Making human immune systems more interpretable through systems immunology.

The human immune system is a distributed system of specialized cell populations with unique functions that collectively give rise to immune responses to infections and during immune-mediated diseases. Cell composition, plasma proteins, and functional responses vary among individuals, making the system difficult to interpret, but this variation is nonrandom. With careful analyses using novel experimental and computational tools, human immune system composition and function carry interpretable information. Here, we propose that systems-level analyses offer an opportunity to make human immune responses more interpretable in the future, and we discuss herein important considerations and lessons learned to this end. Predictable human immunology holds implications for better diagnostic and curative precision in patients with infectious and immune-associated diseases.

Rhinovirus-induced wheeze was associated with asthma development in predisposed children.

AIM: This study explored whether early-life factors, such as rhinovirus-induced wheeze and allergic sensitisation, were related to asthma at 11 years of age. METHODS: We focused on 107 children aged 6-48 months, who attended the paediatric emergency department at Astrid Lindgren's Children's Hospital in Stockholm, Sweden, with acute wheeze in 2008-2012. They also attended follow-up visits at 11 years of age and were compared with 46 age-matched healthy controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with logistic regression. RESULTS: We found that 62.6% of the acute wheeze cases had asthma at 11 years of age. Rhinoviruses at inclusion were the only common airway viruses associated with an increased asthma risk (OR 2.4, 95% CI 1.02-5.6). Other increased risks were parental heredity for asthma and/or allergies (adjusted OR 3.4, 95% CI 1.1-9.9) and allergic sensitisation at 2 years of age (adjusted OR 3.0, 95% CI 1.02-8.7). The highest prevalence of asthma was when children had both rhinovirus-induced wheeze at inclusion and allergic sensitisation at 7 years of age. CONCLUSION: Our findings highlight the importance of hereditary factors and allergic sensitisation on the development of asthma and suggest that rhinoviruses are associated with asthma development in predisposed children.

Bacterioplankton communities reveal horizontal and vertical influence of an Island Mass Effect.

Coral reefs are highly productive ecosystems with distinct biogeochemistry and biology nestled within unproductive oligotrophic gyres. Coral reef islands have often been associated with a nearshore enhancement in phytoplankton, a phenomenon known as the Island Mass Effect (IME). Despite being documented more than 60 years ago, much remains unknown about the extent and drivers of IMEs. Here we utilized 16S rRNA gene metabarcoding as a biological tracer to elucidate horizontal and vertical influence of an IME around the islands of Mo'orea and Tahiti, French Polynesia. We show that those nearshore oceanic stations with elevated chlorophyll a included bacterioplankton found in high abundance in the reef environment, suggesting advection of reef water is the source of altered nearshore biogeochemistry. We also observed communities in the nearshore deep chlorophyll maximum (DCM) with enhanced abundances of upper euphotic bacterioplankton that correlated with intrusions of low-density, O2 rich water, suggesting island influence extends into the DCM.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.

RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-ß and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation.

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. RESULTS: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring.

Multimorbidity in asthma, association with allergy, inflammatory markers and symptom burden, results from the Swedish GA2 LEN study.

BACKGROUND: Asthma is common worldwide and a large part of subjects with asthma have concomitant allergic multimorbidity in the form of rhinitis and/or eczema. OBJECTIVE: The aim of this study is to investigate whether the presence of allergic multimorbidity in asthma relates to allergic sensitization, allergic and respiratory symptoms, quality of life, inflammatory markers, lung function, use of medication and background factors. METHODS: A total of 437 asthmatics from the (GA2 LEN) cross-sectional survey in Sweden were grouped depending on the presence of rhinitis and/or eczema. The impact of allergic multimorbidity was assessed in terms of allergic sensitization, allergic and respiratory symptoms, quality of life, type-2 inflammatory markers (exhaled nitric oxide, eosinophil activation markers, periostin), lung function, use of medication and background factors. RESULTS: Subjects with asthma, rhinitis and eczema were more likely to be sensitized to seasonal allergens (67% vs 32%, P < .001), food allergens (54% vs 18%, P < .001) and to have a higher degree of sensitization than subjects with only asthma (23% vs 10%, P < .001). Subjects with allergic multimorbidity more often had allergic reactions to food (28% vs 10%, P = .002), more respiratory symptoms and anxiety/depression (40% vs, 14%, P < .001) than subjects with only asthma, despite having similar levels of type 2 inflammatory markers. Individuals with allergic multimorbidity were more likely to be diagnosed with asthma before the age of 12 (48% vs 27%, P = .016) and to have maternal heredity for allergy (53% vs 33%, P = .011) than subjects with only asthma. CONCLUSION AND CLINICAL RELEVANCE: Asthmatics with allergic multimorbidity are more likely to be sensitized to seasonal aeroallergens, food allergens and they have a higher degree of sensitization compared with those with only asthma. Allergic multimorbidity is associated with respiratory and allergy symptoms, anxiety and/or depression.

IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways.

BACKGROUND: Specific inflammatory pathways are indicated to contribute to severe asthma, but their individual involvement in the development of airway hyperresponsiveness remains unexplored. OBJECTIVE: This experimental study in human small bronchi aimed to provide insight into which of the type 2 and type 17 cytokines cause hyperresponsiveness of airway smooth muscle. METHODS: Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells were treated for 2 and 1 day(s), respectively, with 100 ng/mL of IL-4, IL-5, IL-13, or IL-17A, and contractile responses, Ca2+ mobilization, and receptor expression were assessed. RESULTS: Treatment with IL-13 increased the potency of histamine, carbachol, and leukotriene D4 as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In human airway smooth muscle cells, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca2+ mobilization that was accompanied with increased mRNA expression of histamine H1 and cysteinyl leukotriene CysLT1 receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated upregulation of H1 and CysLT1 receptors, without showing an alteration of muscarinic M3 receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca2+ mobilization, or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab prevented the effects of both IL-13 and IL-4 in human bronchi and human airway smooth muscle cells. CONCLUSIONS: The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for the treatment of airway hyperresponsiveness in asthma.

Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.

BACKGROUND: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1ß, IL-8, and IL-1ß. CONCLUSIONS: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Elevated pCO2 alters marine heterotrophic bacterial community composition and metabolic potential in response to a pulse of phytoplankton organic matter.

Factors that affect the respiration of organic carbon by marine bacteria can alter the extent to which the oceans act as a sink of atmospheric carbon dioxide. We designed seawater dilution experiments to assess the effect of pCO2 enrichment on heterotrophic bacterial community composition and metabolic potential in response to a pulse of phytoplankton-derived organic carbon. Experiments included treatments of elevated (1000 p.p.m.) and low (250 p.p.m.) pCO2 amended with 10 µmol L-1 dissolved organic carbon from Emiliana huxleyi lysates, and were conducted using surface-seawater collected from the South Pacific Subtropical Gyre. To assess differences in community composition and metabolic potential, shotgun metagenomic libraries were sequenced from low and elevated pCO2 treatments collected at the start of the experiment and following exponential growth. Our results indicate bacterial communities changed markedly in response to the organic matter pulse over time and were significantly affected by pCO2 enrichment. Elevated pCO2 also had disproportionate effects on the abundance of sequences related to proton pumps, carbohydrate metabolism, modifications of the phospholipid bilayer, resistance to toxic compounds and conjugative transfer. These results contribute to a growing understanding of the effects of elevated pCO2 on bacteria-mediated carbon cycling during phytoplankton bloom conditions in the marine environment.

Fixed airflow obstruction relates to eosinophil activation in asthmatics.

BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO. OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics. METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN). RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 µg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO. CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

A longitudinal assessment of circulating YKL-40 levels in preschool children with wheeze.

BACKGROUND: The chitinase-like protein YKL-40 (CHI3L1) is elevated in the circulation of adults and schoolchildren with chronic severe asthma. It is unknown whether YKL-40 is altered in younger, preschool children with wheeze, acute or chronic. We therefore examined YKL-40 in preschool children during an acute episode of wheeze and during remission, in comparison with healthy controls. METHODS: Blood was obtained from 128 children (aged 6-44 months) at the emergency department during an acute episode of wheeze, and at two follow-up visits (approximately 3 months and 1 year later), as well as from 100 age-matched healthy controls on one occasion. Plasma YKL-40 levels were examined in relation to CHI3L1 rs4950928 genotype and clinical characteristics including Asthma Predictive Index, medication use, time spent with respiratory symptoms, atopic status, and blood leukocytes. RESULTS: Children with wheeze had higher median YKL-40 levels at the acute visit (14.7 (11.5-22.6) ng/ml, p < 0.001) and 3-month follow-up (15.9 (11.5-20.2), p < 0.001) compared to the 1-year follow-up (11.9 (9.5-17.3)). YKL-40 levels in healthy controls (13.6 (11.0-17.0)) tended to be lower than those during acute wheeze (p = 0.07) and 3-month follow-up (p = 0.04), but were no different at the 1-year follow-up. CHI3L1 rs4950928 affected YKL-40 in all subjects, with highest levels present in those with the CC genotype (p < 0.001). Genotype frequency was similar in the two subject groups. YKL-40 levels showed a positive correlation with blood neutrophil counts but no consistent relationships with clinical characteristics of relevance to continuous wheeze. CONCLUSION: YKL-40 levels were elevated during acute wheeze in preschool children, a finding which may be related to current neutrophilic inflammation, but YKL-40 was not associated with characteristics of persistent wheeze in this young cohort.

