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  1. Wise SK, Damask C, Roland LT, Ebert C, Levy JM, Lin S, et al.
    Int Forum Allergy Rhinol, 2023 Apr;13(4):293-859.
    PMID: 36878860 DOI: 10.1002/alr.23090
    BACKGROUND: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document.

    METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work.

    RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost.

    CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.

  2. Chen M, Zhang B, Li C, Kulaveerasingam H, Chew FT, Yu H
    Plant Physiol, 2015 Sep;169(1):391-402.
    PMID: 26152712 DOI: 10.1104/pp.15.00943
    Seed storage reserves mainly consist of starch, triacylglycerols, and storage proteins. They not only provide energy for seed germination and seedling establishment, but also supply essential dietary nutrients for human beings and animals. So far, the regulatory networks that govern the accumulation of seed storage reserves in plants are still largely unknown. Here, we show that TRANSPARENT TESTA GLABRA1 (TTG1), which encodes a WD40 repeat transcription factor involved in many aspects of plant development, plays an important role in mediating the accumulation of seed storage reserves in Arabidopsis (Arabidopsis thaliana). The dry weight of ttg1-1 embryos significantly increases compared with that of wild-type embryos, which is accompanied by an increase in the contents of starch, total protein, and fatty acids in ttg1-1 seeds. FUSCA3 (FUS3), a master regulator of seed maturation, binds directly to the TTG1 genomic region and suppresses TTG1 expression in developing seeds. TTG1 negatively regulates the accumulation of seed storage proteins partially through transcriptional repression of 2S3, a gene encoding a 2S albumin precursor. TTG1 also indirectly suppresses the expression of genes involved in either seed development or synthesis/modification of fatty acids in developing seeds. In addition, we demonstrate that the maternal allele of the TTG1 gene suppresses the accumulation of storage proteins and fatty acids in seeds. Our results suggest that TTG1 is a direct target of FUS3 in the framework of the regulatory hierarchy controlling seed filling and regulates the accumulation of seed storage proteins and fatty acids during the seed maturation process.
  3. Tan EC, Lee BW, Tay AW, Chew FT, Tay AH
    Allergy, 1999 Apr;54(4):402-3.
    PMID: 10371104
  4. Lee BW, Yap HK, Chew FT, Quah TC, Prabhakaran K, Chan GS, et al.
    Cytometry, 1996 Mar 15;26(1):8-15.
    PMID: 8809475
    Flow cytometric analysis of lymphocyte subsets were evaluated in 391 healthy Asian subjects ranging in age from birth to 40 years. Lymphocyte subsets were analysed using specific monoclonal antibodies: CD20 (B cells), CD3 and CD2 (T cells), CD16 and CD56+ (NK cells), CD4/CD3+ (helper-inducer T cells), CD8/ CD3+ (suppressor/cytotoxic T cells), HLA-DR expression on CD3 and CD25 (Tac) on CD3. The total white cell count, absolute lymphocyte counts, and B cell percentages peaked in infancy and declined steadily with age. Absolute counts of each subset, which were derived from absolute lymphocyte counts, also followed this trend. Increases with age were seen in the NK, T cell (CD2, CD3), and CD8 percentages. Males tended to have higher NK and CD8 percentages than females, and, conversely, females had higher CD3 and CD4 percentages than males. Comparison of our results with studies involving Caucasian subjects indicated higher NK percentages in our Asian population and lower CD4 absolute counts in the males of our population. These results indicate the presence of age, sex, and probable racial differences in lymphocyte subset expression. Our results may serve as reference standards for the Asian population.
  5. Pang SL, Ho KL, Waterman J, Teh AH, Chew FT, Ng CL
    Acta Crystallogr F Struct Biol Commun, 2015 Nov;71(Pt 11):1396-400.
    PMID: 26527267 DOI: 10.1107/S2053230X1501818X
