokers, nonsmoking asthmatics demonstrated higher sputum ECP and eosinophil levels [52]. High IL-18 levels in the sputum of nonsmoking asthmatics were associated with FEV1 decline [66]. ...
Bronchial asthma (BA) is considered a chronic inflammatory disorder associated with airway hyperresponsiveness (AHR). Increased oxidative stress (OS) is a clinical feature of BA, which promotes the inflammatory responses in bronchial/airway epithelial cells. Smokers and nonsmokers with asthma have been shown to have increases in several OS and inflammatory biomarkers. A few studies suggest a relationship between antioxidant intake from diet/supplements and BA in smoking and nonsmoking asthmatics. Dietary carotenoids and vitamin C (VC) intake might reduce BA risk in smokers and/or non-smokers. Evidence is lacking on the protective role of antioxidant vitamin and/or mineral consumption against BA in smokers and nonsmokers with respect to inflammation and OS biomarkers. Therefore, the aim of this review is to highlight current knowledge regarding the relations between antioxidant intake, BA and its associated biomarkers in smokers and nonsmokers.
... Cigarette smoking is associated with the development of airflow obstruction over time through the narrowing the airways . The mechanism is as follows: cigarette smoking alters the airway , the number of white blood cells responsible to heal injuries and infections (Chalmers et al., 2001;Telenga et al., 2013;Thomson et al., 2004 and can cause airway inflammation (Boulet et al., 2006;Chalmers et al., 2001;Thomson et al., 2004;Wu et al., 2017). Cigarette smoking induces oxidative stress (Takahashi et al., 2018;Thomson et al., 2004) which releases proinflammatory signaling activating white blood cells responsible for combating infections and healing injuries increasing their numbers and inducing tissue damage to the epithelium and other structures of the respiratory system leading to asthma. ...
... Cigarette smoking is associated with the development of airflow obstruction over time through the narrowing the airways . The mechanism is as follows: cigarette smoking alters the airway , the number of white blood cells responsible to heal injuries and infections (Chalmers et al., 2001;Telenga et al., 2013;Thomson et al., 2004 and can cause airway inflammation (Boulet et al., 2006;Chalmers et al., 2001;Thomson et al., 2004;Wu et al., 2017). Cigarette smoking induces oxidative stress (Takahashi et al., 2018;Thomson et al., 2004) which releases proinflammatory signaling activating white blood cells responsible for combating infections and healing injuries increasing their numbers and inducing tissue damage to the epithelium and other structures of the respiratory system leading to asthma. ...
Purpose:
The strength of the association between obesity and mortality rate (MR) varies by body mass index (BMI) and sociodemographic groups. We test the hypothesis that the association between obesity and MR varies, in part, due to the moderating effect of parental BMI and birth weight.
Methods:
Data come from the 1958 National Child Development Study, an ongoing longitudinal dataset initiated in 1958 with baseline measures of birth weight from 18,059 infants born in Great Britain over one week. We tested whether the association between BMI and MR was moderated by parental BMI and birth weight using generalized additive proportional hazards models.
Results:
The association between adult BMI and MR was moderated by birth weight and maternal BMI, such that the association between BMI and MR was weaker among individuals with a higher birth weight (p =.0148) and stronger among individuals born to mothers with a higher BMI (p =.032). At any given level of BMI approximately greater than 25, individuals with low birth weight or born to mothers with a higher BMI, had a higher MR. Paternal BMI did not significantly modify the relationship between BMI and MR (p =.5168).
Conclusion:
Results suggest that the relationship between obesity and MR is modified by birth weight and maternal BMI.
... ıt has been shown that factors other than smoking, such as air pollution, obesity, occupational agents, increasing age, and steroid therapy, predispose to airway neutrophilia in asthma (7)(8)(9). ıt is known that smoking is a factor that increases the number of neutrophils in the sputum (10,11). Active smoking is associated with lower forced expiratory volume in the first second (FeV 1 ) and forced vital capacity (FVC), a higher ratio of neutrophils in induced sputum, and worse asthma control (12,13). ...
... ıt is known that active smokers' sputum contains more neutrophils than non-smokers (10)(11)(12). ın this study, ex-smokers were examined differently, and among asthma patients with ACT> 20 using ıCS/ lABA, 48% were eosinophilic, and 52% were noneosinophilic. ın another study, no change was found in eosinophils after smoking cessation, while neutrophilic inflammation decreased in patients who quit smoking (20). ...
Introduction:
This study aims to investigate the relationship between induced sputum eosinophilia and pulmonary functions in ex-smoker asthma patients controlled with an ICS/LABA therapy.
Materials and methods:
Asthma patients who are known to use ICS/LABA regularly for at least three months, without an attack in the last month, quit smoking (5-20 pack-years) and have asthma under control (ACT> 20), and concurrent with induced sputum cytology who had spirometry and lung volume measurements were included in the study. Cytology results, induced sputum eosinophil and neutrophil counts, FEV1 (L), FEV1 (%), FVC (L), FVC (%), RV (L), RV (%) and RV/TLC (%) values of all patients were recorded. The relationship between sputum neutrophil and eosinophil count and pulmonary function test parameters was evaluated.
Result:
Seventeen (68%) of the patients were female, eight (32%) were male, and the mean age was 49.7 ± 13.6 years. The mean sputum eosinophil percentage was 9.4 ± 16.7, and the neutrophil percentage was 71.4 ± 20.5. A positive correlation was found between induced sputum eosinophil percentage values and FEV1 (L) (r= +0.472; p= 0.01) and FVC (L) (r= +0.502; p= 0.01). No correlation was found between the FEV1/FVC%, FEV1%, FVC%, RV (L), RV%, and RV/TLC% values and the percentage of induced sputum eosinophils (p> 0.05).
Conclusions:
It was observed that controlled asthmatic patients with induced sputum eosinophilia treated with ICS/LABA and who quit smoking had high FVC (L) and FEV1 (L) levels.
... In asthma, 10-30% of individuals smoke cigarettes (14). The reduced effectiveness of CS in patients with asthma who continue to smoke cigarettes is well described (15)(16)(17)(18)(19). In a randomized controlled trial (RCT) of 44 nonsmokers and 39 light smokers with mild asthma, subjects received the ICS beclomethasone BID or oral montelukast QD. ...
... Also, sputum IL-8 was increased in smokers compared with nonsmokers, both in asthmatics and nonasthmatics. Lung function was reported to worsen as IL-8 increased (16). In an RCT of 38 steroid-naïve adult asthmatic patients (21 non-smokers), fluticasone (1000µg once daily) gave a significantly greater increase in mean morning PEF in non-smoking asthmatics compared with smoking asthmatics (19). ...
The use of inhaled corticosteroids (ICS) in combination with inhaled bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is a common practice in primary care settings. However, ICS-containing therapies may be less effective in patients with COPD compared with asthma, and in individuals with COPD who continue to smoke cigarettes. Preclinical studies suggest that inflammation in COPD is very different than in asthma. Glucocorticoid receptor (GR) functioning and other innate anti-inflammatory mechanisms are altered in cells exposed to cigarette smoke. COPD may be relatively insensitive to ICS, especially in individuals who continue to smoke. PICS-containing therapies in patients with asthma who continue to smoke may also be less effective compared with patients who do not smoke. ICS-containing therapies may be inappropriately used in some patients with COPD, and their long-term use is associated with an increased risk for side effects including pneumonia and bone fractures in some patients. Treatment for patients with COPD should be carefully evaluated, and anti-inflammatory/bronchodilatory strategies should be chosen based on individual patient characteristics and recommendations in current guidelines.
... Airway inflammation in asthmatic smokers differs from asthmatic non-smokers with higher total sputum cell counts, predominance of activated macrophages and neutrophils in sputum, airways, and lung parenchyma as in early COPD [119,120]. Previous data showed that smokers with asthma have higher sputum matrix metalloproteinase (MMP)-12 concentrations compared to non-smokers and the levels are inversely associated with lung function and positively related to ...
... Airway inflammation in asthmatic smokers differs from asthmatic non-smokers with higher total sputum cell counts, predominance of activated macrophages and neutrophils in sputum, airways, and lung parenchyma as in early COPD [119,120]. Previous data showed that smokers with asthma have higher sputum matrix metalloproteinase (MMP)-12 concentrations compared to non-smokers and the levels are inversely associated with lung function and positively related to sputum neutrophil counts [121]. This neutral endopeptidase is primarily responsible for the degradation of extracellular matrix components during the remodelling processes essential for normal tissue growth and repair. ...
Asthma is a chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Evidence suggests that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations. The aim of this review is to summarize the current knowledge on the effect of various outdoor and indoor pollutants on asthma outcomes, their burden on its management, as well as to highlight the measures that could result in improved asthma outcomes. Traffic-related air pollution, nitrogen dioxide and second-hand smoking (SHS) exposures represent significant risk factors for asthma development in children. Nevertheless, a causal relation between air pollution and development of adult asthma is not clearly established. Exposure to outdoor pollutants can induce asthma symptoms, exacerbations and decreases in lung function. Active tobacco smoking is associated with poorer asthma control, while exposure to SHS increases the risk of asthma exacerbations, respiratory symptoms and healthcare utilization. Other indoor pollutants such as heating sources and molds can also negatively impact the course of asthma. Global measures, that aim to reduce exposure to air pollutants, are highly needed in order to improve the outcomes and management of adult and pediatric asthma in addition to the existing guidelines.
... A previous study found that non-Th2-related cytokines such as IL-8 were higher in ACOS compared with asthma. 25 Meanwhile, Chalmers et al (2001) found that smoking history in asthmatic patients had a positive correlation with IL-8, and a negative correlation between FEV1 and sputum IL-8 was observed. 26 In our study, we found that the serum concentration of IL-8 was decreased in the ACOS group, and a positive correlation between serum IL-8 and FEV1/FVC was observed. ...
... 25 Meanwhile, Chalmers et al (2001) found that smoking history in asthmatic patients had a positive correlation with IL-8, and a negative correlation between FEV1 and sputum IL-8 was observed. 26 In our study, we found that the serum concentration of IL-8 was decreased in the ACOS group, and a positive correlation between serum IL-8 and FEV1/FVC was observed. A recent study showed that neither IL-8 nor IL-5/IL-8 produced sufficient sensitivity and specificity to accurately identify the various diagnostic categories of asthma, COPD, and ACOS. ...
Background
Asthma-COPD overlap (ACO; previously referred to as asthma-COPD overlap syndrome) is characterized by persistent airflow limitation consistent with COPD, together with several distinguishing features of asthma. Asthma-COPD overlap syndrome is a condition of mixing symptoms of asthma and COPD, because of its complexity, it is difficult to find effective diagnostic markers in clinic.
Purpose
Our aims were to detect the expression of serum cytokines in patients with asthma, explore the diagnostic potential of differential serum cytokines in ACOS.
Patients and Methods
Ninety asthmatic patients were divided into ACOS group and non-ACOS group according to the major and minor criteria of ACOS, 15 kinds of cytokines including IL-3, IL-4, IL-8, IL-9, IL-13, IL-17A, VEGFA, VEGFC, VEGFD, bFGF, Fit-1 PIGF, Tie-2 were detected by MSD, and IL-27 and TGF-beta were determined by ELISA assay.
Results
The serum levels of IL-9, VEGFA and PIGF in patients with ACOS were significantly higher than those in non-ACOS group (P<0.05, respectively), while the level of IL-8 and IL-17A in subjects with ACOS was lower than that in the non-ACOS group (P<0.05, respectively). We analyzed the correlation between several difference factors and FEV1/FVC% in the ACOS group, found VEGFA was negatively correlated with FEV1/FVC%, while IL-8 and IL-17A were positively correlated with FEV1/FVC%. Finally, three correlation factors were analyzed by ROC curve for the occurrence of ACOS.
Conclusion
The results suggested that IL-8 was highly sensitive and VEGFA was highly specificity, both of which could be used as biomarkers for the diagnosis of ACOS.
