Mild Childhood Asthma Research Articles

Enhancers regulate genes linked to severe and mild childhood asthma

BackgroundChildren with severe asthma suffer from recurrent symptoms and impaired quality of life despite advanced treatment. Underlying causes of severe asthma are not completely understood, although genetic mechanisms are known to be important. ObjectiveThe aim of this study was to identify gene regulatory enhancers in leukocytes, to describe the role of these enhancers in regulating genes related to severe and mild asthma in children, and to identify known asthma-related SNPs situated in proximity to enhancers. MethodsGene enhancers were identified and expression of enhancers and genes were measured by Cap Analysis Gene Expression (CAGE) data from peripheral blood leukocytes from children with severe asthma (n = 13), mild asthma (n = 15), and age-matched controls (n = 9). ResultsFrom a comprehensive set of 8,289 identified enhancers, we further defined a robust sub-set of the high-confidence and most highly expressed 4,738 enhancers. Known single nucleotide polymorphisms, SNPs, related to asthma coincided with enhancers in general as well as with specific enhancer-gene interactions. Blocks of enhancer clusters were associated with genes including TGF-beta, PPAR and IL-11 signaling as well as genes related to vitamin A and D metabolism. A signature of 91 enhancers distinguished between children with severe and mild asthma as well as controls. ConclusionsGene regulatory enhancers were identified in leukocytes with potential roles related to severe and mild asthma in children. Enhancers hosting known SNPs give the opportunity to formulate mechanistic hypotheses about the functions of these SNPs.

Airway smooth muscle as an underutilised biomarker: a case report

BackgroundSevere asthma and chronic obstructive pulmonary disease (COPD) can be challenging to manage, particularly when the clinical features may be similar. With the increased availability of advanced therapies for both entities, it is more important than ever to diagnose and phenotype accurately to inform appropriate treatment decisions. This case highlights the use of endobronchial biopsies to allow for histological evaluation of airways disease, and in particular the role of airway smooth muscle mass as an additional biomarker that could facilitate the diagnostic process.Case presentationA 65 year old woman presented with a diagnosis of severe COPD on the background of previous smoking and mild childhood asthma. Despite taking maximal inhaled pharmacotherapy, she had frequent exacerbations requiring corticosteroids and remained dyspnoeic on mild exertion. Lung function tests showed severe obstruction on spirometry (forced expiratory ratio 43%, forced expiratory volume in 1 s 47% predicted), and single breath Diffusing Capacity for Carbon Monoxide was moderately reduced at 45% predicted. Computed tomography revealed hyperinflation without marked emphysema. Quantitative CT for emphysema distribution demonstrated a relatively small lung fraction of 9.35% with <− 950 Hounsfield units. Bronchoscopy with endobronchial biopsy was undertaken to further determine the underlying pathology, and airway mucosa histology was consistent with typical findings of asthma. The patient was treated with bronchial thermoplasty as she did not meet prescribing criteria for monoclonal antibodies. Six months post treatment, she had a significant improvement in symptom control and medication usage, without any exacerbations.ConclusionsAirway smooth muscle histology is an underutilised biomarker that has a valuable role in phenotyping airways disease in the era of individualised medicine.

Shellfish/crustacean oral allergy syndrome among national service pre-enlistees in Singapore.

BackgroundAll Singaporean males undergo medical screening prior to compulsory military service. A history of possible food allergy may require referral to a specialist Allergy clinic to ensure that special dietary needs can be taken into account during field training and deployment.ObjectiveTo study the pattern of food allergy among pre-enlistees who were referred to a specialist allergy clinic to work up suspected food allergy.MethodsRetrospective study of all pre-enlistees registered in the Clinical Immunology/Allergy New Case Registry referred to the Allergy Clinic from 1 August 2015 to 31 May 2016 for suspected food allergy.ResultsOne hundred twenty pre-enlistees reporting food allergy symptoms other than rash alone were referred to the Allergy Clinic during the study period. Of these, 77 (64.2%) had food allergy. Among those with food allergy, mean age was 19.1 ± 1.5 years. They comprised predominantly Chinese (66.2%) and Malays (20.8%). The most commonly reported foods were shellfish/crustaceans (78%), peanut (15.6%), and egg (6.5%). Self-limiting oral allergy syndrome, OAS (itchy lips and throat with/without lip angioedema) was the most common manifestation (n = 33, 42.9%) followed by anaphylaxis (n = 23, 29.9%). Majority of OAS was from shellfish/crustacean (90.6%); of which shrimp (30.3%), crab (15.2%), and lobster (3.0%) were the most common. Mild childhood asthma (69.7%), allergic rhinitis (6.3%), and eczema (6.1%) were the most common atopic conditions among individuals with shellfish/crustacean OAS. This pattern was similar for shellfish/crustacean anaphylaxis. Skin prick tests were most commonly positive for shrimp (OAS 87.1% vs. anaphylaxis 100%), crab (OAS 95.8% vs. 90.9%), and lobster (OAS 91.7% vs. 63.6%).ConclusionOAS to shellfish/crustaceans was more common than anaphylaxis among this study population of young males referred for food allergy symptoms other than rash alone.

Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations

X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema. To test the hypothesis that co-inheritance of FLG mutations can act as a genetic modifier in XLI. An unusually severe XLI phenotype in addition to eczema and mild childhood asthma was investigated in a female Indian patient by fluorescent in situ hybridization (FISH) for the common STS gene deletion. Direct sequencing of the entire FLG gene was also performed. FISH analysis revealed that the proband was homozygous for the common STS genomic deletion mutation. Further investigation revealed a frame-shift mutation 3672del4 in the gene encoding filaggrin (FLG), leading to premature termination of profilaggrin translation. Interestingly, her father, who had a very typical mild presentation of XLI, did not carry this FLG mutation in addition to his STS deletion. Her mother was a heterozygous carrier of the FLG mutation and consistent with this, had mild symptoms of ichthyosis vulgaris; she was also a heterozygous carrier of the STS deletion. This is the second reported case of the modifying effects of FLG null alleles on XLI and strengthens the hypothesis that filaggrin defects can synergize with STS deficiency to exacerbate the ichthyosis phenotype.

Suppression of plasma matrix metalloproteinase‐9 following montelukast treatment in childhood asthma

Montelukast and ketotifen are commonly prescribed anti-inflammatory medications used in the treatment of childhood asthma. To investigate the modulation effect of montelukast and ketotifen, the levels of exhaled nitric oxide (eNO) and plasma matrix metalloproteinase-9 (MMP-9) were analyzed in a group of 30 children with mild persistent asthma. Patients on montelukast therapy for 8 weeks had significantly decreased levels of eNO and plasma MMP-9, which were associated with improved symptoms and enhanced peak expiratory flow but not significantly associated with increased level of tissue inhibitor metalloproteinase-1 (TIMP-1). In contrast, treatment with ketotifen produced no significant changes in these parameters until 4-6 weeks into the therapy and no effect on plasma MMP-9. Leukotriene antagonists, such as montelukast, may be better non-steroidal anti-inflammatory drugs for preventing airway inflammation in mild childhood asthma.

Regulation of stromal cell-derived factor-1 and exhaled nitric oxide in asthmatic children following montelukast and ketotifen treatment

Background: Montelukast and ketotifen are oral anti-allergy medications in asthmatic children. This study investigates the modulation effect of montelukast and ketotifen on children with intermittent to mild persistent asthma as demonstrated by the levels of peak expiratory flow (PEF), asthma scores (AS), exhaled nitric oxide (eNO) and plasma stromal cell-derived factor-1 (SDF-1) concentration in a randomized, prospective study. Methods: Fifty asthmatic children were enrolled and received 8 weeks of treatment with oral montelukast sodium 5 mg chewable tablet administered once daily, or 1 mg ketotifen, and were followed for a 4-week post-treatment washout period. ENO concentration, AS and PEF were measured before, 2, 4, 6 and 8 weeks after initial treatment, and 4 weeks after cessation of treatment. Results: Montelukast therapy was showed to improve AS, PEF and eNO within 2 weeks and remained the improvement during the treatment period. Montelukast also significantly decreased plasma SDF-1 levels after 8 weeks of treatment. In contrast, the ketotifen treatment revealed no significant effects in these clinical parameters until 4 and 6 weeks of the therapy, and did not suppress plasma SDF-1 levels after 8 weeks of treatment. To prove whether montelukast directly suppressed SDF-1 induction, we studied effects of montelukast on the LPS-induced SDF-1 expression and SDF-1-induced chemotaxis of monocytic (THP-1) cells. Montelukast, but not ketotifen, could suppress SDF-1 expression and its related chemotaxis on THP-1 monocytic cells. Conclusions: Leukotriene receptor antagonist, such as montelukast, may be a better non-steroid anti-inflammatory drug for mild childhood asthma in preventing airway inflammation.