Intranasal corticosteroids reduced acute rhinosinusitis in children with allergic rhinitis: A nested case-control study.

BACKGROUND: Children with allergic rhinitis (AR) have substantially more acute rhinosinusitis than children without AR. We evaluated whether intranasal corticosteroids (INCS), second-generation antihistamines (SGH), and/or intranasal antihistamines (INH) for AR affect acute rhinosinusitis in children with AR aged 2-18 years. METHODS: By using the National Health Research Institutes Database 2005 of Taiwan, a cohort of patients with AR aged 2-18 years treated with AR medications between 2002 and 2018 was made, within which a nested case-control study was performed. Risk settings for acute rhinosinusitis cases matched controls for age, sex, and comorbidities. Current users of INCS, INH, and/or SGH were compared with remote and recent users of any AR medications and current users of INCS with and without SGH were compared with current users of SGH. RESULTS: Current users of SGH and/or INCS had a higher risk of acute rhinosinusitis than remote users of AR drugs, and current users of SGH had a higher risk of acute rhinosinusitis than recent users; however, no difference in the risk of acute rhinosinusitis was found between current users of INCS and recent users of AR drugs. Current users of INCS with and without SGH had a lower risk of acute rhinosinusitis than current users of SGH alone. CONCLUSIONS: Treatment of INCS with and without SGH diminished the risk of acute rhinosinusitis compared with treatment using SGH alone. Adequate INCS treatment for patients with AR is important to reduce the incidence of acute rhinosinusitis.

Maternal and neonatal risk factors of asthma in children: Nationwide population based study.

BACKGROUND: Small population group-based cohorts have found that perinatal factors may contribute to the development of asthma in children. We aimed to investigate maternal and neonatal risk factors for the asthma phenotypes using two databases from the Taiwan's Maternal and Child Health Database (TMCHD) and the National Health Insurance Research Database (NHIRD). METHODS: Perinatal data was obtained from 2004 to 2008 in the TMCHD and linked the NHIRD to obtain relevant medical information regarding maternal and neonatal risk factors of three asthma phenotypes which were identified as transient early asthma, persistent asthma, and late-onset asthma. A multivariate logistic regression analysis was conducted to adjust for covariates. RESULTS: The percentage of non-asthmatic patients was 77.02% and asthmatic (transient early asthma, late onset asthma, and persistent asthma) patients were 8.96%, 11.64%, and 2.42%, respectively. Maternal risk factors-including Cesarean section, maternal asthma, maternal allergic rhinitis (AR), and premature rupture of membranes-and neonatal risk factors, such as male gender, gestational age 29-37 weeks, ventilator use, antibiotics use, AR, and atopic dermatitis, were associated with the development of these three asthma phenotypes. Twins and a gestational age of 28 weeks or less premature were associated with the development of transient early asthma and persistent asthma, but not late onset asthma. Triplets and above were associated with the development of transient early asthma, but not late onset or persistent asthma. CONCLUSION: Various asthma phenotypes have different risk factors; therefore, their distinct risk factors should be identified in order to early diagnosis and treatment.

Peptidylarginine deiminase 2 promotes T helper 17-like T cell activation and activated T cell-autonomous death (ACAD) through an endoplasmic reticulum stress and autophagy coupling mechanism.

Peptididylarginine deiminase type 2 (PADI2) catalyzes the conversion of arginine residues to citrulline residues on proteins. We demonstrate that PADI2 induces T cell activation and investigate how PADI2 promotes activated T cell autonomous death (ACAD). In activated Jurkat T cells, overexpression of PADI2 significantly increases citrullinated proteins and induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, ultimately resulting in the expression of autophagy-related proteins and autophagy. PADI2 promoted autophagy and resulted in the early degradation of p62 and the light chain 3B (LC3B)-II accumulation. In Jurkat T cells, silencing the autophagy-related gene (Atg) 12 protein inhibits PADI2-mediated autophagy and promotes ER stress and apoptosis, whereas overexpression of Atg12 decreased ER stress and prolonged autophagy to promote cell survival. Additionally, PADI2 regulates T cell activation and the production of Th17 cytokines in Jurkat T cells (interleukins 6, IL-17A, IL-17F, IL-21, and IL-22). In Jurkat T cells, silencing IL-6 promotes autophagy mediated by PADI2 and inhibits PADI2-induced apoptosis, whereas silencing Beclin-1 increases the activation and survival of Th17-like T cells while decreasing autophagy and apoptosis. PADI2 silencing alleviates ER stress caused by PADI2 and decreases cytokine expression associated with Th17-like T cell activation and ACAD. We propose that PADI2 was involved in Th17 lymphocyte ACAD via a mechanism involving ER stress and autophagy that was tightly regulated by PADI2-mediated citrullination. These findings suggest that inhibiting Th17 T cell activation and the development of severe autoimmune diseases may be possible through the use of novel antagonists that specifically target PADI2.

