Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Vitamin D ameliorates particulate matter induced mitochondrial damages and calcium dyshomeostasis in BEAS-2B human bronchial epithelial cells.

BACKGROUND: Mitochondria is prone to oxidative damage by endogenous and exogenous sources of free radicals, including particulate matter (PM). Given the role of mitochondria in inflammatory disorders, such as asthma and chronic obstructive pulmonary disease, we hypothesized that supplementation of vitamin D may play a protective role in PM-induced mitochondrial oxidative damages of human bronchial epithelial BEAS-2B cells. METHODS: BEAS-2B cells were pretreated with 1,25(OH)2D3, an active form of vitamin D, for 1 h prior to 24-hour exposure to PM (SRM-1648a). Oxidative stress was measured by flow cytometry. Mitochondrial functions including mitochondrial membrane potential, ATP levels, and mitochondrial DNA copy number were analyzed. Additionally, mitochondrial ultrastructure was examined using transmission electron microscopy. Intracellular and mitochondrial calcium concentration changes were assessed using flow cytometry based on the expression of Fluo-4 AM and Rhod-2 AM, respectively. Pro-inflammatory cytokines, including IL-6 and MCP-1, were quantified using ELISA. The expression levels of antioxidants, including SOD1, SOD2, CAT, GSH, and NADPH, were determined. RESULTS: Our findings first showed that 24-hour exposure to PM led to the overproduction of reactive oxygen species (ROS) derived from mitochondria. PM-induced mitochondrial oxidation resulted in intracellular calcium accumulation, particularly within mitochondria, and alterations in mitochondrial morphology and functions. These changes included loss of mitochondrial membrane integrity, disarrayed cristae, mitochondrial membrane depolarization, reduced ATP production, and increased mitochondrial DNA copy number. Consequently, PM-induced mitochondrial damage triggered the release of certain inflammatory cytokines, such as IL-6 and MCP-1. Similar to the actions of mitochondrial ROS inhibitor MitoTEMPO, 1,25(OH)2D3 conferred protective effects on mtDNA alterations, mitochondrial damages, calcium dyshomeostasis, thereby decreasing the release of certain inflammatory cytokines. We found that greater cellular level of 1,25(OH)2D3 upregulated the expression of enzymatic (SOD1, SOD2, and CAT) and non-enzymatic (GSH and NADPH) antioxidants to modulate cellular redox homeostasis. CONCLUSION: Our study provides new evidence that 1,25(OH)2D3 acts as an antioxidant, enhancing BEAS-2B antioxidant responses to regulate mitochondrial ROS homeostasis and mitochondrial function, thereby enhancing epithelial defense against air pollution exposure.

Comparison of 16S rRNA gene sequencing microbiota among children with serological IgE-mediated food hypersensitivity.

BACKGROUND: We hypothesized that specific food hypersensitivity (FH) in children is linked to specific gut microbiota. The aim of our study was to quantify and evaluate differences in gut microbial composition among children with different IgE-mediated FH. METHODS: Children (n = 81) aged 18 to 36 months were enrolled, fecal samples of 57 children with FH and 24 healthy children were evaluated using next-generation sequencing. Individual microbial diversity and composition were analyzed via targeting the 16 S rRNA gene hypervariable V3-V5 regions. RESULTS: Children with IgE-mediated FH (in milk, egg white, soy) had significantly lower gut microbiota diversity and richness than healthy children. Children with IgE-mediated FH exhibited relatively high abundances of Firmicutes and relative underrepresentation of the phylum Bacteroidetes. We observed significant increases in relative abundances of Ruminococcaceae, Clostridiaceae, and Erysipelotrichaceae (p < 0.01, compared to control) in children with milk hypersensitivity and of Clostridiaceae and Erysipelotrichaceae (p < 0.01) in children with peanut hypersensitivity. We also found significant increases in the numbers of Clostridiaceae, Lachnospiraceae and Pasteurellaceae (p < 0.01) in children with egg white hypersensitivity. CONCLUSIONS: These findings identify early evidence of different gut microbiota development/ differentiation in children with food hypersensitivity. Specific food hypersensitivities may be associated with compositional changes in intestinal microbiota. IMPACT: These findings identify early evidence of different gut microbiota development/differentiation in children with food hypersensitivity. We built a gut microbial profile that could identify toddlers at risk for food hypersensitivity. Children with enriched Firmicutes (phylum) with partial different families may be associated with food hypersensitivity. Enriched family Clostridiaceae, Ruminococcaceae, Lachnospiraceae, or Erysipelotrichaceae in gut microbiota may be associated with specific food hypersensitivities (such as milk, egg white, peanut) in children.