    Dermatophagoides farinae is one of the major house dust mite (HDM) species that cause allergic diseases. N-terminally His-tagged recombinant Der f 21 (rDer f 21), a group 21 allergen, with the signal peptide truncated was successfully overexpressed in an Escherichia coli expression system. The purified rDer f 21 protein was initially crystallized using the sitting-drop vapour-diffusion method. Well diffracting protein crystals were obtained after optimization of the crystallization conditions using the hanging-drop vapour-diffusion method with a reservoir solution consisting of 0.19 M Tris-HCl pH 8.0, 32% PEG 400 at 293 K. X-ray diffraction data were collected to 1.49 Å resolution using an in-house X-ray source. The crystal belonged to the C-centered monoclinic space group C2, with unit-cell parameters a = 123.46, b = 27.71, c = 90.25 Å, β = 125.84°. The calculated Matthews coefficient (VM) of 2.06 Å(3) Da(-1) suggests that there are two molecules per asymmetric unit, with a solvent content of 40.3%. Despite sharing high sequence identity with Blo t 5 (45%) and Blo t 21 (41%), both of which were determined to be monomeric in solution, size-exclusion chromatography, static light scattering and self-rotation function analysis indicate that rDer f 21 is likely to be a dimeric protein.
  6. Pang SL, Ho KL, Waterman J, Rambo RP, Teh AH, Mathavan I, et al.
    Sci Rep, 2019 Mar 20;9(1):4933.
    PMID: 30894561 DOI: 10.1038/s41598-019-40879-x
    Group 21 and 5 allergens are homologous house dust mite proteins known as mid-tier allergens. To reveal the biological function of group 21 allergens and to understand better the allergenicity of the rDer f 21 allergen, we determined the 1.5 Å crystal structure of rDer f 21 allergen from Dermatophagoides farinae. The rDer f 21 protein consists of a three helical bundle, similar to available structures of group 21 and homologous group 5 allergens. The rDer f 21 dimer forms a hydrophobic binding pocket similar to the one in the Der p 5 allergen, which indicates that both of the homologous groups could share a similar function. By performing structure-guided mutagenesis, we mutated all 38 surface-exposed polar residues of the rDer f 21 allergen and carried out immuno-dot blot assays using 24 atopic sera. Six residues, K10, K26, K42, E43, K46, and K48, which are located in the region between the N-terminus and the loop 1 of rDer f 21 were identified as the major IgE epitopes of rDer f 21. Epitope mapping of all potential IgE epitopes on the surface of the rDer f 21 crystal structure revealed heterogeneity in the sIgE recognition of the allergen epitopes in atopic individuals. The higher the allergen-sIgE level of an individual, the higher the number of epitope residues that are found in the allergen. The results illustrate the clear correlation between the number of specific major epitope residues in an allergen and the sIgE level of the atopic population.
  7. Chan SL, Ong TC, Gao YF, Tiong YS, Wang de Y, Chew FT, et al.
    J Immunol, 2008 Aug 15;181(4):2586-96.
    PMID: 18684949
    A high incidence of sensitization to Blomia tropicalis, the predominant house dust mite species in tropical regions, is strongly associated with allergic diseases in Singapore, Malaysia, and Brazil. IgE binding to the group 5 allergen, Blo t 5, is found to be the most prevalent among all B. tropicalis allergens. The NMR structure of Blo t 5 determined represents a novel helical bundle structure consisting of three antiparallel alpha-helices. Based on the structure and sequence alignment with other known group 5 dust mite allergens, surface-exposed charged residues have been identified for site-directed mutagenesis and IgE binding assays. Four charged residues, Glu76, Asp81, Glu86, and Glu91 at around the turn region connecting helices alpha2 and alpha3 have been identified to be involved in the IgE binding. Using overlapping peptides, we have confirmed that these charged residues are located on a major putative linear IgE epitope of Blo t 5 from residues 76-91 comprising the sequence ELKRTDLNILERFNYE. Triple and quadruple mutants have been generated and found to exhibit significantly lower IgE binding and reduced responses in skin prick tests. The mutants induced similar PBMC proliferation as the wild-type protein but with reduced Th2:Th1 cytokines ratio. Mass screening on a quadruple mutant showed a 40% reduction in IgE binding in 35 of 42 sera of atopic individuals. Findings in this study further stressed the importance of surface-charged residues on IgE binding and have implications in the cross-reactivity and use of Blo t 5 mutants as a hypoallergen for immunotherapy.
  8. Goh DL, Chua KY, Chew FT, Liang RC, Seow TK, Ou KL, et al.
    J Allergy Clin Immunol, 2001 Jun;107(6):1082-7.
    PMID: 11398089
    BACKGROUND: We have previously described anaphylaxis induced by edible bird's nest (BN) and demonstrated that this condition is IgE mediated.

    OBJECTIVES: This study aimed at describing the immunochemical properties of the BN allergens. Comparative studies between 3 commercially available sources (according to the country of origin) of BN were also made.