... However, patients with overlap syndrome have worse lung function, more respiratory symptoms and a (11,12) lower health-related quality of life than either disease alone . Smoking inuences the pattern of inammation and steroid (13,14) responsiveness ...
Background: COPD is one of the major causes of chronic morbidity and mortality worldwide. It is the fourth leading cause of death in the world(1). Chronic airow limitation of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Aim and Objective of the study: To Study the changes of Arterial blood gases in COPD phenotypes. Methods: This Descriptive study was carried out on the patients with chronic obstructive pulmonary disease who were admitted to Victoria hospital, Bangalore from AUGUST 2021 to OCTOBER 2021. Arterial blood gas analysis was used as a diagnostic test in 110 cases of Chronic Obstructive Pulmonary Disease. Interpretation and Conclusion: ABG sampling constitutes a more precise measure of successful gas exchange, oxygenation and happens to be only reliable determination of ventilation success as reected by CO2 content . It also provides valuable information on the acid base balance at a specic point in the course of a patient's illness and plays an important role in the management of Chronic Obstructive Pulmonary Disease. Patients regularly treated in phases of Remission and Exacerbations of COPD the course of illness is slower. Decrease of pH and PaO2 and increase of PaCO2 is statistically signicantly smaller in those received regular treatment in phases of remissions. ABG analysis is indicated in acute exacerbations, during assisted ventilation and to decide prognosis. It should become an integral part of patient management.
... Il paradosso potrebbe essere spiegato dagli effetti benefici a breve termine del fumo. Studi sperimentali su topi in cui l'asma è stata indotta prima dell'esposizione al fumo, hanno chiarito che il fumo di sigaretta esercita effetti antinfiammatori a breve termine sull'infiammazione allergica [128][129][130] . L'azione antinfiammatoria a breve termine potrebbe essere riconducibile ad alcune componenti del fumo di sigaretta, come il monossido di carbonio, l'ossido nitrico e la nicotina 129 . ...
Asthma is a chronic condition affecting millions of adolescents worldwide, posing a substantial burden on their physical and psychosocial well-being. This review examines the multifaceted impact of asthma in this age group, encompassing the challenges faced by adolescents and the implications for their overall quality of life leading to limitations in physical activities and de-creased lung function, affecting lung development and brain activities. These persistent symp-toms may disrupt sleep patterns and result in poor academic performance and educational attainment. Moreover, asthma’s psychosocial burden on adolescents is equally significant. Living with a chronic condition can lead to heightened stress, anxiety, and social isolation, im-pacting self-esteem and overall mental health. Adolescents with asthma may also experience stigmatization or peer exclusion due to their condition, further exacerbating emotional distress. A comprehensive approach to managing the burden of asthma in adolescents is essential. Optimizing treatment plans through personalized care and asthma action plans can improve symptom control and mitigate physical limitations. Furthermore, providing adequate education and support to adolescents and their families promotes adherence to treatment regimens, empowering young individuals to take control of their health. Addressing the psychosocial aspects of the asthma burden necessitates a collabora-tive effort involving healthcare professionals, schools, and support networks. Psychosocial interventions, such as cognitive-behavioural therapy and peer support groups, offer valuable tools to enhance coping strategies and foster resilience in adolescents with asthma-related emotional challenges. In conclusion, the burden of asthma in adolescents encompasses physical and psychosocial dimensions, affecting various aspects of their daily lives. Understanding the multifaceted impact of asthma is crucial in providing comprehensive care and support to adolescents, en-abling them to thrive physically and emotionally despite the challenges posed by this chronic respiratory condition and avoiding a possible risk of COPD in adult life. Healthcare providers and support systems can empower adolescents to lead fulfilling lives and achieve their full potential.
... Higher sputum eosinophils, eosinophilic cationic protein (ECP), neutrophils, and IL-8 levels were observed in asthmatic smokers compared to healthy nonsmokers, which were associated with FEV 1 and neutrophil count. Compared to healthy nonsmokers, nonsmoking asthmatics demonstrated higher sputum ECP and eosinophil levels [51]. Serum periostin has been observed in higher levels in nonsmokers than smokers with asthma [52]. ...
Asthma is considered a chronic inflammatory disorder associated with airway hyperresponsiveness (AHR). Increased oxidative stress (OS) is a clinical feature of asthma, which promotes the inflammatory responses in bronchial/airway epithelial cells. Smokers and nonsmokers with asthma have been shown to have increases in several OS and inflammatory biomarkers. However, studies suggest significant differences in OS and inflammation biomarkers between smokers and nonsmokers. A few studies suggest associations between antioxidant intake from diet/supplements and asthma in patients with different smoking status. Evidence is lacking on the protective role of antioxidant vitamin and/or mineral consumption against asthma by smoking status with respect to inflammation and OS biomarkers. Therefore, the aim of this review is to highlight current knowledge regarding the relations between antioxidant intake, asthma, and its associated biomarkers, according to smoking status. This paper can be used to guide future research directions towards the health consequences of antioxidant intake in smoking and nonsmoking asthmatics.
... Asthmatics who smoke have airway inflammation (neutrophilic airway inflammation) that differs from that of non-smoking asthmatics (eosinophilic airway inflammation) [196], and clinical studies that have examined the effect of CS on airway inflammation have generally excluded smokers to avoid the effect of CS on the studies' outcomes [197]. Therefore, there is a lack of information about the effect of CS on airway inflammation in asthma patients. ...
Asthma is a chronic lung disease characterised by the presence of one or more respiratory symptoms, such as wheezing, chest tightness, breathlessness and coughing, which are attributed to airflow obstruction, airway hyperresponsiveness and airway inflammation. Airway inflammation in asthma is categorised into endotypes—namely Type 2 (T2, eosinophilic and T2-high) asthma, which has a good response to corticosteroid treatment, and non-Type 2 (non-T2, neutrophilic and T2-low) asthma, which has a poor response to corticosteroid treatment. Human airway smooth muscles (HASMCs) are crucial components of the airway structural wall because they display an inflammatory response by secreting cytokines and chemokines in response to inflammatory stimuli. Cigarette smoke (CS) is a known risk factor in developing airway inflammation, which can lead to asthma. Clinical studies have shown that asthmatic smokers tend to have low eosinophil counts and high neutrophil counts and display a poor response to corticosteroid therapy. But whether CS can modulate T2 and non-T2 inflammatory responses and induce corticosteroid insensitivity in vitro is largely unknown. It has been suggested that various mechanisms such as oxidative stress and cyclooxygenase-2 (COX-2) induction may play a key role in mediating the CS effect. However, the mechanisms underlying the proinflammatory effect of CS in asthma remain to be explored. We hypothesised that CS extract (CSE) may inhibit the production of T2 inflammatory cytokines (Th2 cytokines and eosinophil chemokines) and induce non-T2 inflammatory cytokines (IL-6, IL-8, and VEGF) in HASMCs via oxidative stress and COX-2 induction, thereby contributing to the development of corticosteroid-insensitive non-T2 endotype in asthma smokers.
... The notion that the adverse consequences of smoking in asthma may be due to altered immune responses in the airway was initially advanced by studies showing that cigarette smoke causes critical changes in the macrophages and neutrophils of asthma patients 30 . In particular, cigarette smoke was found to induce alveolar macrophages and neutrophils to produce proinflammatory cytokines, reactive oxygen species, matrix metalloproteinases, and various chemokines 31 . ...
Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1β, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma. Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
... Program cluster analysis the cluster with the highest percentage of sputum neutrophils (Cluster 5) also had the most severe airflow limitation, the most frequent emergency department visits, hospitalisations, ICU admissions and maintenance treatment with oral corticosteroids(106). Significantly, this cluster analysis was composed entirely of non-smokers, as smoking is associated with increased sputum neutrophil percentage(107). Unsupervised hierarchical clustering of gene expression profiles in asthma identified a transcriptional phenotype with low FEV 1 % predicted and higher sputum neutrophils, with which overexpression of genes in the IL-1 and TNF-α/NF-κB pathway were correlated. ...
Introduction:
Molecular antibodies (mAb) targeting inflammatory mediators are effective in T2-high asthma. The recent approval of Tezepelumab presents a novel mAb therapeutic option to those with T2-low asthma.
Areas covered:
We discuss a number of clinical problems pertinent to severe asthma which are less responsive to current therapies, such as persistent airflow obstruction and airway hyperresponsiveness. We discuss selected investigational approaches, including a number of candidate therapies under investigation in two adaptive platform trials currently in progress, with particular reference to this unmet need, as well as their potential in phenotypes such as neutrophilic asthma and obese asthma, which may or may not overlap with a T2-high phenotype.
Expert opinion:
The application of discrete targeting approaches to T2-low molecular phenotypes, including those phenotypes in which inflammation may not arise within the airway, has yielded variable results to date. Endotypes associated with T2-low asthma are likely to be diverse but await validation. Investigational therapeutic approaches must, likewise, be diverse if the goal of remission is to become attainable for all those living with asthma.
... [71][72][73][74][75] A recent study of predominately former smokers with severe asthma found that a !10-pack-year history was associated with higher proportion of patients with eosinophilic airway inflammation, autoimmunity toward eosinophils, and reduced sputum eosinophil sensitivity to systemic corticosteroids, suggesting a phenotype of severe refractory eosinophilic asthma among former smokers with a history of a higher cumulative exposure to cigarette smoke. 76 Many studies have shown that current smoking was associated with neutrophilic airway inflammation, 68,71,74 whereas other data have shown that neutrophil numbers did not differ from never smokers. 21,69,70,77 A cross-sectional study of over 800 adults with mild-to-severe asthma found similar proportions with eosinophilic, neutrophilic, and paucigranulocytic inflammation among current smokers (37%, 15%, and 45%, respectively) compared with never smokers (43%, 16%, and 37%, respectively). ...
Globally, around half the adult asthma population are current or former cigarette smokers. Cigarette smoking and asthma interact to induce an ‘asthma-smoking phenotype(s)’, which has important implications for diagnosis, pathogenic mechanisms, and management. The lack of progress in understanding the effects of smoking on adults with asthma is due in part to their exclusion from most investigative studies and large clinical trials. In this review, we summarize the adverse clinical outcomes associated with cigarette smoking in asthma, highlight challenges in diagnosing asthma among cigarette smokers with chronic respiratory symptoms, particularly in older individuals with a long-standing smoking history, and review pathogenic mechanisms involving smoking and asthma-related airway inflammation, tissue remodeling, corticosteroid insensitivity, and low-grade systemic inflammation. We discuss key components of management including the importance of smoking cessation strategies, evidence for the effectiveness of the Global Initiative for Asthma recommendations on treatment in cigarette smokers, and the role of treatable traits such as type 2 eosinophilic airway inflammation. Lastly, we provide an algorithm to aid clinicians to manage current and former smokers with asthma. In the future, controlled and pragmatic trials in real-world populations should include cigarette smokers with asthma to provide an evidence base for treatment recommendations.
... Neutrophilia is present in 20-30% of the asthmatic population, although the prevalence varies across regions [96]. This phenotype is more often associated with smoking [97], obesity [98], and various forms of pollution, air pollution, ozone, and other pollutants [99,100]. Neutrophilic inflammation may also be caused by acute airway infections [101], particularly in children [102]. ...
Chronic obstructive pulmonary disease (COPD) and asthma are two of the most common chronic diseases worldwide. Both diseases are heterogenous and complex, and despite their similarities, they differ in terms of pathophysiological and immunological mechanisms. Mounting evidence supports the presence of several phenotypes with various responses to treatment. A systematic and thorough assessment concerning the diagnosis of both asthma and COPD is crucial to the clinical management of the disease. The identification of different biomarkers can facilitate targeted treatment and monitoring. Thanks to the presence of numerous immunological studies, our understanding of asthma phenotypes and mechanisms of disease has increased markedly in the last decade, and several treatments with monoclonal antibodies are available. There are compelling data that link eosinophilia with an increased risk of COPD exacerbations but a greater treatment response and lower all-cause mortality. Eosinophilia can be considered as a treatable trait, and the initiation of inhaled corticosteroid in COPD patients with eosinophilia is supported in many studies. In spite of advances in our understanding of both asthma and COPD in terms pathophysiology, disease mechanisms, biomarkers, and response to treatment, many uncertainties in the management of obstructive airways exist.