Differential DNA methylation profiles of peripheral blood mononuclear cells in allergic asthmatic children following dust mite immunotherapy.

BACKGROUND/PURPOSE: Allergen-specific immunotherapy (SIT) is now considered curative to allergic diseases such as asthma. Mechanistically, our previous work showed DNA hypermethylation of cytokine genes, in T-helper cells, in allergic asthmatic children treated with allergen-SIT. In this study, we extended to work to assess possible changes in the DNA methylomes of peripheral blood mononuclear cells (PBMCs), isolated from mite allergen-SIT asthmatic children, to explore further the underlying methylation changes. METHODS: Thirteen allergic asthmatic children who received Der p-SIT, 12 non-SIT allergic asthmatic controls, and 12 healthy controls were enrolled. Bisulfite-converted DNA from Der p-stimulated PBMCs was analyzed using Human Methylation 450 k BeadChip. Pyrosequencing and quantitative real-time PCR were used to validate the DNA methylation levels and the gene expression of individual samples. RESULTS: We identified 108 significantly differentially methylated regions (DMRs) unique to Der p-treated PBMCs, with 53 probes linked to demethylated DMRs, and 55 probes linked to methylated DMRs. Three associated genes (BCL6, HSPG2, and HSP90AA1), of selected DMRs, were subjected to bisulfite pyrosequencing. Of these, BCL6 showed significant hypomethylation, while HSPG2 and HSP90AA1 were hypermethylated in SIT group, compared to the AA group. Furthermore, SIT group had significantly higher gene expression of BCL6 and lower gene expression of HSPG2. KEGG pathway analysis further revealed DMR genes involved in ECM-receptor interactions, asthma, and antigen processing and presentation pathways. CONCLUSIONS: Several DNA regions showed DNA methylation altered by Der p specific immunotherapy, indicating desensitization-associated methylomes. Genes belonging to these SIT-altered pathways may represent therapeutic targets for better clinical management of asthma.

Dendritic cell upregulation of programmed death ligand-1 via DNA demethylation inhibits experimental autoimmune encephalomyelitis.

Dendritic cells (DCs) play key roles in regulating T cell proliferation and differentiation, and epigenetic modification involves in this process. In the periphery, programmed death ligand-1 (PD-L1) expressed on antigen-presenting cells interacts with programmed death-1 (PD-1) on T cells to negatively regulate T cell responses. In this study, we investigate whether DNA demethylation in DCs, downmodulates CD4+ T cell activation, to halt progression of experimental autoimmune encephalomyelitis (EAE). These results showed that during the development of bone marrow-derived DCs (BMDCs), DNA hypomethylation by 0.1 µM and 1 µM 5-aza-2'-deoxycytidine (5-aza) upregulated PD-L1, but not CD40, CD80, or CD86, with surprising downregulation of PD-L2. In co-culture, 5-aza-treated BMDCs, as well as CD11c+ cells from 5-aza-treated EAE mice, inhibited EAE CD4+ T cell proliferation and cytokine secretion. Additionally, in vivo 5-aza pretreatment arrested disease progression, inflammatory cell infiltration, and CNS demyelination, in EAE mice. Compared to DCs from vehicle control-treated EAE rodents, DCs from 5-aza-treated EAE mice upregulated PD-L1, in correlation with hypomethylation of the Cd274 promoter. Furthermore, antibody-mediated blockage of PD-L1 rescued EAE progression from 5-aza treatment, in vivo, while also disinhibiting EAE CD4+ T cell proliferation, by 5-aza-treated DCs, in vitro. Consequently, we conclude that PD-L1 is upregulated via DNA hypomethylation in DCs, resulting in downregulation of autoimmune effector T cell functions, thereby halting progression of EAE.

