Metabolomics analysis identifies different metabotypes of asthma severity

In this study, we sought to determine whether asthma has a metabolic profile and whether this profile is related to disease severity.We characterised the serum from 22 healthy individuals and 54 asthmatics (12 mild, 20 moderate, 22 severe) using liquid chromatography–high-resolution mass spectrometry-based metabolomics. Selected metabolites were confirmed by targeted mass spectrometry assays of eicosanoids, sphingolipids and free fatty acids.We conclusively identified 66 metabolites; 15 were significantly altered with asthma (p≤0.05). Levels of dehydroepiandrosterone sulfate, cortisone, cortisol, prolylhydroxyproline, pipecolate and N-palmitoyltaurine correlated significantly (p<0.05) with inhaled corticosteroid dose, and were further shifted in individuals treated with oral corticosteroids. Oleoylethanolamide increased with asthma severity independently of steroid treatment (p<0.001). Multivariate analysis revealed two patterns: 1) a mean difference between controls and patients with mild asthma (p=0.025), and 2) a mean difference between patients with severe asthma and all other groups (p=1.7×10−4). Metabolic shifts in mild asthma, relative to controls, were associated with exogenous metabolites (e.g. dietary lipids), while those in moderate and severe asthma (e.g. oleoylethanolamide, sphingosine-1-phosphate, N-palmitoyltaurine) were postulated to be involved in activating the transient receptor potential vanilloid type 1 (TRPV1) receptor, driving TRPV1-dependent pathogenesis in asthma.Our findings suggest that asthma is characterised by a modest systemic metabolic shift in a disease severity-dependent manner, and that steroid treatment significantly affects metabolism.

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Impact of asthma severity as risk factor to future exacerbations in patients admitted for asthma exacerbation

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2021.780 ◽

2021 ◽

Vol 16 ◽

Author(s):

Narongwit Nakwan

Keyword(s):

Risk Factor ◽

Disease Severity ◽

Severe Asthma ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Asthma Severity ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Mild Asthma ◽

The Impact

Background: To investigate the impact of disease severity on exacerbation patterns and identify its potential as a risk factor for future exacerbations in patients admitted for asthma exacerbations.Methods: We analyzed frequency and time to next exacerbation over a period of three years in 532 patients admitted for exacerbation. Disease severity was selected as a potential risk factor for the events. Kaplan-Meier analysis was used to identify the probability of future exacerbations. A Cox-proportional hazards model was used to assess independent relative risks.Results: Of 532 patients analyzed, the frequency of exacerbations rose as the severity of the asthma increased. The exacerbation rates in the following year were 1.66 per person for patients with mild asthma and 3.98 for patients with severe asthma. The median time to the next exacerbation in patients with mild asthma was 61.4 weeks (95% CI, 40.1-82.6) compared to 15.0 weeks (95% CI, 11.3-18.6) in patients with severe asthma (p<0.001). Multivariate analysis showed that asthma severity (severe vs mild asthma, HR=1.42, 95% CI, 1.07-1.89), a history of 1-2 exacerbations (HR=1.95, 95% CI, 1.45-2.63) or > 2 exacerbations (HR=2.32, 95% CI, 1.56-3.44) in the previous 12 months, and a high number of comorbidities (≥5 vs none, HR=2.5, 95% CI, 1.41-4.45) were independent predictors of the probability of future exacerbations.Conclusion: Asthma severity is a strong independent risk factor for future exacerbations, and exacerbation rates also become more frequent as the severity of the asthma increases. These findings help in better understanding of the natural course of exacerbations across the spectrum of asthma disease severity

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Newly Diagnosed Asthma in China: Initial Severity and Changes Over 1-year Management

10.21203/rs.3.rs-659298/v1 ◽

2021 ◽

Author(s):

Zhizhen Hu ◽

Jianwei Xuan ◽

Haijin Zhao ◽

Hangming Dong ◽

Changhui Yu ◽

...