... These prior studies revealed that age was significantly associated with sputum neutrophilia in adults, and that older patients more frequently exhibited NA [25,26]. Furthermore, smoking has been shown to increase neutrophilic inflammation in sputum [27]. Our study showed that the proportion of patients who smoked was highest among patients with NA. ...
Abstract Background There is a need to identify the asthma inflammatory phenotypes of patients to facilitate personalized asthma treatment. Sputum induction is time-consuming and requires expert clinical technique. This study aimed to assess the distribution and characteristics of asthma inflammatory phenotypes in Jilin Province, China; it also aimed to identify an easier method for characterization of an asthma phenotype, rather than sputum cellular analysis. Methods In this study, 232 asthma patients underwent sputum induction following clinical assessment and blood collection. Inflammatory cell counts in sputum were used to classify asthma inflammatory phenotypes. Receiver operating characteristic curve and Spearman correlation coefficient analyses were used to identify correlations between clinical parameters. Results Among the included patients, there had 52.1% paucigranulocytic, 38.4% eosinophilic, 4.3% neutrophilic, and 5.2% mixed granulocytic asthma phenotypes, respectively. In total, 129 (55.6%) patients had asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO); these patients had higher proportion of smokers, higher sputum neutrophil count, worse lung function, and worse asthma control, compared with patients who had asthma alone (p
... Cigarette smoking is closely related to respiratory diseases, although the mechanism of how smoking influences nasal mucosa is not yet clear. Based on previous studies, cigarette smoke might induce the sputum neutrophils in asthma patients 37 and also cause an accumulation of neutrophils in human lung tissue. 38 However, recent studies also found that the expression of IL-17A was increased in the nasal tissue of smokers with asthma and CRS. ...
Background
Nowadays, the heterogeneity of chronic rhinosinusitis (CRS) has attracted extensive attention. The histological patterns and clinical characteristics may vary greatly in different areas and among different groups of people. Prior studies found a shift from the neutrophilic inflammatory pattern to the eosinophilic inflammatory pattern in Asian cities. This study set out with the aim of investigating the changes that have occurred in the past 18 years of southern China and exploring the causes.
Methods
Tissues, clinical, and demographic characteristics were obtained from 473 patients (91 in 2000–2001, 170 in 2010–2011, 212 in 2017–2018) who satisfied the criteria of diffuse (bilateral) chronic rhinosinusitis. The clinical characteristics, including the previous history of allergic rhinitis and asthma, and the major symptoms of rhinosinusitis, were collected. Formalin-fixed nasal tissue was obtained from each patient for calculating inflammatory cells. We also performed immunohistochemistry to evaluate the expression levels of eosinophilic cationic protein (ECP), IgE, myeloperoxidase (MPO), and other Type 1, Type 2, and Type 3 related inflammatory cytokines.
Results
The comorbidity of asthma and atopic disease was higher in 2017–2018 compared to 2000–2001. The histological characteristics revealed a significant increase in tissue eosinophils and decrease in neutrophils in 2017–2018 as compared with 2000–2001. Meanwhile, the proportion of eosinophilic CRS (eCRS) increased significantly from 2000 to 2001 to 2017–2018 (P = 0.03). The tissue eosinophil increase was higher in overweight patients (Body Mass Index, BMI≥24) as compared with non-overweight. There was an increasing trend of ECP, IL-13 and IL-17. Besides, IFN-γ and TNF-α decreased.
Conclusions
There was an eosinophilic shift of diffuse rhinosinusitis inflammatory pattern in southern China over the last 18 years. The proportion of eCRS and difficult-to-treat rhinosinusitis has steadily increased, which is associated with the increase of Type 2, Type 3 cytokines and the decrease of Type 1 cytokines. This study also provided firstly evidence of a strong relationship between overweight and eosinophil shift in the southern Chinese population.
... Acute exposures to allergens and CS promoted increased levels of type-2 cytokines and inflammatory cells in BALF, with the exception of one study where addition of CS exposure for the last 2 weeks of a 5 week HDM model attenuated lung eosinophil levels [168]. Chronic CS exposure (10 weeks) robustly increased neutrophil numbers in the airways [172] and reproduced the pathology of neutrophilic airway inflammation in asthmatic smokers [173]. In addition, histone deacetylase 2 (HDAC2), which is required to mediate the anti-inflammatory effects of glucocorticoids, was found in one model to be reduced by CS exposure and partially restored (to levels of asthma alone) following treatment with the macrolide roxithromycin [172]. ...
Pathological features of both asthma and COPD coexist in some patients and this is termed asthma-COPD overlap (ACO). ACO is heterogeneous and patients exhibit various combinations of asthma and COPD features, making it difficult to characterise the underlying pathogenic mechanisms. There are no controlled studies that define effective therapies for ACO, which arises from the lack of international consensus on the definition and diagnostic criteria for ACO, as well as scant in vitro and in vivo data. There remain unmet needs for experimental models of ACO that accurately recapitulate the hallmark features of ACO in patients. The development and interrogation of such models will identify underlying disease-causing mechanisms, as well as enabling the identification of novel therapeutic targets and providing a platform for assessing new ACO therapies. Here, we review the current understanding of the clinical features of ACO and highlight the approaches that are best suited for developing representative experimental models of ACO.
... Increased eosinophils in both blood (B-Eos) and sputum has been associated with FAO or lower lung function in both asthmatics and non-asthmatics [4][5][6][7][8], though results have been contradictory [9][10][11]. Cigarette smoking has been reported to be related to an increase of leucocytes in blood and sputum in both asthmatics and non-asthmatics [12,13]. Elevated blood neutrophil (B-Neu) count has also been associated with lower lung function both among asthmatics [14] and in the general population [15]. ...
Rationale
Fixed airflow obstruction (FAO) can complicate asthma. Inflammation is a proposed underlying mechanism.
Objective
Our aim in this cross-sectional investigation was to evaluate the blood leucocyte pattern and level of exhaled nitric oxide in asthmatics and non-asthmatics with or without FAO.
Methods
A total of 11,579 individuals aged ≥20 years from the US National Health and Nutrition Examination Survey were included. They were grouped as: controls without asthma and FAO (n = 9,935), asthmatics without FAO (n = 674), asthmatics with FAO (n = 180) and non-asthmatics with FAO (n = 790). FAO was defined as post-bronchodilator FEV1/FVC < lower limit of normal. Exhaled nitric oxide ≥ 25ppb, blood eosinophil levels ≥300 cells/μL, and blood neutrophil levels ≥5100 cells/μL were defined as elevated. Stratified analyses for smoking and smoking history were performed.
Results
Elevated blood eosinophil levels were more common in all groups compared to the controls, with the highest prevalence in the group with asthma and fixed airflow obstruction (p<0.01). In a multiple logistic regression model adjusted for potential confounders including smoking, the asthma groups had significantly higher odds ratios for elevated B-Eos levels compared to the control group (odds ratio 1.4, (confidence interval: 1.1–1.7) for the asthma group without fixed airflow obstruction and 2.5 (1.4–4.2) for the asthma group with fixed airflow obstruction). The group with fixed airflow obstruction without asthma had higher odds ratio for elevated blood neutrophil levels compared to the controls: 1.4 (1.1–1.8). Smoking and a history of smoking were associated to elevated B-Neu levels.
Conclusion
Fixed airflow obstruction in asthma was associated with elevated blood eosinophil levels, whereas fixed airflow obstruction without asthma was associated with elevated blood neutrophil levels.
... 40 Cigarette smoke in asthmatic individuals also increased their sputum interleukin-8 levels in parallel to increased neutrophil percentages. 41 In our study calprotectin levels correlated with smoke amount and blood neutrophil percentage in patients with asthma, suggesting that smoking increases neutrophil proportion in blood leading to calprotectin secretion. Further studies are needed to provide a more specific approach in patients with asthma with neutrophilic airway inflammation and to help in modulating the use of available conventional therapies. ...
Background:
Calprotectin is the major cytosolic protein in neutrophil granulocytes. Although asthma is known to cause eosinophilic inflammation, some patients with asthma have non-eosinophilic inflammation, which is characterized by local neutrophilic inflammation. The aim of this study was to assess calprotectin expression levels in a mouse model of asthma, and to observe the relationship of serum calprotectin level and clinical variables in patients with asthma.
Methods:
Mice were sensitized and challenged with 10 μg and 20 μg of Aspergillus fumigatus, respectively; mice treated with saline were used as a control. The levels of calprotectin were determined using enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemical analysis. The serum levels of calprotectin were also assessed in patients with asthma. The relationship between calprotectin and clinicopathological characteristics was determined.
Results:
Calprotectin, S100A8, and S100A9 expression was elevated in the mouse lungs, calprotectin levels were higher in the serum of patients with asthma (n = 33) compared with those of healthy individuals (n = 28). Calprotectin levels correlated with forced expiratory volume in one second/forced vital capacity (r = -0.215, P = 0.043), smoke amount (r = 0.413, P = 0.017), body mass index (r = -0.445, P = 0.000), and blood neutrophil percentage (r = 0.300, P = 0.004) in patients with asthma.
Conclusion:
Our data suggest that calprotectin could potentially be used as a biomarker for asthma.
... Yet, allergic smokers had reduced eosinophils, implying a moderating effect of smoking on late allergic reactions. Chalmers et al. (2001) have also found reduced eosinophils in asthmatic smokers when compared to nonsmoking asthmatic patients. Our findings may also explain the variability in patients' responses to intranasal steroids, which are considered firstline treatment for chronic rhinitis. ...
... Epidemiological studies have shown that both active smoking and passive smoking exposure (also referred to as environmental tobacco smoke) can be related to the onset and development of respiratory diseases and symptoms (1)(2)(3)(4)(5), with some evidence indicating that the association between cigarette smoking and asthma may be biologically plausible (5,6). For example, cigarette smoking can pose a greater threat to asthmatic smokers than nonsmokers through accelerating decline in lung function, elevating induced sputum neutrophil counts, and impairing the effects of corticosteroids (5,7). Passive smoking exposure is also adversely related to a variety of respiratory outcomes, including the frequent respiratory symptoms, lower respiratory infections, and lung cancer (8,9), especially among susceptible populations such as women (1) and children (10). ...
Background:
The sustained high prevalence of smoking in China has contributed substantially to the burden of chronic diseases, including respiratory diseases. This study compared the prevalence of smoking and respiratory diseases in Chinese adults between two time periods spanning over 25 years.
Methods:
Cross-sectional surveys were performed in four Chinese cities of Chongqing, Lanzhou, Wuhan, and Guangzhou in 1993-1996 (Period 1) and in 2017-2018 (Period 2). Participants completed questionnaires asking smoking status, the presence of asthma and chronic bronchitis, education attainment and household characteristics. Logistic regression models were used to estimate the odds ratios of disease prevalence with regard to active smoking status for men and passive smoking status for women.
Results:
Prevalence of asthma, prevalence of chronic bronchitis, and smoking rate, all decreased from Period 1 to Period 2. We observed strong evidence that active smoking increased prevalence for both asthma and chronic bronchitis in men during Period 1, with spatial heterogeneity and modifying effect by college-level education. Home exposure to passive smoking was associated with increased odds of having chronic bronchitis among female participants in Chongqing during Period 2, although the association was not statistically significant.
Conclusions:
The prevalence for asthma and chronic bronchitis were lower in 2017-2018 compared to 25 years ago in the same four Chinese cities. Decreased smoking rate may have contribution to the improvement of these respiratory diseases. Male smokers, especially those without college-level education, showed higher prevalence of chronic bronchitis compared to nonsmokers during Period 1.
