Prediction of adult asthma risk in early childhood using novel adult asthma predictive risk scores.

BACKGROUND: Numerous risk scores have been developed to predict childhood asthma. However, they may not predict asthma beyond childhood. We aim to create childhood risk scores that predict development and persistence of asthma up to young adult life. METHODS: The Isle of Wight Birth Cohort (n = 1456) was prospectively assessed up to 26 years of age. Asthma predictive scores were developed based on factors during the first 4 years, using logistic regression and tested for sensitivity, specificity and area under the curve (AUC) for prediction of asthma at (i) 18 and (ii) 26 years, and persistent asthma (PA) (iii) at 10 and 18 years, and (iv) at 10, 18 and 26 years. Models were internally and externally validated. RESULTS: Four models were generated for prediction of each asthma outcome. ASthma PredIctive Risk scorE (ASPIRE)-1: a 2-factor model (recurrent wheeze [RW] and positive skin prick test [+SPT] at 4 years) for asthma at 18 years (sensitivity: 0.49, specificity: 0.80, AUC: 0.65). ASPIRE-2: a 3-factor model (RW, +SPT and maternal rhinitis) for asthma at 26 years (sensitivity: 0.60, specificity: 0.79, AUC: 0.73). ASPIRE-3: a 3-factor model (RW, +SPT and eczema at 4 years) for PA-18 (sensitivity: 0.63, specificity: 0.87, AUC: 0.77). ASPIRE-4: a 3-factor model (RW, +SPT at 4 years and recurrent chest infection at 2 years) for PA-26 (sensitivity: 0.68, specificity: 0.87, AUC: 0.80). ASPIRE-1 and ASPIRE-3 scores were replicated externally. Further assessments indicated that ASPIRE-1 can be used in place of ASPIRE-2-4 with same predictive accuracy. CONCLUSION: ASPIRE predicts persistent asthma up to young adult life.

Clinical features and later prognosis of replicable early-life wheeze clusters from two birth cohorts 12 years apart.

BACKGROUND: Clustering techniques can define the heterogeneity of asthma and wheezing. Defining early-life wheezing clusters and associated asthma risk could potentially inform patient management strategies. Clustering models that yield replicable cluster groups will have greater validity and clinical utility. This study sought to identify early-life wheezing clusters that are translatable into clinical practice and assess their stability over time in two whole-population birth cohorts established a decade apart from the same geographical location. METHODS: Nonparametric K-means cluster analysis was performed separately on two birth cohorts from the Isle of Wight, UK; the Isle of Wight Birth Cohort (IOWBC) and Food Allergy and Intolerance Research Cohort (FAIR), using clinically defining variables in wheezing subjects in the first 3-4 years. Associations of resulting clusters with potential early-life risk factors and 10-year asthma outcomes were further assessed. RESULTS: Five clusters were identified in both cohorts: (1) infantile-onset-transient-non-atopic-wheeze, (2) infantile-onset-persistent-non-atopic-wheeze, (3) infantile-onset-atopic-wheeze, (4) early-childhood-onset-non-atopic-wheeze, and (5) early-childhood-onset-atopic-wheeze. Two atopic wheezing clusters (3 and 5) were associated with greatest early-life wheeze frequency, highest wheeze persistence, and asthma prevalence at 10 years. Cluster 1 was commonest but had lowest early-life wheeze frequency and asthma prevalence at 10 years. Cluster 2, characterized by limited atopy but recurrent infantile respiratory infections and ongoing early-life wheezing, had high 10-year asthma prevalence only in IOWBC. CONCLUSIONS: Early-life wheeze comprises several disease clusters (two more severe and three mild-moderate) with differing relationships to later childhood asthma, which can be replicated over time supporting their potential validity and clinical utility.

Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma.

BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. METHODS: Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi-infected monocyte-derived macrophages to identify transcriptomic networks associated with NTHi infection. RESULTS: NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p = .0436) and higher sputum neutrophil proportion (67% vs 25%, p = .0462). WGCNA identified a transcriptomic network of immune-related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p < .05). Macrophage network genes SGPP2 (p = .0221), IL1B (p = .0014) and GBP1 (p = .0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration (IL1B; rho = 0.41, p = .041) and lower prebronchodilator FEV1/FVC% (GBP1; rho = -0.43, p = .046 and IL1B; rho = -0.42, p = .055). CONCLUSIONS: NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes.

Rumen and fecal microbial profiles in cattle fed high lignin diets using metagenome analysis.