Physician adherence to anaphylaxis guidelines among different age groups in emergency departments: 20-Year observational study.

BACKGROUND: Anaphylaxis is an acute and serious allergic reaction. Little is known about physician adherence to anaphylaxis guidelines among patients across different age groups. OBJECTIVE: To investigate real-world physician adherence to anaphylaxis guidelines among children, adults, and older adults in emergency departments. METHODS: This study retrospectively analyzed all consecutive patients with anaphylaxis who presented to 2 emergency departments at 2 branches of the largest tertiary hospital in Taiwan, between 2001 and 2020. Patients who met the diagnostic criteria for anaphylaxis were enrolled and grouped by age: children (<18 years), adults (18-64 years), and older adults (≥65 years). RESULTS: We enrolled 771 patients with anaphylaxis (159 children, 498 adults, and 114 older adults). Intramuscular epinephrine was administered in 294 cases (38.1%). There was a significant age-group difference in the rate of intramuscular epinephrine administration (46.5% in children, 37.3% in adults, and 29.8% in older adults; P trend = .004). When stratified by severity, 14.3% of older adults with moderate reactions received intramuscular epinephrine, whereas 35.2% of adults and 55.3% of children received intramuscular epinephrine (P trend < .001), whereas such difference was not found in patients with severe reactions. Upon discharge from emergency departments, 15.3% received allergist referral (52.2% in children, 6.6% in adults, and 1.8% in older adults; P trend < .001); 12.5% received education on avoidance of triggers (18.9%, 11.4%, and 7.9%; P trend = .01), and 16.1% received education on alarm symptoms (21.4%, 15.1%, and 13.2%; P trend = .05). CONCLUSION: The real-world physician adherence to anaphylaxis guidelines remains suboptimal in emergency departments, particularly among older adults. Physician continuing education is needed to improve the gap between anaphylaxis guidelines and clinical practice.

Prognostic Factors in Children with Acute Kidney Injury Requiring Continuous Renal Replacement Therapy.

INTRODUCTION: This study aimed to evaluate prognostic factors and outcomes in a single-center PICU cohort that received continuous renal replacement therapy (CRRT). METHODS: This retrospective study analyzed clinical characteristics, laboratory data, and outcomes. Ninety-day mortality and advanced chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m2) were defined as primary and secondary outcomes, respectively. RESULTS: Seventy-five patients were enrolled, all of whom received CRRT for indications including acute kidney injury with complicated refractory metabolic acidosis, electrolyte derangement, and existed or impending fluid overload. The 90-day mortality and advanced CKD were 53% and 29%, respectively. Multivariate Cox regression analysis demonstrated that only underlying bone marrow transplantation (BMT) (HR 4.58; 95% CI: 2.04-10.27) and a high pSOFA score (HR 1.12; 95% CI: 1.01-1.23) were independent risk factors for 90-day mortality. Among survivors, ten developed advanced CKD on the 90th day, and this group had a higher serum fibrinogen level (OR 1.01; 95% CI: 1.01-1.03) at the start of CRRT. CONCLUSION: In critically ill children with AKI requiring CRRT, post-BMT and high pSOFA scores are independent risk factors for 90-day mortality. Additionally, a high serum fibrinogen level at the initiation of CRRT is associated with the development of advanced CKD.

Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous.

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PIDs) may be similar diseases with different clinical phenotypes. OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1475 unrelated healthy individuals, which were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. RESULTS: On filtration, 36 patients (30.5%) harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and 4 heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus, regardless of infection susceptibility. Moreover, mutation loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutation loads were observed among cSLE patients with peripubertal disease onset, no significant differences in sex or phenotype were noted among cSLE patients. CONCLUSION: cSLE is mostly not monogenic. Gene-specific analysis and mutation load investigations suggested that rare and predicted damaging variants in PID-related genes can potentially contribute to cSLE susceptibility.