... According to Chalmers and his coworkers (Chalmers et al., 2001) asthmatic smokers have an increased number of cells in the bronchoalveolar lavage, in which neutrophils are more prevalent, in contrast to non-smoking asthmatics; while the number of eosinophils has a decrease in percentage among asthmatic smokers compared to asthmatic non-smokers. The guidelines for treatment of bronchial asthma recommend the inhaled steroids as the most effective anti-inflammatory treatment of asthma (National Heart, Lung and Blood Institute and world Health Organization. ...
The exposure to tobacco smoke could cause bronchoconstriction and acute asthma attack. Smoking asthmatics have an insufficient therapeutic response to the standard therapy and unsatisfactory improvement of the respiratory function. In a randomized parallel study, a therapeutic response to inhaled fluticasone propionate in a dose of 250 µg twice per day was determined in 38 asthmatics with mild asthma, smokers and nonsmokers. Short-acting ß2 agonist (salbutamol) in a dosage of 0.1 mg/per inhaled dose was used as a rescue medication when needed. In patients, asthma was detected with a positive metacholine test and/or positive bronchodilatator response of > 12% with ≥ 200 ml increase of FEV1. They were randomized in two groups according to sex, age and starting values of FEV1. Before and after 6 weeks of treatment with fluticasone propionate of the previously corticosteroid-naive patients, lung function test (spirometry) was performed. A statistically significant effect (p<0.05) was achieved during the fluticasone propionate therapy in a group of non-smoking asthmatic patients. The same effect was not seen in the group of smoking asthmatics. Although the percentage of elevated FEV1 values was small, it was satisfactory because of the starting FEV1 values in patients with mild asthma. More studies are needed in asthmatics determining the asthma symptom score, the number of night awakenings due to asthma, the asthma exacerbations and the frequency of rescue therapy usage which will define the altered therapeutic response to inhaled corticosteroids in smoking asthmatics.
... Yet, allergic smokers had reduced eosinophils, implying a moderating effect of smoking on late allergic reactions. Chalmers et al. (2001) have also found reduced eosinophils in asthmatic smokers when compared to nonsmoking asthmatic patients. Our findings may also explain the variability in patients' responses to intranasal steroids, which are considered firstline treatment for chronic rhinitis. ...
Background: Allergies and smoking are common reasons for nasal mucosa inflammations, which in turn, cause nasal obstructions. Nevertheless, the impact of coexisting allergies and smoking on nasal mucosa inflammation has not been studied.
Objectives: To study the impact of smoking with relation to allergies on nasal mucosa histology and to characterize an immunologic profile using immunohistochemical (IHC) staining.
Methods: A cross-sectional study. Nasal biopsies of inferior turbinates from smokers with different allergic statuses were compared. Demographics, comorbidities, histologic, and immunohistochemical (IHC) staining of CD3, CD68, CD 20, and CD138 receptors were compared and analyzed.
Results: A total of 53 patients were included, of which 20 (37.7%) were smokers, and 20 (37.7%) had allergic backgrounds. Smokers, both allergic and non-allergic, demonstrated reduced edema compared to the control group (p Value = 0.034) and significantly lower eosinophil density in the stroma compared to the allergic nonsmokers’ group (p Value = 0.04). Smokers had a significant negative correlation between the number of cigarettes per day and the expression of CD20 in the stroma (−0.452, p Value = 0.045) and the epithelium (−0.432, p Value = 0.057) in IHC staining. Allergic smokers had a negative correlation (−0.705, p Value = 0.023) between the number of cigarettes per day and the CD68 marked cell expression in the epithelium.
Conclusion: The coexistence of an allergic background and smoking alters known immunologic responses within the nasal mucosa. Smoking may have an immunosuppressive role in the nasal mucosa in both innate and humoral immune systems.
... It would be also interesting to know when the participants of both groups smoked their last CC, which may affect baseline and postexposure variables. 15 To summarize, exposure to nicotine e-cigarette in patients with asthma seems to induce acute bronchoconstriction, small airways dysfunction and aggravation of airway inflammation. Despite CC having much higher lung toxicity than e-cigarette, 4 rising use of e-cigarette in patients with asthma is concerning. ...
See related article See related article
Introduction:
Blood eosinophil count has been shown markedly variable across different populations. However, its distribution in Chinese general population remains unclear. We aimed to investigate blood eosinophil count and its determinants in a Chinese general population.
Methods:
In this population-based study, general citizens of Sichuan province in China were extracted from the China Pulmonary Health study. Data on demographics, personal and family history, living condition, lifestyle, spirometry, and complete blood count test were obtained and analyzed. A stepwise multivariate binary logistic regression analysis was performed to identify determinants of high blood eosinophils (>75th percentile).
Results:
A total of 3,310 participants were included, with a mean age (standard deviation) of 47.0 (15.6) years. In total population, the median blood eosinophil count was 110.0 (interquartile range [IQR]: 67.2-192.9) cells/μL, lower than that in smokers (133.4 cells/μL, IQR: 79.3-228.4) and patients with asthma (140.7 cells/μL, IQR: 79.6-218.2) or post-bronchodilator airflow limitation (141.5 cells/μL, IQR: 82.6-230.1), with a right-skewed distribution. Multivariate analyses revealed that oldness (aged ≥60 years) (odds ratio [OR]: 1.66, 95% confidence interval [CI]: 1.11-2.48), smoking ≥20 pack-years (OR: 1.90, 95% CI: 1.20-3.00), raising a dog/cat (OR: 1.72, 95% CI: 1.17-2.52), and occupational exposure to dust, allergen, and harmful gas (OR: 1.58, 95% CI: 1.15-2.15) were significantly associated with high blood eosinophils.
Conclusion:
This study identifies a median blood eosinophil count of 110.0 cells/μL and determinants of high blood eosinophils in a Chinese general population, including oldness (aged ≥60 years), smoking ≥20 pack-years, raising a dog/cat, and occupational exposure to dust, allergen, and harmful gas.
Background The relationship between airway inflammation in chronic obstructive pulmonary disease (COPD) and clinical characteristics remains unclear. This study aimed to investigate the airway inflammatory phenotypes in COPD and their association with clinical characteristics.
Methods 895 patients with COPD were recruited from Guangdong Province, China in this study. Each patient underwent questionnaire interviews, spirometry testing, CT scans and induced sputum examination. Classification of airway inflammation phenotypes was based on sputum inflammatory cell counts. Covariance analysis was applied to assess associations with airway inflammation phenotypes.
Results In this study, we found that neutrophilic phenotype (NP, 58.0%) was the most common airway inflammation phenotype in patients with COPD, followed by mixed granulocytic phenotype (MGP, 32.6%), eosinophilic phenotype (EP, 5.4%) and paucigranulocytic phenotype (PP, 4.0%). Compared with NP patients, those with MGP exhibited more frequent chronic respiratory symptoms, and a higher proportion of individuals classified under Global Initiative for Chronic Obstructive Lung Disease stages 3 and 4. After adjusting for confounding factors, MGP patients had lower lung function, and more severe emphysema and air trapping. On the contrary, patients with PP had the best pulmonary function and less emphysema and air trapping.
Conclusions NP was the most common airway inflammation phenotype in patients with COPD. Patients with MGP had more respiratory symptoms, greater loss of lung function, and more severe emphysema and gas trapping compared with those with NP. Meanwhile, PP may be a phenotype of mild damage to lung structure in patients with COPD.
This study determined the extent of the therapeutic communication skills of the medical and surgical nurses of the Philippine Public Hospital. This study employed a descriptive and focused research design. It utilized survey and observation methods. The researcher used a researcher-made questionnaire to describe the respondent’s profile and the extent of therapeutic communications skills, frequency counts, means, weighted means, and the rank was used. It reveals that the nurses are competent in therapeutic communication skills at the hospital regarding the Acting-Response Technique and Active Listening Response technique. It revealed that age, gender, ethnic group, the native language spoken, religion, and educational attainment were not significantly correlated to the acting response and acting listening-response techniques regarding the stand, open, lean forward, eye contact, and relax. However, the civil status of the nurse was significantly correlated to acting-response and listening techniques such as opening, paraphrasing, and reflecting. Based on this study’s significant findings, the following recommendations are drawn: Nurses should take graduate studies that will give them in-depth knowledge and practical skills in their field. They need to improve their therapeutic communication skills, develop and maintain a healing relationship in which their patient will experience security, and be optimistic that positive change is possible. Moreover, nurses should always possess a good and caring attitude toward their patients. It must be based on mutual agreement between nurses and patients as to what constitutes nurse caring behaviors. Likewise, to further enhance the therapeutic communication skills of nurses, a monthly orientation program and conducting a series of seminars must be done. Furthermore, the educational institutions offering the nursing course should emphasize their curriculum to improve the therapeutic communication skills of a student nurse.
Background
Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds.
Methods
A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150–299, ≥300 cells/μL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma.
Results
Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/μL in COPD and ≥300 cells/μL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns.
Conclusions
We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.
Asthma occurrence is often associated with cigarette smoking. Surprisingly, active smokers are excluded from most clinical studies. Prevalence of asthma associated with smoking appears to be similar to asthma in the general population. However, in active smokers, asthma tends to be more difficult to manage and more severe. Several studies have demonstrated a poor response to inhaled corticosteroids (ICS) and an accelerated decline of lung function. Smoking decreases exhaled NO rate and down-regulates ICS receptors, which is associated with increased oxidative stress. Data on biologic therapies are scarce. Finally, nicotine dependence seems higher in asthmatic patients and smoking cessation is thus more difficult.
BACKGROUND: Conflicting results have been found among studies assessing the effect of smoking on airway inflammation among asthmatic subjects.
OBJECTIVE: We sought to compare the inflammatory and clinical characteristics of active smokers and nonsmokers with uncontrolled moderate-to-severe asthma.
Methods: We conducted a cross-sectional study comparing active-smoker and nonsmoker subjects with uncontrolled moderate-to-severe asthma. Sociodemographic and clinical data were collected. FeNO levels and spirometry were measured. We obtained sputum and blood cell counts and measured the cotinine level. The clinical data were linked to 3 Québec administrative databases.
RESULTS: A total of 40 active smokers and 39 nonsmokers were included. Uncontrolled asthmatic smokers and nonsmokers had the same clinical characteristics. Although, blood eosinophil counts were similar between groups, the number of subjects with a high sputum eosinophil count (> 10%) was higher in nonsmokers. Asthmatic smokers had lower levels of FeNO than nonsmoker asthmatics.
The nonsmoker group showed a higher number of total asthma exacerbations (1.9 ± 0.7) than the smoker group (1.0 ± 1.2) (p < 0.01) in the year preceding their assessment. The annual costs related to asthma care tended to be higher in uncontrolled asthmatic nonsmokers (352.05 ± 813.45CAD) than in smokers (263.38 ± 684.00CAD), whereas the annual cost for health care of all causes tended to be lower in nonsmokers (1617.57 ± 1736.53 CAD) than in smokers (2575.07 ± 3453.30 CAD).
INTERPRETATION: The clinical characteristics of uncontrolled moderate-to-severe active asthmatic smokers and nonsmokers were similar. Although the FeNO levels were profoundly affected by smoking, the impact of smoking on airway eosinophilic inflammation appeared marginal.
CLINICAL TRIAL REGISTRATION: NCT02833727
Changes in microRNA (miRNA) expression can contribute to the pathogenesis of many diseases, including asthma. We aimed to identify miRNAs that are differentially expressed between asthma patients and healthy controls and explored their association with clinical and inflammatory parameters of asthma.
Differentially expressed miRNAs were determined by small RNA sequencing on bronchial biopsies of 79 asthma patients and 82 healthy controls using linear regression models. Differentially expressed miRNAs were associated with clinical and inflammatory asthma features. Potential miRNA-mRNA interactions were analysed using mRNA data available from the same bronchial biopsies and enrichment of pathways was identified with Enrichr and g:Profiler.