Treatment of allergic rhinitis reduces acute asthma exacerbation risk among asthmatic children aged 2-18 years.

BACKGROUND/PURPOSE: Asthma and allergic rhinitis (AR) frequently coexist in the same individuals in childhood and adolescence. We evaluated whether AR had an impact on acute exacerbation (AE) and whether intranasal corticosteroid (INCS) and second-generation antihistamines (SGH) for AR modified the association of AR with AE in asthmatics aged 2-6 years and 7-18 years. METHODS: Using the National Health Research Institutes (NHRI) Database 2005 of Taiwan, we investigated patients who had been diagnosed with asthma in the years 2000 through 2012 and who had then been followed-up with for at least one year. The risk factors of AE were evaluated using multiple Cox proportional hazards regression analysis. RESULTS: The incidence of AE was higher in the preschool group than the older group (adj. HR: 1.68, 95% CI: 1.44-1.95). The AR with INCS and/or SGH group was found to have a lower risk of AE than the non-AR group (adj. HR: 0.32, 0.44 and 0.30), but the AR without treatment group did not have a significant difference with the non-AR group. After propensity score matching, the use of INCS and/or SGH was associated with a significant reduction in the occurrence of AE among AR patients aged 2-6 years old (adj. HR: 0.38, 0.57 and 0.45) and 7-18 years old (adj. HR: 0.50, 0.52 and 0.35). CONCLUSION: The preschool patients had a higher incidence of AE than the older patients in general. Adequate treatment with INCS and/or SGH in asthma with AR patients is important for reducing the incidence of AE of asthma.

Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T cell tolerance in children with allergic asthma.

Allergen-specific immunotherapy (allergen-SIT) is a highly effective treatment for children with allergic asthma (AA), an immune-mediated chronic disease leading to bronchial muscle hypertrophy and airway obstruction in response to specific allergens. T helper cells and secreted cytokines play important roles in the pathogenesis of asthma, and epigenetic modulation controls genes important for T cell development and cytokine expression. This study evaluated T helper cell-secreted cytokines and DNA methylation patterns in children treated with Dermatophagoides pteronyssinus (Der p) allergen-SIT. Our results showed that after Der p challenge, peripheral blood mononuclear cells (PBMCs) from the SIT group, compared with the non-SIT AA group, produced lower levels of IL-4, IL-5 and IL-2. The SIT group, compared with the AA group, exhibited decreased sensitivity to the Der p allergen, concurrent with IL-4 down-modulation due to increased promoter DNA methylation, as estimated in PBMCs. Our results showed that SIT decreased IL-4 and IL-5, and inhibited T cell proliferation, by inhibiting IL-2 production after the specific allergen challenge. These results suggest that decreased IL-2 production and increased IL-4 cytokine promoter methylation is a potential mechanism of Der p-specific allergen desensitization immunotherapy.

Nebulized hypertonic saline treatment reduces both rate and duration of hospitalization for acute bronchiolitis in infants: an updated meta-analysis.

Nebulized hypertonic saline (HS) treatment reduced the length of hospitalization in infants with acute bronchiolitis in a previous meta-analysis. However, there was no reduction in the admission rate. We hypothesized that nebulized HS treatment might significantly decrease both the duration and the rate of hospitalization if more randomized controlled trials (RCTs) were included. We searched MEDLINE, PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials (CENTRAL) without a language restriction. A meta-analysis was performed based on the efficacy of nebulized HS treatment in infants with acute bronchiolitis. We used weighted mean difference (WMD) and risk ratio as effect size metrics. Eleven studies were identified that enrolled 1070 infants. Nebulized HS treatment significantly decreased the duration and rate of hospitalization compared with nebulized normal saline (NS) [duration of hospitalization: WMD = -0.96, 95% confidence interval (CI) = -1.38 to -0.54, p < 0.001; rate of hospitalization: risk ratio = 0.59, 95% CI = 0.37-0.93, p = 0.02]. Furthermore, nebulized HS treatment had a beneficial effect in reducing the clinical severity (CS) score of acute bronchiolitis infants post-treatment (Day 1: WMD = -0.77, 95% CI = -1.30 to -0.24, p = 0.005; Day 2: WMD = -0.85, 95% CI = -1.30 to -0.39, p < 0.001; Day 3: WMD = -1.14, 95% CI = -1.69 to -0.58, p < 0.001). There was no decrease in the rate of readmission (risk ratio = 1.08, 95% CI = 0.68-1.73, p = 0.74). Nebulized HS treatment significantly decreased both the rate and the duration of hospitalization. Due to the efficacy and cost-effectiveness, HS should be considered for the treatment of acute bronchiolitis in infants.