    METHODS: Crude extracts of commercially available processed BN from Sarawak (Malaysia), Thailand, and Indonesia and fresh unprocessed BN from the caves of Sarawak were obtained by means of aqueous extraction. Specific IgE toward these sources were determined by using fluorescence allergosorbent tests (FASTs). Cross-reactivity studies between the 3 sources of commercially available processed BN were carried out by means of FAST inhibition. Immunochemical characterization by means of IgE immunoblot, periodate treatment, and heat stability studies were carried out on fresh unprocessed BN from Sarawak.

    RESULTS: Serum from allergic patients showed differences in IgE binding to the 3 sources of commercially available BN, with the highest levels of specific IgE recorded with the Sarawak source (P

  9. Ooi TE, Yeap WC, Daim LD, Ng BZ, Lee FC, Othman AM, et al.
    Proteome Sci, 2015;13:28.
    PMID: 26617468 DOI: 10.1186/s12953-015-0085-2
    BACKGROUND: The oil palm Elaeis guineensis Jacq. which produces the highest yield per unit land area of the oil crops is the most important commercial oil crop in South East Asia. The fleshy mesocarp of oil palm fruit, where oil is mostly derived from, contains up to 90 % dry weight of oil (one of the most concentrated in plant tissues). Hence, there is attention given to gain insights into the processes of oil deposition in this oil rich tissue. For that purpose, two-dimensional differential gel electrophoresis (DIGE) coupled with western assays, were used here to analyze differential protein levels in genetically-related high-and low-yielding oil palm mesocarps.

    RESULTS: From the DIGE comparative analysis in combination with western analysis, 41 unique differentially accumulated proteins were discovered. Functional categorization of these proteins placed them in the metabolisms of lipid, carbohydrate, amino acids, energy, structural proteins, as well as in other functions. In particular, higher abundance of fructose-1,6-biphosphate aldolase combined with reduced level of triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase may be indicative of important flux balance changes in glycolysis, while amino acid metabolism also appeared to be closely linked with oil yield.

    CONCLUSIONS: Forty-one proteins in several important biological pathways were identified as exhibiting differential in abundance at critical oil production stages. These confirm that oil yield is a complex trait involving the regulation of genes in multiple biological pathways. The results also provide insights into key control points of lipid biosynthesis in oil palm and can assist in the development of genetic markers for use in oil palm breeding programmes.

  10. Teh CK, Ong AL, Kwong QB, Apparow S, Chew FT, Mayes S, et al.
    Sci Rep, 2016;6:19075.
    PMID: 26743827 DOI: 10.1038/srep19075
    GWAS in out-crossing perennial crops is typically limited by insufficient marker density to account for population diversity and effects of population structure resulting in high false positive rates. The perennial crop oil palm is the most productive oil crop. We performed GWAS for oil-to-dry-mesocarp content (O/DM) on 2,045 genotyped tenera palms using 200K SNPs that were selected based on the short-range linkage disequilibrium distance, which is inherent with long breeding cycles and heterogeneous breeding populations. Eighty loci were significantly associated with O/DM (p ≤ 10(-4)) and three key signals were found. We then evaluated the progeny of a Deli x AVROS breeding trial and a 4% higher O/DM was observed amongst those having the beneficial genotypes at two of the three key loci (p < 0.05). We have initiated MAS and large-scale planting of elite dura and pisifera parents to generate the new commercial tenera palms with higher O/DM potential.
  11. Wong YC, Teh HF, Mebus K, Ooi TEK, Kwong QB, Koo KL, et al.
    BMC Genomics, 2017 06 21;18(1):470.
    PMID: 28637447 DOI: 10.1186/s12864-017-3855-7
    BACKGROUND: The oil yield trait of oil palm is expected to involve multiple genes, environmental influences and interactions. Many of the underlying mechanisms that contribute to oil yield are still poorly understood. In this study, we used a microarray approach to study the gene expression profiles of mesocarp tissue at different developmental stages, comparing genetically related high- and low- oil yielding palms to identify genes that contributed to the higher oil-yielding palm and might contribute to the wider genetic improvement of oil palm breeding populations.