In total 78 differentially expressed miRNAs were identified in bronchial biopsies of asthma patients compared to controls, of which 60 remained differentially expressed after controlling for smoke and inhaled corticosteroid treatment. We identified several asthma associated miRNAs, including miR-125b-5p and miR-223-3p, based on a significant association with multiple clinical and inflammatory asthma features and their negative correlation with genes associated with the presence of asthma. The most enriched biological pathway(s) affected by miR-125b-5p and miR-223-3p were inflammatory response and cilium assembly and organisation. Of interest, we identified that lower expression of miR-26a-5p was linked to more severe eosinophilic inflammation as measured in blood, sputum as well as bronchial biopsies. Collectively, we identified miR-125b-5p, miR-223-3p and miR-26a-5p, as potential regulators that could contribute to the pathogenesis of asthma.
This article describes the features of asthma phenotypes such as asthma in smokers and asthma and obesity. The role of cysteinyl leukotrienes is discussed in the formation of inflammation in these phenotypes of asthma. The leukotriene receptor antagonists, including montelukast are effective in therapy of this category of patients.
There have been considerable advances in our understanding of asthmatic airway inflammation, resulting in a paradigm shift of classifying individuals on the basis of either the presence or the absence of type 2 (T2) inflammatory markers. Several novel monoclonal antibody therapies targeting T2 cytokines have demonstrated significant clinical effects including reductions in acute exacerbations and improvements in asthma-related quality of life and lung function for individuals with T2-high asthma. However, there have been fewer advancements in developing therapies for those without evidence of T2 airway inflammation (so-called non-T2 asthma). Here, we review the heterogeneity of molecular mechanisms responsible for initiation and regulation of non-T2 inflammation and discuss both current and potential future therapeutic options for individuals with non-T2 asthma.
Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent diseases that may overlap (ACO) in some patients generating a heterogeneous condition with features of both diseases. Despite there is no clear definition of ACO and subsequently, prevalence among the studies is highly variable, it is commonly agreed that inhaled corticosteroids are useful treatment for these patients. After clustering patients according to their clinical and inflammatory characteristics, a practical, easy-to-apply clinical algorithm is proposed to identify it, moving toward better identification and personalized therapy.
This systematic review and meta-analysis assess the change in inflammation biomarkers level among chronic psychoactive substance users. To meet the required inclusion criteria, all studies had to describe human participants with an age ≥18y., experiencing chronic psychostimulant (nicotine, amphetamine, cocaine), sedative (benzodiazepine, opioids) and/or cannabinoid use. The comparison group was defined as healthy participants. Studies where included if they reported at least one of the pro/inflammatory biomarkers. Study bias was examined by Funnel plots and heterogeneity by computing the I2 statistics. Only 21 eligible studies were selected based on 26216 study participants. A small and significant effect size of 0.18 mg/L (95% CI:0.10-0.27) was detected in favour of chronic smokers (z = 4.33;P < 0.0001). There was evidence of publication bias for studies measuring IL-6 and IL-10 association with cocaine and IL-6 in association with cannabis. In summary, except for chronic tobacco users, there was no evidence of association between other chronic substances abuse and inflammatory levels. More studies are needed to inform policy and decision makers about the utility of anti-inflammatory based targeted intervention programmes.
Résumé
Introduction
La prévalence du tabagisme chez les patients asthmatiques est identique ou plus élevée qu’en population générale.
Objectifs
Cette revue systématique étudie les conséquences du tabagisme sur l’asthme, les stratégies de sevrage tabagique (ST) chez l’asthmatique et les conséquences du ST sur l’asthme.
Résultats
Le tabagisme actif ou passif peut favoriser le développement de l’asthme et a des nombreux effets délétères sur l’asthme. Les rares études sur le ST chez les fumeurs asthmatiques montrent l’efficacité des stratégies classiques du ST chez ces patients (substituts nicotiniques, varénicline, bupropion, thérapies cognitives et comportementales). L’arrêt du tabagisme des parents ayant des enfants asthmatiques est essentiel et repose sur les mêmes stratégies. La cigarette électronique peut être une aide utile à l’arrêt du tabac chez certains patients. L’arrêt du tabagisme est bénéfique chez les fumeurs asthmatiques : réduction des symptômes, des exacerbations aiguës, de l’hyperréactivité bronchique et de l’inflammation bronchique ; diminution du recours aux médicaments d’urgence et des doses de corticostéroïdes inhalés ; amélioration du contrôle de l’asthme, de la qualité de vie et de la fonction respiratoire.
Conclusion
Chez les patients asthmatiques, il est essentiel d’évaluer le statut tabagique et les professionnels de santé doivent les aider à arrêter de fumer.
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) defines a subgroup of patients with asthma who have persistent airflow obstruction or patients with COPD who may exhibit variable airflow limitation and/or evidence of type 2 inflammation. Additional investigations are needed to determine whether ACO represents a distinct disorder with unique underlying pathophysiology, whether ACO patients should be managed differently from those with asthma or COPD, and whether the diagnosis affects long-term outcomes. This article presents the data about the clinical features of ACO, the current information regarding the underlying pathophysiology of the syndrome, and current understanding of therapeutic options.
Background
Asthmatic smokers have reduced quality of life and need frequent specialist visits/hospitalization. Smoking habit represents for asthmatics a higher risk for comorbidities and lung function impairment. The impact of cigarette smoking on asthmatics should be addressed to evaluate the related risk factors.
Methods
This real-life observational study evaluated demographic, clinical/functional, and biological parameters of 521 asthmatic patients stratified as never (0 PY), light (1–10 PY), and heavy smokers (>10PY).
Results
The heavy smokers with asthma were more frequently older, male, overweight, and non-allergic than other asthmatics. Although similar ICS dose and severity among groups, heavy smokers had more significant airflow limitation (FEV1/FVC = 0.65 ± 0.10, p < 0.01; FEV1%pred = 79.20 ± 21.20, p < 0.01), air trapping (RV %pred. = 135.6 ± 44.8, p < 0.05; RV/TLC = 0.48 ± 0.12, p < 0.05), and fixed airflow obstruction (post-bronchodilation FEV1/FVC = 0.66 ± 0.10; p = 0.01) than never and light smokers with asthma. Heavy smokers also demonstrated reduced blood eosinophils (p < 0.05) and FeNO (p < 0.01), increased frequency of type-2 low inflammation and LABA/LAMA use but had less frequently persistent rhinitis and chronic rhinosinusitis with nasal polyposis. Heavy smokers showed higher prevalence of paraseptal/bullous emphysema and arterial hypertension. Considering the risk analysis, heavy smokers showed less chance to have allergy (OR = 0.5), persistent rhinitis (OR = 0.6), chronic rhinosinusitis with nasal polyposis (OR = 0.3), or high FeNO (OR = 0.4), but they were prone to develop fixed airflow obstruction (post-bronchodilation FEV1%pred<80%, OR = 2.0, and post-bronchodilation FEV1/FVC≤0.70, OR = 2.0).
Conclusions
Heavy smokers had more severe obstructive impairments than light and never smokers with similar ICS dose, showing a steroid insensitivity, but displayed less allergy with low FeNO and blood eosinophil count, thus being a definite phenotype.
Résumé
Introduction
L’asthme et le tabagisme sont deux problèmes majeurs de santé dans le monde. Le patient asthmatique fumeur présente un phénotype bien distinct au niveau du mécanisme, des symptômes et également de l’évolution.
But
Étudier l’effet du tabagisme sur la présentation clinique, la fonction respiratoire, le contrôle et l’évolution de l’asthme allergique.
Méthodes
Étude rétrospective portant sur 1500 patients asthmatiques allergiques suivis à l’hôpital universitaire Fattouma Bourguiba de Monastir (Tunisie) entre 1997 et 2016. Nous avons comparé deux groupes : groupe 1 (G1 : asthmatiques fumeurs) et groupe 2 (G2 : asthmatiques non-fumeurs).
Résultats
Le tabagisme actif était retrouvé chez 142 patients (9,4 %). Le groupe des fumeurs était caractérisé par un âge de début des signes cliniques plus précoce (G1 : 22,9 ans vs G2 : 27,8 ans ; p < 0,001), un pourcentage plus faible d’atopie personnel (p = 0,002) et d’atopie familial (p = 0,008), une fréquence plus élevée de trouble ventilatoire obstructif (G1 : 18,5 %, G2 : 6,7 % ; p < 0,001) et un taux plus faible de la réversibilité sous bronchodilatateurs (p = 0,01). Une sévérité accrue de la maladie asthmatique était observée dans G1 avec un taux plus faible d’asthme contrôlé (G1 : 59,9 %, G2 : 68,9 % ; p = 0,028), plus d’hospitalisation en pneumologie (p = 0,03), en réanimation (p = 0,04) avec plus de recours à la ventilation mécanique invasive (p = 0,02) et aux traitements paliers 4 et 5 (p = 0,03).
Conclusions
Le tabagisme chez les asthmatiques allergiques est associé à une altération de la fonction respiratoire, un moindre contrôle de l’asthme avec plus de recours aux soins en termes d’hospitalisations et de traitement.
Purpose
Chronic and persistent exposure to negative stress can lead to adverse consequences on health. Particularly, psychosocial factors were found to increase the risk and outcome of respiratory diseases like asthma. Glucocorticoids (GCs) are the most efficient anti-inflammatory therapy for asthma. However, a significant proportion of patients don’t respond adequately to GC administration. GC sensitivity is modulated by genetic and acquired disease-related factors. Additionally, it was proposed that endogenous corticosteroids may limit certain actions of synthetic GCs, contributing to insensitivity. Psychological and physiological stresses activate the hypothalamic-pituitary-adrenal axis, increasing cortisol levels. Here, we review the mechanism involved in altered GC sensitivity in asthmatic patients under stressful situations. Strategies for modulation GC sensitivity and improving GC therapy are discussed.
Methods
PubMed was searched for publications on psychological chronic stress and asthma, GC resistance in asthma, biological mechanisms for GC resistance, and drugs for steroid-resistant asthma, including highly potent GCs.
Findings
GC resistance in patients with severe disease remains a major clinical problem. In asthma, experimental and clinical evidence suggests that chronic stress induces inflammatory changes, contributing to a worse GC response. GC resistant patients can be treated with other broad-spectrum anti-inflammatory drugs, but these generally have major side effects. Different mechanisms of GC resistance have been described and might be useful for developing new therapeutic strategies against it. Novel drugs, such as highly potent GCs, phosphoinositide 3-kinase-delta inhibitors that reestablish histone deacetylase-2 function, decrease of GC receptor phosphorylation by p38 mitogen-activated protein kinase inhibitors, or phosphatase activators, are currently in clinical development and might be combined with GC therapy in the future. Furthermore, microRNAs (small noncoding RNA molecules) operate as posttranscriptional regulators, providing another level of control of GC receptor levels. Empirical results allow postulating that the detection and study of microRNAs might be a promising approach to better characterize and treat asthmatic patients.
Implications
Many molecular and cellular pathobiological mechanisms are responsible of GC resistance. Therefore detecting specific biomarkers to help identify patients who would benefit from new therapies is crucial. Stress consitutes a negative aspect of current lifestyles that increase asthma morbidity and mortality. Adequate stress management could be an important and positive intervention. (Clin Ther. 2020; 42:XXX–XXX) © 2020 Elsevier HS Journals, Inc.
The literature review provides up-to-date information about the clinical course of bronchial asthma (BA) in smokers with small airway diseases. Special attention is paid to the combination of bronchial asthma and chronic obstructive pulmonary disease (COPD), namely asthma-COPD overlap syndrome (ACOS). According to literature data, in case of small airway duseases exacerbations are more often and severe in smokers with BA and ACOS. Besides, disease prognosis worsens due to reduction in the efficacy of a baseline therapy. Keywords: bronchial asthma, small airway disease, smoking-related phenotype, asthma-COPD overlap (BA-COPD phenotype). В литературном обзоре представлены современные сведения об особенностях клинического течения бронхиальной астмы (БА) у курильщиков с поражением малых дыхательных путей (МДП). Особое внимание уделено сочетанию бронхиальной астмы и хронической обструктивной болезни лёгких (ХОБЛ; COPD) – синдрому перекрёста БА-ХОБЛ (СПБАХ, asthma-COPD overlap, ACO; фенотип БА-ХОБЛ). Согласно литературным данным, в случае поражения МДП у больных БА с фенотипом курильщика и при сочетании БА-ХОБЛ чаще возникают и тяжелее протекают обострения, ухудшается прогноз заболевания, в т.ч. из-за снижения эффективности базисной терапии. Ключевые слова: бронхиальная астма, поражение малых дыхательных путей, фенотип курильщика, asthma-COPD overlap (фенотип БА-ХОБЛ).