Effect of mite allergen immunotherapy on the altered phenotype of dendritic cells in allergic asthmatic children.

BACKGROUND: Allergic asthma is a T(H)2 inflammatory disease. Dendritic cells (DCs) play key roles in the T(H)1/T(H)2 balance. Allergen specific immunotherapy (SIT) has the potential to modify the course of allergy because the ratio of T(H)1 to T(H)2 cytokines produced is increased after SIT. OBJECTIVE: To determine how SIT affects DCs in children and to define novel parameters of this treatment. METHODS: We investigated the changes of phenotypic and functional variations of monocyte-derived DCs from allergic asthmatic children undergoing complete mite SIT. Peripheral blood monocytes from SIT allergic asthmatic children, allergic asthmatic controls, and healthy controls were cultured with granulocyte-macrophage colony-stimulating factor and interleukin 4 and then stimulated with Dermatophagoides pteronyssinus (Der p) allergen or lipopolysaccharide (LPS). The expressions of surface molecules on monocyte-derived DCs were assessed by flow cytometry. Cytokine production by cultured monocyte-derived DCs was determined by enzyme-linked immunosorbent assay. RESULTS: After LPS stimulation, monocyte-derived DCs of the allergic asthmatic group had a higher CD86 and lower HLA-DR expression than the healthy controls. In SIT patients, the expression was similar to that of the healthy controls. After Der p stimulation monocyte-derived DCs of the allergic asthmatic patients displayed lower Toll-like receptor 4 (TLR4), whereas again in SIT patients the expression was similar to that of healthy controls. CONCLUSION: These findings indicate that SIT normalizes the expression of CD86, HLA-DR, and TLR4 on DCs. Moreover, CD86, HLA-DR, and TLR4 may be useful parameters for monitoring SIT. Decreased TLR4 expression in allergic asthmatic patients might be compensated by TLR4 agonists, with the potential of amplifying the effects of SIT.

Bacterial infection in association with snakebite: a 10-year experience in a northern Taiwan medical center.

BACKGROUND: Microbiological data of secondary wound infections following snakebites is rarely reported in Taiwan. The objective of this study was to assess the secondary wound infection after venomous snakebites. METHODS: We conducted a 10-year retrospective survey on patients admitted for venomous snakebites and microbiological data of wound cultures at a medical center in northern Taiwan. RESULTS: Between April 2001 and April 2010, 231 patients who experienced snakebites were included. Male predominated, accounting for 62.3% (144). The age range of patients was 4-95 years. Ninety-five (41.1%) people were bitten by Trimeresurus mucrosquamatus, followed by Tstejnegeri, and cobra. A total of 61 pathogens were obtained from 21 patients. Thirty-nine (63.9%) isolates were gram-negative bacteria, 14 (23%) gram-positive pathogens, and 8 (13.1%) anaerobic pathogens. There were 17 patients bitten by cobra in these 21 patients. Morganella morganii and Enterococcus species were the most common pathogens identified in the wound cultures. CONCLUSION: Cobra bite causes more severe bacterial infection than other kinds of snakebites. Oral amoxicillin/clavulanate plus ciprofloxacin or parenteral piperacillin/tazobactam alone can be the choices for empirical or definitive treatment, and surgical intervention should be considered for established invasive soft tissue infections.

Two different tests for total bilirubin in neonates and infants.

BACKGROUND: The most readily available methods for testing serum total bilirubin in neonates are the capillary tube-directed optics color method and serum biochemistry. Because inconsistency between these two methods may cause confusion in clinical practice, this study was designed to quantify their differences. METHODS: In 46 neonates with clinical jaundice, total bilirubin was measured by two different methods, using a nonchemical photometric device and a laboratory analyzer. RESULTS: Differences in results between these two methods were statistically significant, especially when total bilirubin level exceeded 15 mg/dL. CONCLUSION: Clinicians should be aware of the differences between the two methods when making decisions in patient care.