Lymphocyte disturbance and functional assessment of the [Asp521Asn] ZAP70 mutation.

Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαß:CD3:zeta complex to diversify and amplify TCR signaling. Patients with ZAP70 mutations can present with phenotypes of immune dysregulation as well as infection. We identified the first Taiwanese boy with the [Asp521Asn] ZAP70 mutation who presented with recurrent pneumonia, inflammatory bowel disease-like diarrhea, transient hematuria and autoimmune hepatitis. He had isolated CD8 lymphopenia, eosinophilia, hypogammaglobulinemia, and impaired lymphocyte proliferation. Downstream CD3/CD28 signaling, phosphorylation of AKT, ZAP70 and Ca2+ influx were decreased in [Asp521Asn] ZAP70 lymphocytes. Immunophenotyping analysis revealed expansion of transitional B and CD21-low B cells, Th2-skewing T follicular helper cells, but lower Treg cells. The Asp521Asn-ZAP70 hindered TCR-CD3 downstream phosphorylation and disturbed lymphocyte subgroup "profiles" leading to autoimmunity/autoinflammation. Further large-scale studies are warranted to clarify this lymphocyte disturbance. The prognosis significantly depends on hematopoietic stem cell transplantation, but not the genotype, the presence of opportunistic infections or immune dysregulation.

Distinct Lymphocyte Immunophenotyping and Quantitative Anti-Interferon Gamma Autoantibodies in Taiwanese HIV-Negative Patients with Non-Tuberculous Mycobacterial Infections.

PURPOSE: The presence of anti-interferon-γ autoantibodies (AutoAbs-IFN-γ) is not rare in patients suffering from persistent non-tuberculous mycobacterial (NTM) infections that are characteristic of adult-onset immunodeficiency syndrome. The immune disturbances in this distinct disorder remain to be elucidated. METHODS: Patients with NTM infections but without effective response over 3 months' treatment were referred to our institute to quantify their level of AutoAbs-IFN-γ after excluding defective IL12/23-IFN-γ circuit and reactive oxygen species production. The AutoAbs-IFN-γ and percentage of lymphocyte subpopulations most relevant to T and B cell pools were assessed and compared with age-matched healthy controls. RESULTS: A total of 31 patients were enrolled during the 15-year study period (2008-2022), 20 patients with > 50% suppression of IFN-γ detection at 1:100 serum dilution were classified into the Auto-NTM group. The remaining 11 with negligible suppression were assigned to the No Auto-NTM group. Mycobacterium chimaera-intracellulare group (MAC), M. kansasii, and M. abscessus were the most common pathogens. Pneumonia (19 vs 7), lymphadenitis (11 vs 5), Salmonella sepsis (6 vs 2), osteomyelitis (5 vs 1), and cutaneous herpes zoster (4 vs 4) were the main manifestations in both the Auto-NTM and No Auto-NTM groups who had similar onset-age (55.3 vs 53.6 years; p = 0.73) and follow-up duration (71.9 vs 54.6 months; p = 0.45). The Auto-NTM group had significantly higher transitional (IgM + + CD38 + +), CD19 + CD21-low, and plasmablast (IgM-CD38 + +) in the B cell pool, with higher effector memory (CD4 + /CD8 + CD45RO + CCR7 -), senescent CD8 + CD57 + , and Th17 cells, but lower naïve (CD4 + /CD8 + CD45RO - CCR7 +) and Treg cells in the T cell pool when compared to the No Auto-NTM and healthy groups. NTM patients with/without AutoAbs-IFN-γ had lower Th1-like Tfh (CD4 + CXCR5 + CXCR3 + CCR6 -) cells. All Auto-NTM patients still had non-remitted mycobacterial infections and higher AutoAbs-IFN-γ despite anti-CD20 therapy in 3 patients. CONCLUSION: In patients with suspected adult-onset immunodeficiency syndrome, two thirds (20/31) were recognized as having significantly inhibitory AutoAbs-IFN-γ with higher antibody-enhancing transitional, CD19 + CD21-low and plasmablast B cells; as well as higher effector memory, senescent CD8 + CD57 + and Th17 cells, but lower naïve T and Treg cells in contrast to those with negligible AutoAbs-IFN-γ. Such immunophenotyping disturbances might correlate with the presence of AutoAbs-IFN-γ. However, the mutual mechanisms need to be further clarified.

Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease.

PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

Early infancy dysbiosis in food protein-induced enterocolitis syndrome: A prospective cohort study.

BACKGROUND: The microbiome associations of food protein-induced enterocolitis syndrome (FPIES) are understudied. We sought to prospectively define the clinical features of FPIES in a birth cohort, and investigate for the evidence of gut dysbiosis. METHODS: We identified children diagnosed with FPIES in the Gastrointestinal Microbiome and Allergic Proctocolitis Study, a healthy infant cohort. Children were assessed and stools were collected at each well child visit. The clinical features of the children with FPIES were summarized. Stool microbiome was analyzed using 16S rRNA sequencing comparing children with and without FPIES. RESULTS: Of the 874 children followed up for 3 years, 8 FPIES cases (4 male) were identified, yielding a cumulative incidence of 0.92%. The most common triggers were oat and rice (n = 3, each) followed by milk (n = 2). The children with FPIES were more likely to have family history of food allergy (50% vs. 15.9% among unaffected, p = .03). The average age of disease presentation was 6 months old. During the first 6 months of life, stool from children with FPIES contained significantly less Bifidobacterium adolescentis, but more pathobionts, including Bacteroides spp. (especially Bacteroides fragilis), Holdemania spp., Lachnobacterium spp., and Acinetobacter lwoffii. The short-chain fatty acid (SCFA)-producing Bifidobacterium shunt was expressed significantly less in the stool from FPIES children. CONCLUSIONS: In this cohort, the cumulative incidence over the 3-year study period was 0.92%. During the first 6 months of life, children with FPIES had evidence of dysbiosis and SCFA production pathway was expressed less in their stool, which may play an important role in the pathogenesis of FPIES.

Comorbidities of systemic lupus erythematosus prior to and following diagnosis in different age-at-onset groups.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a female-dominated autoimmune disease that can occur at any age and has a diverse course. The clinical manifestation of this disease can vary depending on the patient's age at onset. The aim of this study was to characterise the comorbidities at the time of SLE diagnosis and after in different age groups. METHODS: A total 1042 incident cases of SLE with a Catastrophic Illness Card in 2005 and 10,420 age- and sex-matched controls from the general population registered in the National Health Insurance Research Database in Taiwan were enrolled in the study. The risk of comorbidities before (adjusted odds ratio, [aOR]) and after (adjusted hazard ratio, [aHR]) of SLE was analysed. The burden of these SLE-associated comorbidities was weight by the Charlson comorbidity index (CCI). We used the cumulative incidence to evaluate the impact of comorbidities on different age onset groups. RESULTS: In this study, musculoskeletal diseases had the highest positive association (aOR, 5.29; 95% confidence interval [CI]: 4.25-6.57) prior to the diagnosis of SLE and they were also the most common developing incident comorbidity after the diagnosis (HR, 13.7; 95% CI: 11.91-15.77). It only took less than 1 year for 50% of the late-onset SLE patients to develop any increase in CCI score. The developing comorbidities attributed to 16.3% all-cause mortality and they had the greatest impact on late-onset SLE patients, with 33.3% cumulative incidence to all-cause mortality. There is no difference in the incidence of infectious diseases across different age groups. The herpes zoster infection had the greatest cumulative incidence among the category of infection diseases in child-onset SLE patients. CONCLUSION: SLE patients had increased risks of multiple pre-existing comorbidities at diagnosis. The developed comorbidity after diagnosis could contribute to all-cause mortality. The herpes zoster infection is primarily an issue in child-onset SLE patients.

Cord blood IgE predicts allergic sensitization, elevation of exhaled nitric oxide, and asthma in schoolchildren.