Forty healthy young subjects, ages 20 to 49 yr, underwent videobronchoscopy, mucosal biopsy, and bronchial lavage to evaluate the airway inflammation produced by habitual smoking of marijuana and/or tobacco. Videotapes were graded in a blinded manner for central airway erythema, edema, and airway secretions using a modified visual bronchitis index. The bronchitis index scores were significantly higher in marijuana smokers (MS), tobacco smokers (TS), and in combined marijuana/tobacco smokers (MTS), than in nonsmokers (NS). As a pathologic correlate, mucosal biopsies were evaluated for the presence of vascular hyperplasia, submucosal edema, inflammatory cell infiltrates, and goblet cell hyperplasia. Biopsies were positive for two of these criteria in 97% of all smokers and for three criteria in 72%. By contrast, none of the biopsies from NS exhibited greater than one positive finding. Finally, as a measure of distal airway inflammation, neutrophil counts and interleukin-8 (IL-8) concentrations were determined in bronchial lavage fluid. The percentage of neutrophils correlated with IL-8 levels and exceeded 20% in 0 of 10 NS, 1 of 9 MS, 2 of 9 TS, and 5 of 10 MTS. We conclude that regular smoking of marijuana by young adults is associated with significant airway inflammation that is similar in frequency, type, and magnitude to that observed in the lungs of tobacco smokers.
Interleukin-8 (IL-8) is a potent chemotactic protein for polymorphonuclear leukocytes (PMN). Here we examine whether PMN synthesize and release IL-8 in response to stimulation by leukotriene B4 (LTB4). PMN isolated from normal heparinized peripheral human blood were incubated in RPMI culture medium at 37 degrees C in 5% CO2, with and without LTB4. The culture supernatants were tested for IL-8 bioactivity through chemotactic activity measurements with and without neutralizing anti-IL-8 serum. Immunoreactive IL-8 was quantified by ELISA, and de novo IL-8 synthesis was evaluated by metabolic labeling with [35S]cysteine followed by immunoprecipitation. LTB4 stimulated PMN to produce IL-8 in a dose- and time-dependent manner. The IL-8 concentrations reached maximal levels after 16 h of incubation with LTB4. Significant increases in IL-8 production occurred with LTB4 doses of 10 to 1,000 nM/ml. Immunoprecipitation of labeled IL-8 documented new synthesis of IL-8 by LTB4-treated PMN. Northern blot analysis of total RNA from PMN using a 30 mer oligonucleotide for IL-8 demonstrated increased mRNA expression in LTB4-stimulated PMN compared with untreated PMN. These data show that peripheral blood PMN can be stimulated by LTB4 to synthesize and secrete biologically active IL-8. PMN and other cells capable of producing LTB4 may induce IL-8 protein production by inflammatory PMN and thereby amplify or perpetuate the acute inflammatory response by recruiting additional PMN into an inflammatory site.
Asthma and chronic obstructive pulmonary disease are characterized by chronic airway inflammation. Studies using bronchoalveolar lavage (BAL) have shown an increased proportion of eosinophils in the BAL fluid from asthmatics compared with that from normal subjects, whereas studies of chronic obstructive pulmonary disease (COPD) have shown increased numbers of neutrophils. Induced sputum allows sampling of respiratory tract secretions from patients and control subjects, providing a noninvasive method of studying airway secretions and allowing characterization of cells and measurement of soluble markers. We investigated whether induced sputum was a useful method of studying airway fluid from patients with moderate to severe COPD and whether it could be used to compare inflammation in this condition with that in asthma. An initial reproducibility study was undertaken. Sputum was induced twice in 13 patients with severe COPD at a 14-d interval. Total and differential cell counts were carried out and were found to be reproducible over this period. Sputum was then induced in 14 patients with COPD, 23 patients with asthma, 12 healthy cigarette smokers, and 16 normal nonsmoking control subjects. We found a significant increase in neutrophils and increased concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-8 (IL-8) in the patients with COPD compared with the smoking and nonsmoking control subjects. Interleukin-8, but not TNF alpha, was significantly higher in the COPD group than in the asthmatic group. We conclude that the cytokines TNF alpha and IL-8 may be involved in the inflammation in COPD.
We have investigated whether IL-8 is present in airway secretions from patients with asthma and chronic obstructive pulmonary disease (COPD) to obtain information on its possible role in airway inflammation in obstructive airways disease. In the bronchoalveolar lavage fluid (BALF) from 11 clinically stable patients with asthma the levels of IL-8 were increased compared to 10 healthy subjects (median: controls 21.5 pg/ml, asthma 244 pg/ml: p < 0.005). In the patients with asthma the levels of IL-8 correlated with the percentage neutrophils in the BALF (r = 0.81; p < 0.001) and with a parameter of the permeability of the respiratory membrane, the quotient (alpha 2-macroglobulin in BALF)/(alpha 2-macroglobulin in serum) (r = 0.66; p < 0.025). In the sputum sol phase of 9 patients with symptomatic asthma the levels of IL-8 were lower than in 9 patients with COPD (asthma: 6.4 ng/ml; COPD: 16.3 ng/ml; p < 0.02) and significantly correlated with those of neutrophilic myeloperoxidase (MPO; r = 0.85; p < 0.005). The increased levels of IL-8 in the airway secretions from both patients with asthma and COPD may be markers of an ongoing inflammatory process, which is more pronounced in patients with COPD. In patients with asthma the strong correlation between the levels of IL-8 and the percentage neutrophils and/or the levels of MPO points to a role of IL-8 in the recruitment and activation of neutrophils in the airway lumen.
Sputum examination is being used increasingly as a noninvasive method to assess airway inflammation. Expectorated sputum has variable contamination with saliva. Methods of processing have included the selection of portions of the sample considered to be representative of pulmonary origin versus use of the whole specimen, which is confounded by varying volumes of saliva. We compared cell profiles and eosinophilic cationic protein (ECP) concentration in sputum selected from the expectorate and in the usually discarded residual portion to determine to what degree salivary contamination is minimized and if the results are representative of lower respiratory secretions. Sputum was induced with hypertonic saline in six healthy and nine asthmatic subjects. All portions considered to be of pure lower respiratory tract origin were selected from the residual. The selected and residual portions were treated with dithiothreitol, total cell counts and cell viability were obtained, cytospins were made for differential cell counts and supernatant was collected for ECP assay. Selected portions of the specimens, in comparison with the residual portion showed: little squamous cell contamination (median 1.2 vs 70%; p < 0.001); higher total cell counts.mL-1 (5.1 vs 0.5 x 10(6) cells.mL-1; p < 0.001); higher number of viable nonsquamous cells per sample (1.9 vs 0.6 x 10(6) cells; p < 0.001); higher slide quality score (7 vs 4; p < 0.001); and higher levels of ECP (768 vs 136 micrograms.L-1; p < 0.001). There were no differences in the differential cell counts of eosinophils (1.3 vs 3.8%), neutrophils (44 vs 32%), and lymphocytes (0.6 vs 0.6%). While the proportion of macrophages was lower (36 vs 54%; p < 0.05), the absolute number (41 vs 19 x 10(4) cells; p < 0.05) was higher in the selected portion. In summary, selection of all portions of induced sputum from the expectorate minimized the confounding influence of saliva. Loss of nonsquamous cells in the residual portion was variable but usually less than one third of those in the selected portion. With one exception, this loss had little influence on the differential counts of inflammatory cells. Similar observations apply to eosinophilic cationic protein levels. We conclude that, in healthy subjects and treated asthmatics, inflammatory markers in the selected portion of the expectorate can be used to represent those in the lower respiratory tract in general.
The aim of this study was to determine the dose-response relationship between cigarette smoke exposure and pulmonary cell and cytokine concentrations in bronchoalveolar lavage (BAL). BAL cells and BAL supernatant concentrations of tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 from 14 healthy smokers and 16 healthy nonsmokers were quantified. Statistically greater concentrations of neutrophils, macrophages, IL-1 beta, IL-6, IL-8 and MCP-1 were observed among smokers compared with nonsmokers (p < or = 0.0007 in all cases). Cigarette smoking, categorized ordinally as: less than one pack, one pack, or greater than one pack per day, was predictive of BAL macrophages (p < 0.0001), neutrophils (p = 0.015), IL-1 beta (p < 0.001) and IL-8 (p = 0.02). We conclude that concentrations of macrophages, neutrophils, IL-1 beta and IL-8 are elevated in the pulmonary microenvironment of smokers in a cigarette dose-dependent manner. Based on the present findings, we would caution against simple analyses that treat current smokers as a homogeneous group and which do not account for smoking intensity.
Cigarette smoking causes the development of chronic bronchitis and chronic obstructive pulmonary disease. We hypothesized that exposure to cigarette smoke might initiate release of inflammatory mediators by bronchial epithelial cells. To evaluate this, the effect of cigarette smoke extract (CSE) on IL-8 release from cultured human bronchial epithelial cells was examined. CSE augmented IL-8 release from bronchial epithelial cells in a concentration- and time-dependent manner. Most of the augmenting activity of CSE on IL-8 release from bronchial epithelial cells was lost after volatilization or lyophilization treatment. Two major volatile factors in cigarette smoke, acrolein and acetaldehyde, augmented IL-8 release. Four cell strains were tested and showed increased IL-8 release in response to CSE. In addition, bronchoalveolar lavage was performed on 11 nonsmokers and 12 smokers. IL-8 concentration was greater in the proximal, bronchial samples than in distal, alveolar samples, and IL-8 in BAL from smokers was higher than in BAL from nonsmokers. There was a significant correlation between IL-8 concentration and neutrophil count in bronchial samples of BAL fluid. These data support the hypothesis that exposure to cigarette smoke may induce bronchial epithelial cells to release IL-8 and that this may contribute to airway inflammation in smokers.
Analysis of bronchoalveolar lavage fluid has improved our understanding of the pathogenesis of asthma. Safety issues and access to expert resources limit this techniques as a research tool. Induced sputum is a non-invasive method of collecting airway fluid which is applicable to subjects with a range of severity of airflow obstruction. The method of sputum collection and processing differs between groups. A study was undertaken to compare induced sputum with bronchoscopically collected fluid.
Sixteen patients with mild stable asthma underwent both sputum induction and bronchoscopic examination with bronchial washings and bronchoalveolar lavage (BAL) in random order, with each procedure being separated by an interval of 12 days. Airway fluid was processed and stained for differential cell counting.
Induced sputum was relatively rich in neutrophils and eosinophils compared with bronchial washings and BAL fluid (mean (SE) 1.3 (0.4)%, 5.0 (2.7)%, and 36.4 (3.7)% neutrophils and 0.6 (0.1)%, 1.6 (0.6)%, and 3.3 (1.1)% eosinophils in BAL fluid, bronchial washings, and induced sputum, respectively). The proportions of cells obtained at sputum induction correlated with those in bronchial washings but not BAL fluid (r = 0.6 and 0.7 for neutrophils and eosinophils, respectively, p < 0.05). By contrast, induced sputum had a lower proportion of lymphocytes and macrophages than bronchial washings or BAL fluid, without any correlation.
Induced sputum is rich in neutrophils and eosinophils and poor in lymphocytes, suggesting an origin in the larger airways. Induced sputum adequately reflects the findings in fluid collected by direct bronchoscopy.