Coconut coir (a lignin-rich, organic material) is widely used for its commercial and economic benefits. In this study, crossbred (exotic) and Kankrej (indigenous) breeds of cattle were fed diets containing 7 or 14% coconut coir. Metagenomic analyses (16S rRNA gene amplicon and shotgun sequencing) were used to characterize the microbial community in the rumen and fecal samples along with their functional capabilities. Both amplicon and shotgun analyses revealed the predominance of bacterial phyla, Bacteroidetes, Firmicutes, Actinobacteria and Fibrobacter in ruminal liquid, ruminal solid and fecal samples. 16S rRNA gene amplicon sequencing revealed a total of 18 different bacterial taxa were found to be enriched exclusively in the animals fed with 14% coir. The shotgun analysis revealed abundance of bacterial genera, Fibrobacter, Clostridium, Prevotella, Butyrivibrio, and Ruminococcus in both liquid and solid fractions of ruminal contents, while in the fecal sample, Bacteroides, Alistipes, Plaudibacter, Parabacteroides, Porphyromonas, and Victivallis and archaeal genus, Methanocorpusculum were abundant. The functional analysis based on dbCAN database suggested that among the Glycoside hydrolase family, genes that encode oligosaccharide degrading enzymes, GH3, GH13 (p-value < 0.05), and GH43 were abundant in the feces. In ruminal solid, cellulase encoding the GH5 family was abundant. Also, lignocellulosic binding modules encoded by the CBM family, including cellulose (CBM3) and hemicellulose binding modules (CBM32 and CBM67) were abundant. Thus, the study indicated the enrichment of lignocellulosic enzymes in ruminal contents in response to feeding the coconut coir, which could be mined for potential biofuel production and other biotechnological applications.

Real-world Omalizumab and Mepolizumab treated difficult asthma phenotypes and their clinical outcomes.

BACKGROUND: Omalizumab and Mepolizumab are biologic drugs with proven efficacy in clinical trials. However, a better understanding of their real-world effectiveness in severe asthma management is needed. OBJECTIVES: To better understand the real-world effectiveness of Omalizumab and Mepolizumab, elucidate the clinical phenotypes of patients treated with these drugs, identify baseline characteristics associated with biologic response and assess the spectrum of responses to these medications. METHODS: Using real-world clinical data, we retrospectively phenotyped biologic naïve patients from the Wessex AsThma CoHort of difficult asthma (N = 478) commenced on Omalizumab (N = 105) or Mepolizumab (N = 62) compared to severe asthma patients not receiving biologics (SNB, N = 178). We also assessed multiple clinical endpoints and identified features associated with response. RESULTS: Compared to SNB, Omalizumab patients were younger, diagnosed with asthma earlier, and more likely to have rhinitis. Conversely, compared to SNB, Mepolizumab patients were predominantly older males, diagnosed with asthma later, and more likely to have nasal polyposis but less dysfunctional breathing. Both treatments reduced exacerbations, Acute Healthcare Encounters [AHE] (emergency department or hospital admissions), maintenance oral corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6) scores. Omalizumab response was independently associated with more baseline exacerbations (p = .024) but fewer AHE (p = .050) and absence of anxiety (p = .008). Lower baseline ACQ6 was independently associated with Mepolizumab response (p = .007). A composite group of non-responders demonstrated significantly more psychopathologies and worse baseline subjective disease compared to responder groups. CONCLUSIONS AND CLINICAL RELEVANCE: In a difficult asthma cohort, Omalizumab and Mepolizumab were used in distinct clinical phenotypes but were both multidimensionally efficacious. Certain baseline clinical characteristics were associated with poorer biologic responses, such as psychological co-morbidity, which may assist clinicians in biologic selection. These characteristics also emphasize the need for comprehensive approaches to support these patients.

Integrated hydrochemical and ERT approach for seawater intrusion study in a coastal aquifer: a case study from Jafrabad Town, Gujarat State, India.

Hydrochemical and geophysical approach has been adopted to evaluate the seawater intrusion (SWI) in coastal aquifers of Jafrabad Town, Gujarat State, India. Electrical Resistivity Tomography (no. 9) was carried out with spread length of 160-400 m which provided penetration depth of about 23 to 76 m. Very low resistivity zone (0-3 Ω-m range) has been observed in the ERT profiles conducted in the study area. Parameters, namely, TDS, Na, and Cl, have been considered to examine the signature of SWI. The results obtained from ionic ratios, Piper plot, and Chaddha's diagram also confirm the influence of saline water within aquifer. The very low resistivity signature is correlated with the high TDS values in the nearby wells. SWI has been observed up to 9 km from the coast, and it is observed at a depth of 20-22 m in the existing limestone mines near the coast.