Keyword(s):

Severe Asthma ◽

Asthma Severity ◽

Initial Diagnosis ◽

Mild Asthma ◽

First Year ◽

Newly Diagnosed ◽

Medical Database ◽

Asthma Patients ◽

First Diagnosis

Abstract Background: The prevalence of adult asthma is increasing in China. However, there are no large sample, epidemiological data describing asthma severity at the time of new diagnosis and changes during follow-up management. Thus, the purpose of this study was to use a large health care database to examine asthma severity at initial diagnosis, and changes in severity over the first year of management.Methods: Data of patients with a first diagnosis of asthma were extracted from the SuValue electronic medical database. Inclusion criteria were: 1) At least 14 years old at the time of first diagnosis; 2) Initial diagnosis from 2001 to March 2019; 3) Followed-up for at least 12 months; 4) Had a follow-up visit every 3 months. Disease severity at diagnosis and at each follow-up visit, medications prescribed, and symptoms were collected and analysed.Results: A total of 7,654 adult patients with newly diagnosed asthma from tertiary hospitals (26.38%) and secondary hospitals (73.62%) who were followed-up for at least 12 months were included. Approximately 54% were females, and the proportion of patients over 60 years old was the highest (38%). Of all patients, 53.91% were not prescribed medications to control asthma, suggesting that these patients were mild asthma. Approximately 16% of patients were prescribed oral corticosteroid and/or inhaled corticosteroid and long-acting β2-agonist combination, suggesting moderate to severe asthma. The proportions of patients with moderate and severe decreased during the first 6 months, and then the proportions remained stable. The proportion of patients with severe asthma remained stable from the 6th month onward. At the end of the year 2.7% of patients had severe asthma. Patients with mild asthma tended to continue to have mild asthma in the following 3 months (> 76.19%). However, of the patients with mild and moderate asthma at 3 months, 92.85% and 75.1%, respectively, had a reduction in severity and had mild asthma at 12 months. On the other hand, 1.26% and 3.15%, respectively, progressed to severe asthma by 12 months.Conclusion: During the first year after an initial diagnosis of asthma patients diagnosed with mild asthma tended to not progress and remained stable with mild asthma over the year. The proportions of patients diagnosed with moderate and severe asthma remained stable over the year. Further study is needed to examine the clinical features of newly diagnosed patients with severe asthma who do not experience a reduction in severity in order to target these patients for more intensive treatment and reduce the disease burden.

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Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort

European Respiratory Journal ◽

10.1183/13993003.00198-2019 ◽

2019 ◽

Vol 54 (3) ◽

pp. 1900198 ◽

Cited By ~ 10

Author(s):

Ina Sintobin ◽

Valerie Siroux ◽

Gabriële Holtappels ◽

Christophe Pison ◽

Rachel Nadif ◽

...

Keyword(s):

Severe Asthma ◽

Asthma Severity ◽

Mild Asthma ◽

Lower Airway ◽

Cross Sectional ◽

Prick Test ◽

Asthma Exacerbations ◽

Increased Risk ◽

Disease Modifier ◽

Subsequent Risk

IntroductionEvidence is accumulating that Staphylococcus aureus plays an important role as disease modifier in upper and lower airway diseases. Sensitisation to S. aureus enterotoxins (SEs) was associated with an increased risk of severe asthma in previous cross-sectional studies, but evidence from longitudinal studies is lacking. We aimed to assess associations between SE-sensitisation and the subsequent risk for asthma severity and exacerbations.MethodsThis is a nested case–control study from the 20-year Epidemiological Study of the Genetics and Environment of Asthma (EGEA) cohort, including 225 adults (75 without asthma, 76 with mild asthma and 74 with severe asthma) in EGEA2 (2003–2007). For 173 of these individuals, SE-sensitisation was measured on samples collected 11 years earlier (EGEA1). Cross-sectional associations were conducted for EGEA1 and EGEA2. Longitudinal analyses estimated the association between SE-sensitisation in EGEA1 and the risk of severe asthma and asthma exacerbations assessed in the follow-up. Models were adjusted for sex, age, smoking, parental asthma/allergy and skin-prick test to house dust mite.ResultsSE-sensitisation varied between 39% in controls to 58% and 76% in mild and severe asthma, respectively, in EGEA1. An adjusted cross-sectional association showed that SE-sensitisation was associated with an increased risk of severe, but not for mild asthma. SE-sensitisation in EGEA1 was associated with severe asthma (adjusted OR 2.69, 95% CI 1.18–6.15) and asthma exacerbations (adjusted OR 4.59, 95% CI 1.40–15.07) assessed 10–20 years later.ConclusionFor the first time, this study shows that being sensitised to SEs is associated with an increased subsequent risk of severe asthma and asthma exacerbations.