    RESULTS: A total of 3412 (2001 annotated) gene candidates were found to be significantly differentially expressed between high- and low-yielding palms at at least one of the different stages of mesocarp development evaluated. Gene Ontologies (GO) enrichment analysis identified 28 significantly enriched GO terms, including regulation of transcription, fatty acid biosynthesis and metabolic processes. These differentially expressed genes comprise several transcription factors, such as, bHLH, Dof zinc finger proteins and MADS box proteins. Several genes involved in glycolysis, TCA, and fatty acid biosynthesis pathways were also found up-regulated in high-yielding oil palm, among them; pyruvate dehydrogenase E1 component Subunit Beta (PDH), ATP-citrate lyase, β- ketoacyl-ACP synthases I (KAS I), β- ketoacyl-ACP synthases III (KAS III) and ketoacyl-ACP reductase (KAR). Sucrose metabolism-related genes such as Invertase, Sucrose Synthase 2 and Sucrose Phosphatase 2 were found to be down-regulated in high-yielding oil palms, compared to the lower yield palms.

    CONCLUSIONS: Our findings indicate that a higher carbon flux (channeled through down-regulation of the Sucrose Synthase 2 pathway) was being utilized by up-regulated genes involved in glycolysis, TCA and fatty acid biosynthesis leading to enhanced oil production in the high-yielding oil palm. These findings are an important stepping stone to understand the processes that lead to production of high-yielding oil palms and have implications for breeding to maximize oil production.

  12. Ruzlan N, Low YSJ, Win W, Azizah Musa N, Ong AL, Chew FT, et al.
    Sci Rep, 2017 Aug 29;7(1):9626.
    PMID: 28852058 DOI: 10.1038/s41598-017-10195-3
    The fructose-1,6-bisphosphate aldolase catalyzed glycolysis branch that forms dihydroxyacetone phosphate and glyceraldehyde-3-phosphate was identified as a key driver of increased oil synthesis in oil palm and was validated in Saccharomyces cerevisiae. Reduction in triose phosphate isomerase (TPI) activity in a yeast knockdown mutant resulted in 19% increase in lipid content, while yeast strains overexpressing oil palm fructose-1,6-bisphosphate aldolase (EgFBA) and glycerol-3-phosphate dehydrogenase (EgG3PDH) showed increased lipid content by 16% and 21%, respectively. Genetic association analysis on oil palm SNPs of EgTPI SD_SNP_000035801 and EgGAPDH SD_SNP_000041011 showed that palms harboring homozygous GG in EgTPI and heterozygous AG in EgGAPDH exhibited higher mesocarp oil content based on dry weight. In addition, AG genotype of the SNP of EgG3PDH SD_SNP_000008411 was associated with higher mean mesocarp oil content, whereas GG genotype of the EgFBA SNP SD_SNP_000007765 was favourable. Additive effects were observed with a combination of favourable alleles in TPI and FBA in Nigerian x AVROS population (family F7) with highest allele frequency GG.GG being associated with a mean increase of 3.77% (p value = 2.3E-16) oil content over the Family 1. An analogous effect was observed in yeast, where overexpressed EgFBA in TPI - resulted in a 30% oil increment. These results provide insights into flux balances in glycolysis leading to higher yield in mesocarp oil-producing fruit.
  13. Chan PW, Chew FT, Tan TN, Chua KB, Hooi PS
    Pediatr Pulmonol, 2002 Jul;34(1):47-51.
    PMID: 12112797 DOI: 10.1002/ppul.10095
    Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection (LRTI) in young children. We determined if there was a seasonal variation in Malaysia in the incidence of RSV infection in young children admitted with LRTI, and possible associations of RSV infection with local meteorological parameters. A total of 5,691 children, aged less than 24 months and hospitalized with LRTI (i.e., bronchiolitis and pneumonia) between 1982-1997, were included in this study. Nasopharyngeal samples were collected and examined for RSV by immunofluorescence, viral culture, or both. Seasonal variations were determined by analyzing the monthly RSV-positive isolation rate via time series analysis. Possible correlations with local meteorological parameters were also evaluated.RSV was isolated in 1,047 (18.4%) children. Seasonal variations in RSV infection rate were evident and peaked during the months of November, December, and January (test statistics [T] = 53.7, P < 0.001). This seasonal variation was evident for both bronchiolitis and pneumonia categories (T = 42.8 and 56.9, respectively, P < 0.001). The rate of RSV infection appeared to correlate with the monthly number of rain days (r = 0.26, P < 0.01), and inversely with the monthly mean temperature (r = -0.38, P < 0.001). In the tropics, seasonal variations in the incidence of RSV infection are evident, with an annual peak in November, December, and January. This information provides a guide for healthcare provisions and implementation of RSV prevention.
  14. Kwong QB, Teh CK, Ong AL, Chew FT, Mayes S, Kulaveerasingam H, et al.
    BMC Genet, 2017 Dec 11;18(1):107.
    PMID: 29228905 DOI: 10.1186/s12863-017-0576-5
    BACKGROUND: Genomic selection (GS) uses genome-wide markers as an attempt to accelerate genetic gain in breeding programs of both animals and plants. This approach is particularly useful for perennial crops such as oil palm, which have long breeding cycles, and for which the optimal method for GS is still under debate. In this study, we evaluated the effect of different marker systems and modeling methods for implementing GS in an introgressed dura family derived from a Deli dura x Nigerian dura (Deli x Nigerian) with 112 individuals. This family is an important breeding source for developing new mother palms for superior oil yield and bunch characters. The traits of interest selected for this study were fruit-to-bunch (F/B), shell-to-fruit (S/F), kernel-to-fruit (K/F), mesocarp-to-fruit (M/F), oil per palm (O/P) and oil-to-dry mesocarp (O/DM). The marker systems evaluated were simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs). RR-BLUP, Bayesian A, B, Cπ, LASSO, Ridge Regression and two machine learning methods (SVM and Random Forest) were used to evaluate GS accuracy of the traits.