MetaRNAseq analysis of surti buffalo rumen content reveals that transcriptionally active microorganisms need not be abundant.

The present study describes rumen microbiota composition and their functional profiles in Indian Surti buffaloes by metagenomic (MG) and metatranscriptomic (MT) approaches. The study compares samples from buffaloes fed three different proportion of roughages; green and dry type of roughage; and different rumen liquor fractions. Irrespective of sample, Bacteroidetes and Firmicutes were the most predominant bacterial phyla, followed by Proteobacteria, Fibrobacteres and Actinobacteria while, Prevotella, Bacteroides, Ruminococcus and Clostridium were the most abundant genera. Different proportions of taxa were observed in both MG and MT approaches indicating the differences in organisms present and organisms active in the rumen. Higher proportions of fungal taxa were observed in MT while important organisms like Fibrobacter and Butyrivibrio and abundant organisms like Bacteroides and Prevotella were underrepresented in MT data. Functionally, higher proportions of genes involved in Carbohydrate metabolism, Amino acid metabolism and Translation were observed in both data. Genes involved in Metabolism were observed to be underrepresented in MT data while, those involved in Genetic information processing were overrepresented in MT data. Further, genes involved in Carbohydrate metabolism were overexpressed compared to genes involved in Amino acid metabolism in MT data compared to MG data which had higher proportion of genes involved in Amino acid metabolism than Carbohydrate metabolism. In all significant differences were observed between both approaches, different fractions of rumen liquor (liquid and solid) and different proportions of roughage in diet.

Metagenomic characterisation of ruminal bacterial diversity in buffaloes from birth to adulthood using 16S rRNA gene amplicon sequencing.

Microbial colonisation in the forestomach of a ruminant is one of the most crucial factors in determining many of its physiological developments and digestive capabilities. The present study attempts to identify establishment pattern of microbes in relation to food, age and rumen development in the buffalo calves at every fortnight interval from birth to 6 months of age, followed by every month till animals became 1 year of age. Diversity study based on 16S rRNA gene sequencing identified rapidly changing bacterial population during initial 60 days of life, which got assemblage as rumen became physiologically mature with increasing age of animals. A lactate fermenting aerobic to facultative anaerobic genera found during initial 30 days of life were expeditiously replaced by strict anaerobic cellulolytic bacterial population with increasing age. The study confirms that initial colonisation mainly depends on the oral cavity and skin of the mother, followed by the surrounding environment and feed offered, which is reversed in order once animal gets older. Some of the well-described genera based on culture-dependent studies like Ruminococcus spp. were found to be in lesser proportion suggesting an additional role of other microbes or niche in cellulose degradation. We report the presence of Porphyromonas spp. and Mannheimia glucosidal for the first time in bovine infants.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Distinctive lung function trajectories from age 10 to 26 years in men and women and associated early life risk factors - a birth cohort study.

Pre-bronchodilator lung function including forced vital capacity (FVC), forced expiratory flow in 1 second (FEV1), their ratio (FEV1/FVC), and forced expiratory flow 25-75% (FEF25-75) measured at age 10, 18, and 26 years in the Isle of Wight birth cohort was analyzed for developmental patterns (trajectories). Early life risk factors before the age of 10 years were assessed for the trajectories. METHOD: Members of the birth cohort (1989/90) were followed at age 1, 2, 4, 10, 18, and 26 years. Allergic sensitization and questionnaire data were collected. Spirometry tests were performed and evaluated according to the American Thoracic Society (ATS) criteria at 10, 18, and 26 years. To identify developmental trajectories for FVC, FEV1, FEV1/FVC, and FEF25-75 from 10 to 26 years, a finite mixture model was applied to the longitudinal lung function data, separately for males and females. Associations of early life factors with the respective lung function trajectories were assessed using log-linear and logistic regression analyses. RESULTS: Both high and low lung function trajectories were observed in men and women. FVC continued to grow beyond 18 years in men and women, whereas FEV1 peaked at age 18 years in female trajectories and in one male trajectory. For the FEV1/FVC ratios and FEF25-75 most trajectories appeared highest at age 18 and declined thereafter. However, the low FEV1/FVC trajectory in both sexes showed an early decline at 10 years. Lower birth weight was linked with lower lung function trajectories in males and females. Eczema in the first year of life was a risk factor for later lung function deficits in females, whereas the occurrence of asthma at 4 years of age was a risk factor for later lung function deficits in males. A positive skin prick test at age four was a risk for the low FEV1 trajectory in females and for the low FEV1/FVC trajectory in males. CONCLUSION: Men and women showed distinctive lung function trajectories and associated risk factors. Lower lung function trajectories can be explained by not achieving maximally attainable function at age 18 years and by a function decline from 18 to 26 years.