Increased YKL-40 and Chitotriosidase in Asthma and Chronic Obstructive Pulmonary Disease.

RATIONALE: Serum chitinases may be novel biomarkers of airway inflammation and remodeling, but less is known about factors regulating their levels. OBJECTIVES: To examine serum chitotriosidase activity and YKL-40 levels in patients with asthma and chronic obstructive pulmonary disease (COPD) and evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations, and allergen exposure. METHODS: Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, as well as the CHIT1 rs3831317 and CHI3L1 rs4950928 genotypes, were examined in subsets of patients with mild to moderate asthma (n = 76), severe asthma (n = 93), and COPD (n = 64) taking part in the European multicenter BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) study. Blood was obtained at baseline, before and after a 2-week oral steroid intervention, up to six times during a 1-year period, and during exacerbations. Baseline chitinase levels were also measured in 72 healthy control subjects. The effect of allergen inhalation on blood and sputum YKL-40 levels was measured in two separate groups of patients with mild atopic asthma; one group underwent repeated low-dose allergen challenge (n = 15), and the other underwent high-dose allergen challenge (n = 16). MEASUREMENTS AND MAIN RESULTS: Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and those with COPD compared with healthy control subjects. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, but associations with disease remained following adjustment for these factors. Correlations were observed with lung function but not with other biomarkers, including exhaled nitric oxide, blood eosinophils, periostin, and IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels. CONCLUSIONS: YKL-40 and chitotriosidase are increased in asthma and more so in COPD. The data in the present study support these substances as being relatively steroid-insensitive, non-T-helper cell type 2-type biomarkers distinctly related to chronic inflammatory disease processes.

Predicting asthma morbidity in children using proposed markers of Th2-type inflammation.

BACKGROUND: Assessment of inflammation is becoming a common practice in the clinical work-up of children with persistent asthma. Biomarkers of Th2-mediated inflammation include blood eosinophils (B-Eos), exhaled nitric oxide (FeNO), total serum IgE (S-IgE), and serum periostin. The aim of this study was to investigate the associations between asthma morbidity and increased levels of these biomarkers in pediatric asthma. METHODS: School-age children (n = 96) with various manifestations of persistent asthma were included in this nationwide Swedish study. The protocol included the asthma control test, Juniper's quality of life questionnaire (QoL), assessment of pulmonary function, bronchial hyperresponsiveness, height-adjusted FeNO, blood sampling for S-IgE, B-Eos, and periostin, and high-resolution computed tomography (HRCT) of the lungs. RESULTS: Children with both high levels of height-adjusted FeNO and B-Eos were younger (p = 0.001), had more often severe asthma (p = 0.015), were more allergic (p < 0.001), had a reduced asthma control (p = 0.035), reduced QoL (p = 0.035), more exacerbations (p = 0.004), reduced FEV1/FVC (p = 0.001), and increased bronchial hyperresponsiveness (p < 0.001) as well as greater bronchial wall thickening on HRCT (p = 0.022) compared to those with low levels of both biomarkers. Grouping children according to high and low serum periostin levels did not relate to differences in clinical characteristics and biomarkers. CONCLUSIONS: Assessment of both local and systemic Th2-mediated inflammation by the analysis of easily attainable biomarkers such as exhaled NO and blood eosinophils has a high predictive value for the identification of children with the highest asthma morbidity. Adjusting FeNO values according to the individual child's height increases the clinical usefulness of this biomarker.

On the biosynthesis of 15-HETE and eoxin C4 by human airway epithelial cells.