Interleukin (IL)-8 is a C-X-C chemokine that potently chemoattracts and activates neutrophils. We determined whether IL-8 could be produced by human airway smooth muscle cells in culture and examined its regulation. TNF-alpha stimulated IL-8 mRNA expression and protein release in a time- and dose-dependent manner, whereas IFN-gamma alone had no effect. Both cytokines together did not induce greater IL-8 release compared to TNF-alpha alone. IL-1beta was more potent in inducing IL-8 release and, together with TNF-alpha, there was a synergistic augmentation of IL-8 release. IL-8 release induced by TNF-alpha and IFN-gamma was partly inhibited by the Th-2-derived cytokines IL-4, IL-10, and IL-13, as well as by dexamethasone. In addition to its contractile responses, airway smooth muscle cells have synthetic and secretory potential with the release of IL-8 and subsequent recruitment and activation of neutrophils in the airways. Release of IL-8 can be modulated by Th-2-derived cytokines and corticosteroids.
Airway inflammation in asthma can be measured directly by invasive bronchoalveolar lavage (BAL), directly and relatively noninvasively by induced sputum and indirectly from peripheral blood. We compared cellular and fluid phase indices of inflammation in induced sputum, BAL and blood from 11 adults with mild stable asthma. On one day, induced sputum selected from saliva was collected and on the next, blood and BAL. Median results of sputum compared with BAL showed a higher number of nonsquamous cells (53 versus 0.8 x 10(6) cells x mL(-1), p=0.003), more neutrophils (34.3 versus 1.0%, p<0.001), CD4+ and CD19+ T-cells (76.5 versus 54.7%, p=0.01 and 5.2 versus 1.1%, p=0.03, respectively), fewer macrophages (603 versus 95.0%, p=0.002) and markedly higher levels of eosinophil cationic protein (ECP) (264 versus 2.0 microg x L(-1), p<0.001), tryptase (17.6 versus 2.2 UI x L(-1), p<0.001) and fibrinogen (1,400 versus 150 microg x L(-1), p=0.001). Sputum and BAL neutrophils and CD4+ T-cells were strongly correlated. Sputum and BAL differed from blood by having higher proportions of T-cells (94.9 and 98.9% versus 87.7%, p=0.002) and lower proportions of CD19+ T-lymphocytes (p=0.04 and 0.006). Sputum also differed from blood by having higher proportions of CD4+ T-cells (76.5 versus 51.4%, p=0.001), lower proportions of CD8+ cells (24.0 versus 403%, p=0.04) and a higher CD4+/CD8+ ratio (3.3 versus 1.4, p=0.01). We conclude that in mild asthmatics, sputum, bronchoalveolar lavage and blood measure different compartments of inflammation. Induced selected sputum has the advantage over bronchoalveolar lavage of higher density of cell recovery and stronger signal for fluid-phase markers.
Acute exposure to cigarette smoke causes airway hyperresponsiveness (AHR) in guinea-pigs, which resolves within a few hours. Repeated exposure may have a different effect on the airways. To address this question, guinea-pigs were repeatedly exposed to cigarette smoke (six cigarettes for 1 h x day(-1)) for 14 consecutive days. Airway responsiveness to inhaled histamine and differential cell counts in bronchoalveolar lavage fluid (BALF) were evaluated 1 day after the last exposure. Significant neutrophilia in BALF was observed after 3 days of smoke exposure. Significant eosinophilia in BALF and AHR were observed after 14 days of smoke exposure, but not after 3 or 7 days of smoke exposure. These changes persisted until 3 days after the last exposure and resolved 7 days afterwards. Histologically, the recruited eosinophils were observed predominantly in the airways, but not in the alveoli. Treatment with E-6123, a specific platelet-activating factor receptor antagonist (1 mg x kg(-1) x day(-1) p.o. during smoke exposure) significantly inhibited the eosinophil influx and AHR. Repeated exposure to cigarette smoke may induce prolonged airway inflammation and airway hyperresponsiveness in guinea-pigs. Platelet-activating factor or platelet-activating factor-like lipids may play a key role in airway hyperresponsiveness, presumably by the induction of eosinophilic airway inflammation.
To investigate the relationship between airflow limitation and airway inflammation in smokers, we examined paraffin-embedded bronchial biopsies obtained from 30 smokers: 10 with severe airflow limitation, eight with mild/moderate airflow limitation, and 12 control smokers with normal lung function. Histochemical and immunohistochemical methods were performed to assess the number of inflammatory cells in the subepithelium and the expression of CC chemokines macrophage inflammatory protein (MIP)-1alpha and -1beta in the bronchial mucosa. Compared with control smokers, smokers with severe airflow limitation had an increased number of neutrophils (p < 0.02), macrophages (p < 0.03), and NK lymphocytes (p < 0.03) in the subepithelium, and an increased number of MIP-1alpha+ epithelial cells (p < 0.02). When all smokers were considered together, the value of FEV1 was inversely correlated with the number of neutrophils (r = -0.59, p < 0.002), macrophages (r = -047, p < 0. 012), NK-lymphocytes (r = -0.51, p < 0.006) in the subepithelium, and with the number of MIP-1alpha+ epithelial cells (r = -0.61, p < 0.003). We conclude that in smokers the severity of airflow limitation is correlated with the severity of airway inflammation and that severe airflow limitation is associated with an increased number of neutrophils, macrophages, NK lymphocytes, and MIP-1alpha+ cells in the bronchial mucosa.
Although the prevalence of asthma and morbidity related to asthma are increasing, little is known about the natural history of lung function in adults with this disease.
We used data from a longitudinal epidemiologic study of the general population in a Danish city, the Copenhagen City Heart Study, to analyze changes over time in the forced expiratory volume in one second (FEV1) in adults with self-reported asthma and adults without asthma. The study was conducted between 1976 and 1994; for each patient, three measurements of lung function were obtained over a 15-year period. The final data set consisted of measurements from 17,506 subjects (8136 men and 9370 women), of whom 1095 had asthma.
Among subjects who participated in all three evaluations, the unadjusted decline in FEV1 among subjects with asthma was 38 ml per year, as compared with 22 ml per year in those without asthma. The decline in FEV1 normalized for height (FEV1 divided by the square of the height in meters) was greater among the subjects with asthma than among those without the disease (P<0.001). Among both men and women, and among both smokers and nonsmokers, subjects with asthma had greater declines in FEV1 over time than those without asthma (P<0.001). At the age of 60 years, a 175-cm-tall nonsmoking man without asthma had an average FEV1 of 3.05 liters, as compared with 1.99 liters for a man of similar age and height who smoked and had asthma.
In a sample of the general population, people who identified themselves as having asthma had substantially greater declines in FEV1 over time than those who did not.
An easy and safe dose-response histamine-inhalation test is described, to measure the level of non-specific bronchial reactivity.
The test was performed in 307 subjects. Non-specific bronchial reactivity was increased in 3% of presumed normal subjects, in 100% of active asthmatics and in 69% of asymptomatic asthmatics with previous symptoms only at times of exposure to clinically relevant allergens. It was also increased in 47% of patients with cough and no other chest symptoms, in 40% of patients with rhinitis and vague chest symptoms not by themselves diagnostic of asthma, and in 22% of patients with rhinitis and no chest symptoms.
The patients with asthma were studied when their asthma was well controlled and when their minimum drug requirements had been established. The mean level of bronchial reactivity increased with increasing minimum drug requirements. The level of bronchial reactivity also showed a strong negative correlation with the forced expiratory volume in 1 sec (FEV1). Atopic subjects, with or without asthma, showed a significant positive correlation between the level of bronchial reactivity and atopic status as indicated by the number of positive allergy skin tests.
Airway inflammation is considered to be important in asthma but is relatively inaccessible to study. Less invasive methods of obtaining sputum from patients unable to produce it spontaneously should provide a useful investigational tool in asthma.
A method to induce sputum with inhaled hypertonic saline was modified for use in 17 asthmatic patients and 17 normal subjects who could not produce sputum spontaneously. The success rate and safety of the method, the reproducibility of cell counts, and differences in cell counts between the asthmatic and normal groups were examined. Hypertonic saline solution 3-5% was inhaled for up to 30 minutes after inhalation of salbutamol. Subjects were asked to expectorate sputum every five minutes. The quality of the sample was scored on the volume of plugs and the extent of salivary contamination. Plugs from the lower respiratory tract were selected for a total cell count and for differential cell counts of eosinophils and metachromatic cells (mast cells and basophils) in direct smears.
Adequate samples from the lower respiratory tract were obtained in 76% of first attempts. The mean fall in the forced expiratory volume in one second (FEV1) during inhalation of saline was 5.3% and the maximum fall 20%. Eosinophil and metachromatic cell counts were reproducible (reliability coefficient 0.8 and 0.7 respectively). When compared with sputum from normal subjects sputum from asthmatic patients contained a significantly higher proportion of eosinophils (mean 18.5% (SE 3.8%) v 1.9% (0.6%)) and metachromatic cells (0.50% (0.18%) v 0.039% (0.014%)). In the asthmatic group the differential eosinophil count correlated with the baseline FEV1.
Induced sputum is capable of detecting differences in cell counts between normal and asthmatic subjects and merits further development as a potential means of assessing airway inflammation in asthma.
The respiratory manifestations of cystic fibrosis (CF) are characterized by neutrophil-dominated airway inflammation. Since a variety of inflammatory stimuli are capable of inducing bronchial epithelial cells to express the gene for IL-8, a cytokine that attracts and activates neutrophils, mediators in respiratory epithelial lining fluid (ELF) of CF individuals might induce IL-8 production by epithelial cells, thus recruiting neutrophils to the airways. BET-1A human bronchial epithelial cells at rest or incubated with normal ELF showed little IL-8 gene expression, but after incubation with CF ELF, a marked increase in IL-8 transcript levels was observed. CF ELF contained high levels of neutrophil elastase (NE) and various serine protease inhibitors prevented CF ELF from inducing IL-8 gene expression in BET-1A cells, suggesting that NE was the dominant inducer for IL-8 production in CF ELF. The addition of purified NE caused BET-1A cells to increase IL-8 gene transcription with accumulation of mRNA transcripts and to release IL-8-like neutrophil chemotactic activity. These observations suggest a self-perpetuating inflammatory process on the CF bronchial surface where NE released by neutrophils induced the bronchial epithelium to secrete IL-8, which in turn recruits additional neutrophils to the bronchial surface.
We have previously demonstrated that cultured human bronchial epithelial cells produce cytokines with potent proinflammatory properties on exposure to several stimuli in vitro, and we have hypothesized that these epithelial cell-derived factors may contribute to the pathogenesis of some inflammatory diseases of the bronchial mucosa, particularly asthma, by promoting the infiltration of granulocytes and T cells and their local activation. We provide, in this study, direct evidence of an increased expression of granulocyte-macrophage-colony-stimulating factor, interleukin-6, and interleukin-8 genes and proteins in bronchial epithelium from patients with symptomatic asthma. The up regulation of the production of these cytokines in bronchial epithelial cells of patients with asthma could be abolished in vitro by corticosteroids (hydrocortisone, 10(-7) mol/L), but the up regulation also spontaneously disappeared during a period of 6 days after the removal of the cells from the diseased tissue.
We studied the relationship of serum IgE levels and eosinophil counts with passive smoking in 9-year-old, nonselected children from three Italian towns near Rome. Male children of smoking parents had a significantly higher total count and percentage of eosinophils (p = 0.008) and higher IgE levels (p = 0.01) than male children of nonsmoking parents. Prevalence of eosinophilia (defined as greater than or equal to 4% of total white blood cell count) was significantly correlated with the number of cigarettes smoked by parents among boys (p = 0.003) but not among girls (p = 0.20). There was a significant trend (p = 0.008) for prevalence of eosinophilia to increase with increasing levels of serum IgE. For any given level of serum IgE, the frequency of eosinophilia was higher among children of smoking parents than among children of nonsmoking parents. When parental smoking was studied in a multivariable analysis and after controlling for the other variable, it was still significantly associated with eosinophilia in the children of these smoking parents but not with serum IgE levels. We conclude that parental smoking is associated with a significant enhancement of the expression of the most important markers of allergic sensitization in the children of smoking parents. This is particularly evident for boys and may explain, at least in part, the increased frequency of respiratory symptoms in children of smoking parents.