Protocol for the Wessex AsThma CoHort of difficult asthma (WATCH): a pragmatic real-life longitudinal study of difficult asthma in the clinic.

BACKGROUND: Asthma is now widely recognised to be a heterogeneous disease. The last two decades have seen the identification of a number of biological targets and development of various novel therapies. Despite this, asthma still represents a significant health and economic burden worldwide. Why some individuals should continue to suffer remains unclear. METHODS: The Wessex Asthma Cohort of Difficult Asthma (WATCH) is an ongoing 'real-life', prospective study of patients in the University Hospital Southampton Foundation Trust (UHSFT) Difficult Asthma service. Research data capture is aligned with the extensive clinical characterisation required of a commissioned National Health Service (NHS) Specialist Centre for Severe Asthma. Data acquisition includes detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, radiological imaging (in a small subset) and collection of biological samples (blood, urine and sputum). Prospective data are captured in parallel to clinical follow up appointments, with data entered into a bespoke database. DISCUSSION: The pragmatic ongoing nature of the WATCH study allows comprehensive assessment of the real world clinical spectrum seen in a Specialist Asthma Centre and allows a longitudinal perspective of deeply phenotyped patients. It is anticipated that the WATCH cohort would act as a vehicle for potential collaborative asthma studies and will build upon our understanding of mechanisms underlying difficult asthma.

Transcriptomic profiling of developing fiber in levant cotton (Gossypium herbaceum L.).

Cotton (Gossypium spp.) is an imperative economic crop of the globe due to its natural textile fiber. Molecular mechanisms of fiber development have been greatly revealed in allotetraploid cotton but remained unexplored in Gossypium herbaceum. G. herbaceum can withstand the rigors of nature like drought and pests but produce coarse lint. This undesirable characteristic strongly needs the knowledge of fiber development at molecular basis. The present study reported the transcriptome sequence of the developing fiber of G. herbaceum on pyrosequencing and its analysis. About 1.38 million raw and 1.12 million quality trimmed reads were obtained followed by de novo assembly-generated 20,125 unigenes containing 14,882 coding sequences (CDs). BLASTx-based test of homology indicated that A1-derived transcripts shared a high similarity with Gossypium arboreum (A2). Functional annotation of the CDs using the UniProt categorized them into biological processes, cellular components, and molecular function, COG classification showed that a large number of CDs have significant homology in COG database (6215 CDs), and mapping of CDs with Kyoto Encyclopedia of Genes and Genomes (KEGG) database generated 200 pathways ultimately showing predominant engagement in the fiber development process. Transcription factors were predicted by comparison with Plant Transcription Factor Database, and their differential expression between stages exposed their important regulatory role in fiber development. Differential expression analysis based on reads per kilobase of transcript per million mapped reads (RPKM) value revealed activities of specific gene related to carbohydrate and lipid synthesis, carbon metabolism, energy metabolism, signal transduction, etc., at four stages of fiber development, and was validated by qPCR. Overall, this study will help as a valuable foundation for diploid cotton fiber improvement.

Leptin receptor gene polymorphisms and sex modify the association between acetaminophen use and asthma among young adults: results from two observational studies.

BACKGROUND: Epidemiologic studies have demonstrated associations between acetaminophen use and asthma. This investigation sought to determine whether sex modifies the acetaminophen-asthma association and whether leptin (LEP) and leptin receptor (LEPR) gene polymorphisms modulate the sex-specific associations. METHODS: Data from the Isle of Wight birth cohort (IOW; n = 1456, aged 18 years) and Kuwait University Allergy (KUA; n = 1154, aged 18-26 years) studies were analyzed. Acetaminophen use and current asthma were self-reported. Genotype information for eighteen polymorphisms in LEP and LEPR genes were available in the IOW study. Associations between acetaminophen use and asthma were stratified by sex and genotype. Poisson regression models with robust variance estimation were evaluated to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). RESULTS: Acetaminophen use was dose-dependently associated with an increased prevalence of current asthma in the IOW and KUA studies. In both studies, sex-stratified analysis showed that acetaminophen use was associated with asthma among males, but not in females (Pinteraction <  0.05). Moreover, a sex- and genotype-stratified analysis of the IOW data indicated that acetaminophen was associated with asthma to a similar extent among males and females carrying two common alleles of LEPR polymorphisms. In contrast, among those carrying at least one copy of the minor allele of LEPR polymorphisms, the magnitude of association between acetaminophen use and asthma was pronounced among males (aPR = 6.83, 95% CI: 2.87-16.24), but not among females (aPR = 1.22, 95% CI: 0.61-2.45). CONCLUSIONS: The identified sex-related effect modification of the acetaminophen-asthma association varied across LEPR genotypes, indicating that the sex-specific association was confined to individuals with certain genetic susceptibility. If the acetaminophen-asthma association is causal, then our findings will aid susceptibility-based stratification of at-risk individuals and augment preventive public health efforts.

Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Functional gene profiling through metaRNAseq approach reveals diet-dependent variation in rumen microbiota of buffalo (Bubalus bubalis).

Recent advances in next generation sequencing technology have enabled analysis of complex microbial community from genome to transcriptome level. In the present study, metatranscriptomic approach was applied to elucidate functionally active bacteria and their biological processes in rumen of buffalo (Bubalus bubalis) adapted to different dietary treatments. Buffaloes were adapted to a diet containing 50:50, 75:25 and 100:0 forage to concentrate ratio, each for 6 weeks, before ruminal content sample collection. Metatranscriptomes from rumen fiber adherent and fiber-free active bacteria were sequenced using Ion Torrent PGM platform followed by annotation using MG-RAST server and CAZYmes (Carbohydrate active enzymes) analysis toolkit. In all the samples Bacteroidetes was the most abundant phylum followed by Firmicutes. Functional analysis using KEGG Orthology database revealed Metabolism as the most abundant category at level 1 within which Carbohydrate metabolism was dominating. Diet treatments also exerted significant differences in proportion of enzymes involved in metabolic pathways for VFA production. Carbohydrate Active Enzyme(CAZy) analysis revealed the abundance of genes encoding glycoside hydrolases with the highest representation of GH13 CAZy family in all the samples. The findings provide an overview of the activities occurring in the rumen as well as active bacterial population and the changes occurring through different dietary treatments.

Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.

BACKGROUND: Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood. OBJECTIVE: We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients. METHODS: One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis. RESULTS: Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3-like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels. CONCLUSION: In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.

Identifying the heterogeneity of young adult rhinitis through cluster analysis in the Isle of Wight birth cohort.

BACKGROUND: Rhinitis affects many young adults and often shows comorbidity with asthma. OBJECTIVE: We hypothesized that young adult rhinitis, like asthma, exhibits clinical heterogeneity identifiable by means of cluster analysis. METHODS: Participants in the Isle of Wight birth cohort (n = 1456) were assessed at 1, 2, 4, 10, and 18 years of age. Cluster analysis was performed on those with rhinitis at age 18 years (n = 468) by using 13 variables defining clinical characteristics. RESULTS: Four clusters were identified. Patients in cluster 1 (n = 128 [27.4%]; ie, moderate childhood-onset rhinitis) had high atopy and eczema prevalence and high total IgE levels but low asthma prevalence. They showed the best lung function at 18 years of age, with normal fraction of exhaled nitric oxide (Feno), low bronchial hyperresponsiveness (BHR), and low bronchodilator reversibility (BDR) but high rhinitis symptoms and treatment. Patients in cluster 2 (n = 199 [42.5%]; ie, mild-adolescence-onset female rhinitis) had the lowest prevalence of comorbid atopy, asthma, and eczema. They had normal lung function and low BHR, BDR, Feno values, and total IgE levels plus low rhinitis symptoms, severity, and treatment. Patients in cluster 3 (n = 59 [12.6%]; ie, severe earliest-onset rhinitis with asthma) had the youngest rhinitis onset plus the highest comorbid asthma (of simultaneous onset) and atopy. They showed the most obstructed lung function with high BHR, BDR, and Feno values plus high rhinitis symptoms, severity, and treatment. Patient 4 in cluster 4 (n = 82 [17.5%]; ie, moderate childhood-onset male rhinitis with asthma) had high atopy, intermediate asthma, and low eczema. They had impaired lung function with high Feno values and total IgE levels but intermediate BHR and BDR. They had moderate rhinitis symptoms. CONCLUSION: Clinically distinctive adolescent rhinitis clusters are apparent with varying sex and asthma associations plus differing rhinitis severity and treatment needs.