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Risk factors of asthma exacerbation based on asthma severity: a nationwide population-based observational study in South Korea

BMJ Open ◽

10.1136/bmjopen-2017-020825 ◽

2018 ◽

Vol 8 (3) ◽

pp. e020825 ◽

Cited By ~ 16

Author(s):

Hye-Rim Kang ◽

Hyun Jin Song ◽

Jin Hyun Nam ◽

Sung-Hyun Hong ◽

So-Young Yang ◽

...

Keyword(s):

Risk Factors ◽

Observational Study ◽

Severe Asthma ◽

Asthma Exacerbation ◽

Asthma Severity ◽

Population Based ◽

Mild Asthma ◽

High Dose ◽

Moderate Asthma ◽

History Of

ObjectivesAsthma exacerbation, associated with many risks factors, can reflect management failure. However, little is known about how risk factors are associated with exacerbation, according to asthma severity. We aimed to investigate differences in risk factors in patients with different asthma severity and evaluate whether risk factors differed between frequent exacerbators and patients with single exacerbation.DesignNationwide population-based observational study.SettingKorean National Sample Cohort database.ParticipantsWe included 22 130 adults with asthma diagnoses more than twice (ICD-10 (International Classification of Diseases, Tenth revision) codes J45 and J46) and one prescription for asthma medication from 2010 to 2011.Outcome measuresAsthma exacerbation was defined as having a corticosteroid (CS) burst characterised by a prescription of high-dose oral CS for ≥3 days or one systemic CS injection, hospitalisation or emergency department visit.ResultsAmong severities, history of CS bursts was significantly associated with exacerbation. In mild and moderate asthma, exacerbation was significantly associated with age ≥45 years, being female, gastro-oesophageal reflux disease and chronic rhinitis. High medication possession ratio (MPR≥50%), compared with low MPR (<20%) showed adjusted ORs of 0.828 (95% CI 0.707 to 0.971) and 0.362 (0.185 to 0.708) in moderate and severe asthma, respectively. In severe asthma, compared with mild asthma, only allergic rhinitis and history of hospitalisation were strongly associated with exacerbation. When comparing frequent exacerbators to patients with single exacerbation, age ≥45 years, atopic dermatitis, anxiety and history of CS burst were significant risk factors in mild and moderate asthma, whereas no risk factors were significant in severe asthma.ConclusionsDifferent associations between risk factors and asthma exacerbations based on asthma severity suggest that patients with mild asthma require greater attention to their age and comorbidities, whereas those with severe asthma require greater attention to hospitalisation history and drug adherence.

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The Modulation of PCSK9 and LDLR by Supercritical CO2 Extracts of Mentha longifolia and Isolated Piperitone Oxide, an In Vitro Study

Molecules ◽

10.3390/molecules26133886 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3886

Author(s):

Stefania Sut ◽

Irene Ferrarese ◽

Maria Giovanna Lupo ◽

Nicola De Zordi ◽

Elisa Tripicchio ◽

...