We have undertaken detailed cellular and ultrastructural examination of bronchial biopsies and bronchial lavage fluid from allergic asthmatic patients in order to determine the nature and degree of the inflammatory processes in mild allergic asthma. Eight atopic asthmatic patients (mean PC20 histamine, 0.90 mg/ml) and four nonasthmatic control subjects underwent fiberoptic bronchoscopy. All asthmatic subjects were clinically stable for 2 wk prior to bronchoscopy and required either no treatment or inhaled albuterol alone. A single 50-ml bronchial wash was undertaken, followed by endobronchial biopsy of subcarinae. These procedures were repeated in the asthmatic subjects 18 h after bronchial provocation with allergen or methacholine. Subsequently, all subjects underwent bronchial reactivity testing with inhaled histamine. The clinical and physiologic data were not revealed to the pathologist interpreting the specimens. The asthmatic subjects shed a significantly greater number of epithelial cells into the lavage fluid than did the nonasthmatic subjects (7.23 versus 1.48 x 10(4)/ml, p = 0.048). There was a statistically significant inverse correlation between the lavage epithelial cell count and bronchial reactivity (rho = -0.64, p = 0.03). In the asthmatic subjects, but not in the control subjects, there was extensive deposition of collagen beneath the epithelial basement membrane, mast cell degranulation, and mucosal infiltration by eosinophils, which exhibited morphologic evidence of activation. Eosinophils, monocytes, and platelets were found in contact with the vascular endothelium, with emigration of eosinophils and monocytes in the asthmatic subjects. These changes were found irrespective of bronchial challenge with allergen. We conclude that allergic asthma is accompanied by extensive inflammatory changes in the airways, even in mild clinical and subclinical disease.
In recent studies, sputum smear cell counts were found to be reproducible and usefully applied to research in asthma and other airway conditions. However, cell definition on the smears is poor, and the procedure is tedious and has limited utility. The objective of this study is to improve the methods of sputum examination. The subjects used in this study were people with bronchitis or asthma from whom sputum could be obtained. By inverted microscopy, portions of fresh sputum were selected to exclude salivary contamination. These portions were exposed to different volumes of dithiothreitol for varied time intervals. We used the resulting cell suspensions to perform total cell counts and prepare cytospins for differential cell counts and immunohistochemical stains for GM-CSF, EG2, TNF alpha and IL-8. Cytospins were compared with smears for differential cell counts on the same sputum specimens. Excellent cell dispersion and definition in cytospins could be observed. The time required for differential cell counting on cytospins was reduced and cytospin counts were more reproducible than smears. Greater duration of treatment of sputum with dithiothreitol tended to increase total cell counts and significantly decreased EG2 staining but had no effect on differential cell counts or the cytokine cell components. Therefore the proposed method of sputum examination involving cell dispersion and use of cytospins overcomes a number of the disadvantages of the examination of smears.
Neutrophils are possibly involved in the pathogenesis of various lung diseases through the release of numerous mediators. In the present study, we studied the regulation of IL-8 gene induction and protein secretion in human blood neutrophils. Northern blot analysis revealed that LPS increased IL-8 mRNA levels in neutrophils, with a maximal fivefold increase by 2 h. IL-8 mRNa levels returned to baseline values within 12 h. In contrast, LPS-stimulated monocytes demonstrated a sustained increase of IL-8 mRNA levels for more than 24 h. TNF-alpha, IL-1 beta, and phorbol myristate acetate also increased IL-8 mRNA levels in neutrophils. Immunohistochemical analysis confirmed that IL-8 was localized within stimulated neutrophils. IL-8 secretion by neutrophils and monocytes was quantified using a specific ELISA for IL-8. Resting neutrophils secreted minimal IL-8 activity. However when cells were stimulated with LPS, TNF-alpha, or IL-1B, neutrophils secreted IL-8. IL-8 secretion was most marked during the first 2 h after stimulation and decreased thereafter. In contrast, monocytes maintained a high rate of IL-8 secretion over 12 h. Although a single monocyte secreted 70-fold more IL-8 than did a single neutrophil after 4 h of incubation, the high abundance of neutrophils in peripheral blood made the neutrophil-secreted IL-8 more significant. During the first 2 h, neutrophils secreted approximately 40% of the IL-8 released by monocytes in the same volume of blood. This ratio decreased to 9% after 12 h. Neutrophil-secreted IL-8 may play an autocrine or paracrine role during the initial stage of inflammation.
We have studied bronchial biopsies from 14 patients with newly diagnosed asthma (four men and 10 women), who had had asthma symptoms, on average, 7.4 months (range, 2 to 12 months) and from four control subjects. The patients had not received corticosteroids, disodium cromoglycate, or theophylline before the study. The bronchial biopsies were taken, using a rigid-tube bronchoscope under local anaesthesia, from two different airway levels: (1) inside the right upper lobe bronchus, and (2) at the opening of the right middle lobe. The specimens were prepared for both light and electron microscopy. The use of Slot grids 1 x 2 mm enabled a large area of the thin sections to be photographed and analyzed by applying a graphic Autocad program. There was an increase in the numbers of mast cells (p < 0.001), eosinophils (p < 0.05), lymphocytes (p < 0.05), and macrophages (p < 0.05) in the epithelium of patients with newly diagnosed asthma as compared with those in control subjects. In the lamina propria, these asthmatic patients had more eosinophils (p < 0.001), lymphocytes (p < 0.001), macrophages (p < 0.001), and plasma cells (p < 0.001) than did the control subjects. We conclude that, in asthma, an airway inflammatory process is present even at a clinically early stage of the disease. In the asthmatic airways, there are signs of a general inflammatory response caused by more than one cell type.
The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects. For this purpose 85 allergic and nonallergic asthmatic subjects were randomized into three groups, which were given high-dose (1,600 micrograms/d) inhaled budesonide, low-dose (400 micrograms/d) inhaled budesonide, and oral theophylline (600 mg/d), respectively, and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein (ECP), eosinophil protein x/eosinophil derived neurotoxin (EPX/EDN) as eosinophil markers, and myeloperoxidase (MPO) and lactoferrin (LF) as neutrophil markers. Lung functions (FEV1% predicted, and histamine PC20) and the eosinophil markers ECP and EPX/EDN were improved and reduced, respectively, by budesonide in a dose-dependent and temporally parallel fashion. Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment. The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects, since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide. MPO but not LF was reduced after several months of treatment in all three groups, but only in nonsmokers. We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients, and that smoking asthmatic subjects are resistant to inhaled corticosteroids.
The role of glucocorticoids in the treatment of chronic obstructive pulmonary disease (COPD) is controversial. We have previously described high numbers of neutrophils and high concentrations of the inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), and of the cell activation markers eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO), and human neutrophil lipocalin (HNL) in COPD patients as compared with controls, and have postulated that the cytokines TNF-alpha and IL-8 play a role in propagating the inflammatory response in COPD. We have now studied the effects of inhaled and oral glucocorticoids on these inflammatory indices in induced sputum. Initially, we studied the effect of a 2-wk course of inhaled budesonide (800 mg twice daily for 2 wk) in 13 patients with severe COPD (mean FDV1: 35% predicted). There was no clinical benefit in either lung function or symptom scores, and no significant change in the inflammatory indices as measured by total and differential cell counts and concentrations of TNF-alpha eosinophil activation markers ECP and EPO, and neutrophil activation markers MPO and HNL. Because the lack of anti-inflammatory effect might have been due to poor drug delivery as a result of severe airflow limitation, we undertook a study examining the antiinflammatory effect of oral prednisolone (30 mg daily for 2 wk) in patients with COPD and undertook the same measurements in 10 patients with atopic asthma. Sputum eosinophil numbers, ECP, and EPO were significantly reduced in the asthmatic patients but were not modified in COPD. This confirms the clinical impression that inhaled steroids have little antiinflammatory effect, at least in the short term in this group of patients, and suggests that the inflammatory process in COPD is resistant to the antiinflammatory effect of glucocorticoids.
To assess the characteristics of airway inflammation in patients with COPD.
We measured the sputum concentration of interleukin-8 (IL-8), a chemokine involved in the migration and activation of neutrophils and eosinophils. We also measured myeloperoxidase (MPO) as a parameter of neutrophil activity and eosinophil cationic protein (ECP) as a parameter of eosinophil activity. Spontaneous sputum samples were obtained from 33 patients with stable COPD and 30 patients with asthma. Induced sputum samples were obtained from 12 normal control subjects.
The sputum concentration of IL-8 was significantly higher in the patients with COPD than in the patients with asthma or in the control subjects (p<0.0001). Concentrations of MPO and ECP were significantly higher in the patients with COPD than in the control subjects but did not differ significantly between the patients with COPD and those with asthma. In the patients with COPD, the sputum concentration of IL-8 was significantly correlated with the concentration of MPO (r=0.55, p<0.001) and of ECP (r=0.53, p<0.01). The sputum concentration of IL-8 was negatively correlated with FEV1/FVC (r=-0.78, p<0.0001) in the COPD group.
Results suggest the activation of both neutrophils and eosinophils in the airways of patients with COPD. It appears that IL-8 plays a primary role in this activation. The sputum concentration of IL-8 appeared to be closely associated with the degree of airflow obstruction in patients with COPD and may serve as a marker in evaluating the severity of airway inflammation, which is a risk factor for COPD.
The severity of asthma can be graded from mild intermittent to severe persistent. Airway inflammation is a feature of persistent asthma. We compared several markers of inflammation in mucosal biopsies and bronchoalveolar lavage fluid (BAL fluid) from 12 healthy control subjects, 24 patients with intermittent asthma, and 18 patients with mild-to-moderate persistent asthma. Epithelial shedding, eosinophil (EG2-positive cells), and activated T-cell (UCHL1) counts in biopsies, and ECP levels in BAL fluids were significantly increased in patients with intermittent asthma by comparison with control subjects and this increase was significantly greater for patients with persistent asthma. Alveolar macrophage activation (percentage of hypodense cells) and the thickness of the basement membrane were significantly increased in asthmatic subjects as compared with controls but there was no difference between the two asthmatic groups. Hyaluronic acid levels in BAL fluids were significantly increased in patients with persistent asthma by comparison with control subjects and patients with intermittent asthma. Mast cell numbers (toluidine blue) in biopsies and histamine or levels in BAL fluids were similar in the three groups. This study shows that airways inflammation is present in patients with intermittent asthma but to a lesser extent than in patients with persistent asthma.
Asthma and chronic obstructive pulmonary disease are characterized by airway inflammation, which can be assessed by bronchoscopic techniques as well as by the analysis of induced sputum. A method to induce sputum with inhaled hypertonic saline was adapted for use in 21 chronic obstructive pulmonary disease (COPD) patients (mean baseline forced expiratory volume in one second (FEV1) 1.60 L, or 54% predicted) and in 16 healthy volunteers. The success rate and safety of the method, were investigated along with the reproducibility of cell counts and differences in cell counts between both groups. All subjects produced adequate samples and the procedure did not alter spirometric values. A marked sputum neutrophilia was noted in patients with COPD (74.9+/-4.7%), whereas mainly macrophages were seen in healthy volunteers (74.0+/-4.0%). Reliability of the cell counts was high, both within investigators (r=0.99 neutrophils, r=0.99 macrophages) and between investigators (r=0.95 neutrophils, r=0.77 macrophages). In patients with COPD, an inverse correlation was noted between percentage of neutrophils and FEV1 (r(s)=-0.48, p<0.05). Immunostaining revealed a large proportion of activated macrophages in both groups. It was concluded that induction of sputum is a safe and reproducible method to study the composition of airway secretions in patients with chronic obstructive pulmonary disease.
Smoking and bronchial hyperresponsiveness in non-atopic and atopic young adults
- Sunyer
IL-4 and IL-3 stimulate GM-CSF and IL-8 production by human airway epithelial cells [abstract]
- Nakamura