BACKGROUND: Few data are available in Asian children regarding the validity of cord blood immunoglobulin E (IgE) in predicting allergic sensitization and pulmonary function. The relationship between cord blood IgE and fraction of exhaled nitric oxide (FeNO) remains unknown. This study investigated the associations of cord blood IgE with allergic sensitization, FeNO, pulmonary function, and allergic diseases in Asian children. METHODS: Five hundred and sixty-six Asian children with valid cord blood IgE measurements at birth participated a 6-year follow-up visit including a questionnaire, serum total and allergen-specific IgE, FeNO measurement, and spirometry. Regression-based analyses with covariates adjustment were applied. RESULTS: Cord blood IgE levels were significantly associated with FeNO levels (ß = 0.131, p < .001) and serum total IgE levels (ß = 0.325, p < .001). Cord blood IgE levels were positively associated with allergic sensitization (adjusted odds ratio [AOR] = 2.22, p < .001), and sensitization to mites (p = .002), animals (p = .023), and foods (p = .048). Subjects with cord blood IgE ≥0.24 kU/L (the optimal cutoff) were significantly associated with an increased risk of allergic sensitization (AOR = 2.63, p < .001) and asthma (AOR = 2.35, p = .024) than those with cord blood IgE <0.24 kU/L. Subjects with cord blood IgE ≥0.24 kU/L had significantly higher FeNO levels than those with cord blood IgE <0.24 kU/L (p = .028). There were no significant associations between cord blood IgE levels and pulmonary function parameters. CONCLUSION: Cord blood IgE ≥0.24 kU/L predicts allergic sensitization, FeNO elevation, and asthma among Asian schoolchildren, suggesting cord blood IgE would be useful for identifying newborns at risk of subsequent allergic sensitization and allergic airway inflammation.

Metabolomics analysis reveals molecular linkages for the impact of vitamin D on childhood allergic airway diseases.

BACKGROUND: Several studies have reported the relevance between serum vitamin D and allergic immunoglobulin E (IgE) responses and atopic diseases. However, a metabolomics-based approach to the impacts of vitamin D on allergic reactions remains unclear. METHODS: A total of 111 children completed a 3-year follow-up were enrolled and classified based on longitudinal vitamin D status (≥ 30 ng/ml, n = 54; 20-29.9 ng/ml, n = 41; <20 ng/ml, n = 16). Urinary metabolomic profiling was performed using 1 H-Nuclear magnetic resonance (NMR) spectroscopy at age 3. Integrative analyses of their associations related to vitamin D levels, atopic indices, and allergies were performed, and their roles in functional metabolic pathways were also assessed. RESULTS: Six and five metabolites were identified to be significantly associated with vitamin D status and atopic diseases, respectively (FDR-adjusted p-value <.05). A further correlation analysis revealed that vitamin D-associated 3-hydroxyisobutyric acid and glutamine were positively correlated with atopic disease-associated succinic acid and alanine, respectively. Furthermore, hippuric acid was negatively correlated with atopic disease-associated formic acid, which was positively correlated with vitamin D level (p < .01). Absolute eosinophil count (AEC) was positively correlated with serum D. pteronyssinus- and D. farinae-specific IgE level (p < .01) but negatively correlated with vitamin D level (p < .05). Amino acid metabolisms were significantly associated with vitamin D related to childhood allergies. CONCLUSION: Integrative metabolomic analysis provides the link of vitamin D-associated metabolites with the gut microbiome and immunoallergic reactions related to childhood allergies.

Decline in hospitalization for childhood asthma in different air pollution regions in Taiwan, 2001-2012.

This study aimed to investigate the trends in childhood asthma hospitalization in regions with differing levels of air pollution in Taiwan, 2001-2012. Joinpoint regression was used to identify significant trend changes. The hospitalization rate varied according to gender, geographic region, and age. The incidence of childhood asthma hospitalization decreased from 127.99 to 76.67 (/100,000 population), with an average annual percentage change of around -4.1%; in the Yilan region, the average air pollution concentrations were 19.92 µg/m3, 39.47 µg/m3, 25.99 ppb, 2.19 ppb, and 11.23 ppb for PM2.5, PM10, O3, SO2, and NO2, respectively, which were lower than Taiwan's average values; however, the childhood asthma hospitalization rate was the highest (179.75/100,000 population). The national trend in childhood asthma hospitalization exhibited a significant decrease. The effects of air pollution on childhood asthma were greater in the higher-level air pollution regions, while less association was observed in the lower-level air pollution regions.