Keyword(s):

Mass Spectrometry ◽

Cell Lines ◽

Hepatoma Cell ◽

Density Lipoprotein ◽

In Vitro Study ◽

Volatile Constituent ◽

Dependent Manner ◽

Human Hepatoma Cell ◽

Concentration Dependent Manner

In the present study the ability of supercritical carbon dioxide (SCO2) extracts of M. longifolia L. leaves to modulate low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression was evaluated in cultured human hepatoma cell lines Huh7 and HepG2. Two SCO2 extracts, one oil (ML-SCO2) and a semisolid (MW-SCO2), were subjected to detailed chemical characterization by mono- and bidimensional nuclear magnetic resonance (1D, 2D-NMR), gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography coupled with mass spectrometry (LC-MS). Chemical analysis revealed significant amounts of fatty acids, phytosterols and terpenoids. ML-SCO2 was able to induce LDLR expression at a dose of 60 µg/mL in HuH7 and HepG2 cell lines. Furthermore, ML-SCO2 reduced PCSK9 secretion in a concentration-dependent manner in both cell lines. Piperitone oxide, the most abundant compound of the volatile constituent of ML-SCO2 (27% w/w), was isolated and tested for the same targets, showing a very effective reduction of PCSK9 expression. The overall results revealed the opportunity to obtain a new nutraceutical ingredient with a high amount of phytosterols and terpenoids using the SCO2 extraction of M. longifolia L., a very well-known botanical species used as food. Furthermore, for the first time we report the high activity of piperitone oxide in the reduction of PCSK9 expression.

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Ventilation heterogeneity in children with severe asthma

European Journal of Pediatrics ◽

10.1007/s00431-021-04101-3 ◽

2021 ◽

Author(s):

Amy G. Nuttall ◽

Caroline S. Beardsmore ◽

Erol A. Gaillard

Keyword(s):

Severe Asthma ◽

Airway Disease ◽

Asthma Severity ◽

Small Airway ◽

Cross Sectional ◽

Lung Clearance ◽

Moderate Asthma ◽

Lung Clearance Index ◽

Children With Asthma ◽

Ventilation Heterogeneity

AbstractSmall airway disease, characterised by ventilation heterogeneity (VH), is present in a subgroup of patients with asthma. Ventilation heterogeneity can be measured using multiple breath washout testing. Few studies have been reported in children. We studied the relationship between VH, asthma severity, and spirometry in a cross-sectional observational cohort study involving children with stable mild-moderate and severe asthma by GINA classification and a group of healthy controls. Thirty-seven participants aged 5–16 years completed multiple breath nitrogen washout (MBNW) testing (seven controls, seven mild-moderate asthma, 23 severe asthma). The lung clearance index (LCI) was normal in control and mild-moderate asthmatics. LCI was abnormal in 5/23 (21%) of severe asthmatics. The LCI negatively correlated with FEV1z-score.Conclusion: VH is present in asthmatic children and appears to be more common in severe asthma. The LCI was significantly higher in the cohort of children with severe asthma, despite no difference in FEV1 between the groups. This supports previous evidence that LCI is a more sensitive marker of airway disease than FEV1. MBNW shows potential as a useful tool to assess children with severe asthma and may help inform clinical decisions. What is Known:• Increased ventilation heterogeneity is present in some children with asthma• Spirometry is not sensitive enough to detect small airway involvement in asthma What is New• Lung clearance index is abnormal in a significant subgroup of children with severe asthma but rarely in children with mild-moderate asthma• Our data suggests that LCI monitoring should be considered in children with severe asthma

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Using routinely collected primary care records to identify and investigate severe asthma: a scoping review

npj Primary Care Respiratory Medicine ◽

10.1038/s41533-020-00213-9 ◽

2021 ◽

Vol 31 (1) ◽

Author(s):

Jonathan Stewart ◽

Frank Kee ◽

Nigel Hart

Keyword(s):