    RESULTS: The kinship coefficient between individuals in this family ranged from 0.35 to 0.62. S/F and O/DM had the highest genomic heritability, whereas F/B and O/P had the lowest. The accuracies using 135 SSRs were low, with accuracies of the traits around 0.20. The average accuracy of machine learning methods was 0.24, as compared to 0.20 achieved by other methods. The trait with the highest mean accuracy was F/B (0.28), while the lowest were both M/F and O/P (0.18). By using whole genomic SNPs, the accuracies for all traits, especially for O/DM (0.43), S/F (0.39) and M/F (0.30) were improved. The average accuracy of machine learning methods was 0.32, compared to 0.31 achieved by other methods.

    CONCLUSION: Due to high genomic resolution, the use of whole-genome SNPs improved the efficiency of GS dramatically for oil palm and is recommended for dura breeding programs. Machine learning slightly outperformed other methods, but required parameters optimization for GS implementation.

  15. Tiew PY, Ko FWS, Pang SL, Matta SA, Sio YY, Poh ME, et al.
    Eur Respir J, 2020 08;56(2).
    PMID: 32341102 DOI: 10.1183/13993003.00418-2020
    INTRODUCTION: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis; however, clinical relevance in COPD remains unclear.

    METHODS: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome.

    RESULTS: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD.

    CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.

  16. Mac Aogáin M, Chandrasekaran R, Lim AYH, Low TB, Tan GL, Hassan T, et al.
    Eur Respir J, 2018 07;52(1).
    PMID: 29880655 DOI: 10.1183/13993003.00766-2018
    Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a "research priorities" consensus statement for bronchiectasis.Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S-28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes.The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and ClavisporaAspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations.The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients.
  17. Mac Aogáin M, Tiew PY, Lim AYH, Low TB, Tan GL, Hassan T, et al.
    Am J Respir Crit Care Med, 2019 04 01;199(7):842-853.
    PMID: 30265843 DOI: 10.1164/rccm.201807-1355OC
    RATIONALE: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear.

    OBJECTIVES: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis.

    METHODS: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined.

    MEASUREMENTS AND MAIN RESULTS: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome.

    CONCLUSIONS: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.

  18. Tiew PY, Lim AYH, Keir HR, Dicker AJ, Mac Aogáin M, Pang SL, et al.
    Chest, 2022 01;161(1):40-53.
    PMID: 34364870 DOI: 10.1016/j.chest.2021.07.2165
    BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown.

    RESEARCH QUESTION: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap?

    STUDY DESIGN: Prospective, observational, cross-sectional study.

    METHODS: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes.

    RESULTS: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity.

    CONCLUSIONS: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI.

  19. Tiew PY, Narayana JK, Quek MSL, Ang YY, Ko FWS, Poh ME, et al.
    Eur Respir J, 2023 Jan;61(1).
    PMID: 35926878 DOI: 10.1183/13993003.00507-2022
    BACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown.

    METHODS: A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes.

    RESULTS: Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus-sensitised COPD of patients with frequent exacerbations.

    CONCLUSION: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens.

  20. Tiew PY, Dicker AJ, Keir HR, Poh ME, Pang SL, Mac Aogáin M, et al.
    Eur Respir J, 2021 Mar;57(3).
    PMID: 32972986 DOI: 10.1183/13993003.02050-2020
    INTRODUCTION: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain.

    METHODS: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi.

    RESULTS: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus, Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality.

    CONCLUSION: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality.

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