Effectiveness of eAsthmaCare on Symptoms, Childhood Asthma Control Test, and Lung Function among Asthmatic Children.

A web-based self-health management system-eAsthmaCare, was developed as an intervention for asthmatic children. A randomized controlled trial was performed. Consent was obtained for 98 children with asthma to participate in the study and the pre- and post-test data collection process. The experimental group was given access to eAsthmaCare online management, the control group was subjected to general asthma management. The experimental and control groups' asthma symptoms, Childhood Asthma Control Test (C-ACT) scores, and lung function were evaluated, and their pre- and 3-month post-test results were compared. The following records were maintained: (1) medication record (2) daily asthma symptoms log (3) monthly C-ACT and lung function records. The C-ACT results indicated a p-value of < .01 for: overall improvements to childhood asthma symptoms, time effect, group and time interaction effects, and group and time interaction effects in relation to sleeping condition on the previous day; cough symptom time effect, and group and time interaction effects; the two groups' time effect in relation to cough symptoms; the two groups' time effect in relation to monthly activity restrictions (number of days); and the two groups' time effect in relation to nasal symptoms; the two groups' time effect; and group and time interaction effects (p < .01). In terms of the predictive values for lung function (FVC, FEV1, PEFR), the improvements in both groups were not statistically significant. The implementation of the eAsthmaCare intervention might have a positive impact on pediatric patients, making it an effective management tool for monitoring asthmatic children's physical function and discomfort.

Clinical Features of Female Taiwanese Carriers with X-linked Chronic Granulomatous Disease from 2004 to 2019.

PURPOSE: Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have < 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation. METHODS: Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019. RESULTS: A total of 19 mothers (median 27 years; range 25-60 years) and three of four girls (range 4-6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8-52.4%) and ROS production (38.3%, range 28.2-54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world. CONCLUSION: One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.

Levels of 15-HETE and TXB2 in exhaled breath condensates as markers for diagnosis of childhood asthma and its therapeutic outcome.

BACKGROUND: Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled leukotriene B4 (LTB4 ), characterizes childhood asthma. While fractional exhaled nitric oxide (FeNO) has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment. METHODS: Levels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA. RESULTS: In addition to those previously reported, including LTB4 , the levels of exhaled 15-hydroxyeicosatetraenoic acid (15-HETE), but not thromboxane B2 (TXB2 ), showed significant difference between asthmatics (N = 318) and healthy controls (N = 97), particularly the severe group showed the lowest levels of exhaled 15-HETE. Receiver operating characteristic (ROC) curve analyses revealed similar distinguishing power for the levels of 15-HETE, FEV1 (forced expiratory volume in the first second), and FeNO, while the 15-HETE/LTB4 ratio was significantly lower in subjects with asthma as compared to that of healthy controls (p < 0.0001). Analysis of asthmatics (N = 75) during exacerbation and convalescence showed significant improvement in lung function (FEV1 , p < .001), but not FeNO, concomitant with significantly increased levels of 15-HETE (p < .001) and reduced levels of TXB2 (p < .05) at convalescence, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB4 and lipoxin A4 (LXA4 ) at convalescence were noted only in those at the top 30 percentile during exacerbation. CONCLUSION: The exhaled 15-HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB2 and increased levels of 15-HETE were prominent at convalescence.

Outdoor air pollutants exposure associated with pulmonary function and EBC pH value in atopic asthmatic and non-asthmatic children.