Several lines of evidence indicate that 15-lipoxygenase type 1 (15-LO-1) plays a pathophysiological role in asthma. The aim for this study was to investigate the 15-LO-1 expression and activity in primary human airway epithelial cells cultivated on micro-porous filters at air-liquid interface. Incubation of human airway epithelial cells with arachidonic acid led to the formation of 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and exposing the cells to bacteria or physical injury markedly increased their production of 15-HETE. The cells were also found to convert arachidonic acid to eoxin C4 (EXC4). Subcellular fractionation revealed that the conversion of EXA4 to EXC4 was catalyzed by a soluble glutathione transferase (GST). The GST P1-1 enzyme was found to possess the highest activity of the investigated soluble GSTs. Following IL-4 treatment of airway epithelial cells, microarray analysis confirmed high expression of 15-LO-1 and GST P1-1, and immunohistochemical staining of bronchial biopsies revealed co-localization of 15-LO-1 and GST P1-1 in airway epithelial cells. These results indicate that respiratory infection and cell injury may activate the 15-LO pathway in airway epithelial cells. Furthermore, we also demonstrate that airway epithelial cells have the capacity to produce EXC4.

Effects of selective COX-2 inhibition on allergen-induced bronchoconstriction and airway inflammation in asthma.

BACKGROUND: Prostaglandins that constrict and relax airways are synthesized in reactions catalyzed by either COX-1 or COX-2. It is not known whether selective inhibition of COX-2 makes asthmatic responses better or worse. OBJECTIVE: To determine the effects of the selective COX-2 inhibitor, etoricoxib, on allergen-induced bronchoconstriction in asthmatic subjects. METHODS: Sixteen subjects with mild atopic asthma underwent rising dose inhalation challenges with allergen or methacholine to determine PD20 FEV1 during a control study period or after 10 to 13 days of treatment with etoricoxib (90 mg once daily). The order of study periods was randomized with at least 2-week washout periods. Induced sputum cells and fractional exhaled nitric oxide levels were used to assess airway inflammation and blood assays for COX-1 and COX-2 activity to assess enzyme inhibition. Urinary excretion of lipids was used to assess prostaglandin biosynthesis. RESULTS: Etoricoxib did not change baseline lung function, nor airway responsiveness to allergen or to methacholine. Neither were the allergen-induced increase in sputum eosinophils and fractional exhaled nitric oxide levels affected by treatment. The biochemical effectiveness of the treatment was established both in the blood assays and by the distinct inhibitory effect of etoricoxib on urinary excretion of tetranor-prostaglandin E2 (P < .001). CONCLUSIONS: This first study of COX-2 inhibition in provoked asthma found no negative effects of etoricoxib on allergen-induced airflow obstruction and sputum eosinophils, basal lung function, or methacholine responsiveness. The study suggests that short-term use of COX-2 inhibitors is safe in subjects with asthma.

The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma.

BACKGROUND: Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling. OBJECTIVES: To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling. METHODS: The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928). RESULTS: Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma. CONCLUSIONS: YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype.

Cognitive and mental health trajectories of COVID-19: Role of hospitalisation and long-COVID symptoms.

BACKGROUND: There is considerable evidence of cognitive impairment post COVID-19, especially in individuals with long-COVID symptoms, but limited research objectively evaluating whether such impairment attenuates or resolves over time, especially in young and middle-aged adults. METHODS: Follow-up assessments (T2) of cognitive function (processing speed, attention, working memory, executive function, memory) and mental health were conducted in 138 adults (18-69 years) who had been assessed 6 months earlier (T1). Of these, 88 had a confirmed history of COVID-19 at T1 assessment (≥20 days post-diagnosis) and were also followed-up on COVID-19-related symptoms (acute and long-COVID); 50 adults had no known COVID-19 history at any point up to their T2 assessment. RESULTS: From T1 to T2, a trend-level improvement occurred in intra-individual variability in processing speed in the COVID, relative to the non-COVID group. However, longer response/task completion times persisted in participants with COVID-19-related hospitalisation relative to those without COVID-19-related hospitalisation and non-COVID controls. There was a significant reduction in long-COVID symptom load, which correlated with improved executive function in non-hospitalised COVID-19 participants. The COVID group continued to self-report poorer mental health, irrespective of hospitalisation history, relative to non-COVID group. CONCLUSIONS: Although some cognitive improvement has occurred over a 6-month period in young and middle-aged COVID-19 survivors, cognitive impairment persists in those with a history of COVID-19-related hospitalisation and/or long-COVID symptoms. Continuous follow-up assessments are required to determine whether cognitive function improves or possibly worsens, over time in hospitalised and long-COVID participants.