Primary Care ◽

High Risk ◽

Severe Asthma ◽

Scoping Review ◽

Asthma Severity ◽

Data Sources ◽

Full Potential ◽

High Risk Disease ◽

Asthma Outcomes ◽

Disease Variant

AbstractShielding during the coronavirus pandemic has highlighted the potential of routinely collected primary care records to identify patients with ‘high-risk’ conditions, including severe asthma. We aimed to determine how previous studies have used primary care records to identify and investigate severe asthma and whether linkage to other data sources is required to fully investigate this ‘high-risk’ disease variant. A scoping review was conducted based on the Arksey and O’Malley framework. Twelve studies met all criteria for inclusion. We identified variation in how studies defined the background asthma cohort, asthma severity, control and clinical outcomes. Certain asthma outcomes could only be investigated through linkage to secondary care records. The ability of primary care records to represent the entire known asthma population is unique. However, a number of challenges need to be overcome if their full potential to accurately identify and investigate severe asthma is to be realised.

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Airway synthesis of 20-hydroxyeicosatetraenoic acid: metabolism by cyclooxygenase to a bronchodilator

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.276.2.l280 ◽

1999 ◽

Vol 276 (2) ◽

pp. L280-L288 ◽

Cited By ~ 15

Author(s):

Elizabeth R. Jacobs ◽

Richard M. Effros ◽

John R. Falck ◽

K. Malla Reddy ◽

William B. Campbell ◽

...

Keyword(s):

Mass Spectrometry ◽

Gas Chromatography ◽

Arachidonic Acid ◽

Airway Resistance ◽

Acid Metabolism ◽

Gas Chromatography Mass Spectrometry ◽

Dependent Manner ◽

Hydroxyeicosatetraenoic Acid ◽

Polar Metabolites ◽

H 20

Rabbit airway tissue is a particularly rich source of cytochrome P-4504A protein, but very little information regarding the effect(s) of 20-hydroxyeicosatetraenoic acid (20-HETE) on bronchial tone is available. Our studies examined the response of rabbit bronchial rings to 20-HETE and the metabolism of arachidonic acid and 20-HETE from airway microsomes. 20-HETE (10−8 to 10−6 M) produced a concentration-dependent relaxation of bronchial rings precontracted with KCl or histamine but not with carbachol. Relaxation to 20-HETE was blocked by indomethacin or epithelium removal, consistent with the conversion of 20-HETE to a bronchial relaxant by epithelial cyclooxygenase. A cyclooxygenase product of 20-HETE also elicited relaxation of bronchial rings. [14C]arachidonic acid was converted by airway microsomes to products that comigrated with authentic 20-HETE (confirmed by gas chromatography-mass spectrometry as 19- and 20-HETE) and to unidentified polar metabolites. [3H]20-HETE was metabolized to indomethacin-inhibitable products. These data suggest that 20-HETE is an endogenous product of rabbit airway tissue and may modulate airway resistance in a cyclooxygenase-dependent manner.

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Correlation Between Aeroallergen Sensitization and Pediatric Asthma Severity - Data From the Severe Asthma Research Program (SARP)

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2012.12.868 ◽

2013 ◽

Vol 131 (2) ◽

pp. AB52

Author(s):

Marc D. Ikeda ◽

Merritt L. Fajt ◽

Shean Aujla ◽

Paul Rebovich ◽

Sally E. Wenzel

Keyword(s):

Severe Asthma ◽

Research Program ◽

Pediatric Asthma ◽

Asthma Severity

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Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

Gut ◽

10.1136/gut.45.3.382 ◽

1999 ◽

Vol 45 (3) ◽

pp. 382-388 ◽

Cited By ~ 84

Author(s):

S D Hearing ◽

M Norman ◽

C S J Probert ◽

N Haslam ◽

C M Dayan

Keyword(s):

Ulcerative Colitis ◽

T Lymphocytes ◽

Disease Severity ◽

T Lymphocyte ◽

Peripheral Blood ◽

Steroid Treatment ◽

Steroid Resistance ◽

Severe Ulcerative Colitis ◽

Steroid Sensitivity

BACKGROUNDUp to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown.AIMTo investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes.METHODSEighteen patients with severe UC were studied. After seven days’ treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured.RESULTSIn vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups.CONCLUSIONSResults suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

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