OBJECTIVE: Air pollution is associated with the prevalence of respiratory diseases. This study aimed to evaluate the impacts of outdoor air pollutants and indoor Dermatophagoides pteronyssinus 1 (Der p 1) exposure on levels of fractional exhaled nitric oxide (FeNO), exhaled breath condensate (EBC) pH, and pulmonary function in atopic children. METHODS: This study recruited 59 atopic mild-to-moderate asthmatic children and 23 atopic non-asthmatic children. Data on personal characteristics, FeNO, EBC pH, and pulmonary function were collected. Group 1 allergens of Der p 1 were measured on the tops of mattresses and on bedroom floors in the children's homes, and outdoor air pollutant concentrations were estimated from air quality monitoring stations, using the ordinary kriging method. RESULTS: Exposure levels of outdoor air pollutants, except for particulate matter (PM)2.5, for the recruited children met outdoor air quality standards set by the Taiwan Environmental Protection Agency. The lag effect of outdoor PM10 exposure was negatively associated with the forced expiratory volume in one second (FEV1) [(Lag 1: ß=-0.771, p = 0.028), and O3 (Lag 1-7: ß=-2.02, p = 0.04, Lag 1-28: ß=-3.213, p = 0.029)]. Median pulmonary function parameters differed significantly in forced vital capacity (FVC) (p = 0.004) and FEV1 (p = 0.024) values between atopic asthmatic and non-asthmatic children. No association was found between the FeNO/EBC pH level and exposure to Der p 1 allergen and air pollutants in the recruited children. CONCLUSIONS: Outdoor PM10 and O3 exposure was associated with reduction in FEV1 in atopic asthmatic and non-asthmatic children.

Particulate matter causes telomere shortening and increase in cellular senescence markers in human lung epithelial cells.

Exposure to particulate matter (PM) has been associated with DNA damage, but the relationships between PM, telomere length and cellular senescence remain unclear. This study aimed to investigate the effects and potential mechanisms of PM on telomere length and cellular senescence in human lung epithelial cells. Human lung epithelial A549 cells were exposed to PM for 24 h. Cell viability and cytotoxicity were measured by the WST-1 assay and the lactate dehydrogenase release, respectively. Cellular uptake of PM was observed using transmission electron microscopy. Telomere length was measured using qPCR and expressed as T/S ratio. Cell cycle progression was analyzed by flow cytometry. Expression of human telomerase reverse transcriptase (hTERT) and cell cycle regulators was measured using mRNA by qPCR and protein levels by Western blot. Cellular senescence was determined by the expression of senescence-associated ß-galactosidase (SA-ß-Gal) with fluorescent microscopy and flow cytometry. Exposed to PM at the concentration of 200 µg/ml decreased cell viability and increased LDH levels in culture medium. Remarkably increased uptake of PM, shortening of telomere length, induction of G0/G1 phase arrest, and increased expression of senescence hallmarks were observed after exposure to PM in A549 cells. PM exposure induced upregulation of p21 and downregulation of proliferating cell nuclear antigen (PCNA) and hTERT expression, but no significant change in p53 expression, in A549 cells. Overall, exposure to PM may downregulate hTERT and PCNA through p53-independent induction of p21 expression, leading to telomere shortening, G0/G1 arrest and the onset of cellular senescence in human lung epithelial cells.

Food aversion and poor weight gain in food protein-induced enterocolitis syndrome: A retrospective study.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. Insufficient data exist in regard to gastrointestinal history and outcome, particularly comorbidity, family history, food aversion, and poor body weight gain. OBJECTIVE: We sought to identify the gastrointestinal outcomes and related risk factors in FPIES. METHODS: We analyzed the clinical features and gastrointestinal outcomes of patients with FPIES retrospectively at 4 hospitals in Boston. RESULTS: Two hundred three patients with FPIES were identified, including 180 only with acute FPIES, 8 with chronic FPIES, and 15 with both. Oat (34.5%), rice (29.6%), and cow's milk (19.2%) were the most common food triggers. The prevalence rates of personal history with allergic proctocolitis (23.2%) and family history with inflammatory bowel diseases (9.4%) and celiac disease (7.3%) were higher than those in the general population. Compared with patients with FPIES with 1 or 2 food triggers, the risk of developing food aversion increased in cases triggered by 3 or more foods (adjusted odds ratio, 3.07; 95% CI, 1.38-6.82; P = .006). The risk of poor body weight gain increased in FPIES triggered by cow's milk (adjusted odds ratio, 3.41; 95% CI, 1.21-9.63; P = .02) and banana (adjusted odds ratio, 7.63; 95% CI, 2.10-27.80; P = .002). CONCLUSIONS: Gastrointestinal comorbidities and family history were common in patients with FPIES. Patients with FPIES with 3 or more triggers were at risk of food aversion. Patients with FPIES with cow's milk and banana as triggers were at risk of poor body weight gain.