Publications by authors named "Jing-Long Huang"

248 Publications

Lipopolysaccharide stimulation test on cultured PBMCs assists the discrimination of cryopyrin-associated periodic syndrome from systemic juvenile idiopathic arthritis.

Sci Rep 2021 Jun 7;11(1):11903. Epub 2021 Jun 7.

Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, No.5 Fu-Hsing St., Taoyuan, Taiwan, ROC.

Systemic juvenile idiopathic arthritis (sJIA) and cryopyrin-associated periodic syndrome (CAPS) share many common manifestations. We aim to identify an applicable method to assist disease discrimination. Inflammatory cytokines were measured in the plasma of patients with CAPS, sJIA with persistent disease course and healthy controls. Supernatants collected from non-stimulated peripheral blood mononuclear cells (PBMCs) and those undergone inflammasome stimulation tests utilizing lipopolysaccharide (LPS) with and without adenosine triphosphate (ATP) were investigated. Inflammatory cytokines in patient plasma fail to differentiate sJIA from CAPS. PBMCs from sJIA secrets higher amount of IL-1β and IL-18 while CAPS PBMCs produces more caspase-1 without stimulation. IL-1β, IL-18, and caspase-1 were significantly elevated among CAPS PBMCs (all p < 0.05) upon LPS stimulation, but not when additional ATPs were provided. Levels of cytokines and PBMC responses to the stimulation assays were similar among all sJIA patients regardless of their history of macrophage activation syndrome. Unstimulated PBMC activities and the LPS inflammasome stimulation assay without exogenic ATPs can assist the differentiation of CAPS from sJIA with persistent disease course.
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http://dx.doi.org/10.1038/s41598-021-91354-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185076PMC
June 2021

Age, gender, height and weight in relation to joint cartilage thickness among school-aged children from ultrasonographic measurement.

Pediatr Rheumatol Online J 2021 May 12;19(1):71. Epub 2021 May 12.

Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Among school-age children, the decrease of cartilage thickness (Cth) with increasing age is well known. However, the influence of body mass index (BMI), height or weight on Cth has not been revealed. Here in, we aim to establish an age- and gender-specific Cth standard reference among Asians and investigate the possible prestige of BMI, height and weight.

Methods: A cross-sectional study was performed in healthy Asian children. Bilateral knees, ankles, wrists, second metacarpophalangeals (MCPs) and proximal interphalangeals (PIPs) were measured using ultrasound. The children's height, weight and BMI were also recorded for later adjustment.

Results: A total of 200 school age Asian children (including 86 girls and 114 boys, aged between 5 to 13 years-old) were investigated. Cth differences were observed in the knees, ankles, wrists, MCPs and PIPs between sexes (p < 0.05), with girls having thinner cartilage thickness. While Cth decreases with increasing age (p < 0.0001, 0.039, 0.001, 0.023, 0.091 in girls' knees, ankles, wrists, MCPs and PIPs and p = 0.002, 0.001, < 0.0001, 0.001, 0.045 in boys', respectively). Our data showed that weight, height and BMI are not the main factors contributing to Cth. A formula to calculate gender-specific cartilage thickness for Asian school age children is suggested. There was no difference in Cth after adjusting for height or weight between Asian or Caucasian group.

Conclusions: A formula to calculate gender-specific cartilage thickness for Asian school age children is suggested. Height, weight and BMI were not the major contributor for Cth among school age children.
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http://dx.doi.org/10.1186/s12969-021-00554-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117573PMC
May 2021

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

J Clin Immunol 2021 May 8. Epub 2021 May 8.

Division of Infection, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

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.
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http://dx.doi.org/10.1007/s10875-021-01055-xDOI Listing
May 2021

Distinct lung function and bronchodilator responses between term and preterm young children with recurrent wheezing.

Pediatr Neonatol 2021 Apr 20. Epub 2021 Apr 20.

Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, Chang Gung Memorial Hospital Keelung Branch, Keelung, Taiwan; Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study, Keelung, Taiwan. Electronic address:

Background: Recurrent or unresolved wheezing is a common complaint in certain young children populations, especially those born preterm. Using infant lung function testing, we aimed to distinguish the differences between term and preterm young children with recurrent wheezing.

Methods: Children under 2 years of corrected age were enrolled if they had 3 or more wheezing episodes during the enrollment period. Healthy term controls of comparable age were also recruited for reference. Measurements of lung function were made, including tidal breathing, passive respiratory mechanics, and forced tidal and raised-volume expiration. For children with recurrent wheezing, raised-volume forced expiration was repeated after an adequate delivery of bronchodilator nebulization was achieved.

Results: In total, 68 young children (40 with recurrent wheezing and 28 healthy controls) were recruited. Among children with recurrent wheezing, 23 preterm children (preterm group), and 17 term children (term group) were enrolled. Compared with healthy controls, both the term and preterm groups had lower lung function as measured by absolute values and z scores. The term group performed worse than the preterm group with regard to forced vital capacity, forced expiratory volume at 0.5 s (FEV), and peak expiratory flow. Following bronchodilator nebulization, the term group had significantly higher increases in FEV and forced mid-expiratory flow than the preterm group.

Conclusion: Young children with recurrent wheezing, especially term infants, demonstrated lower lung function than healthy controls. Moreover, the term group evidenced greater responsiveness to bronchodilators than the preterm group. The distinct bronchodilator responses may offer further information to guide the diagnosis and treatment of young children with recurrent wheezing.
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http://dx.doi.org/10.1016/j.pedneo.2021.03.015DOI Listing
April 2021

The Impact of Serum Anti-neutrophil Cytoplasmic Antibody on Clinical Characteristics and Outcomes in Pediatric-Onset Systemic Lupus Erythematosus Patients.

Front Med (Lausanne) 2021 16;8:647510. Epub 2021 Apr 16.

Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.

Systemic lupus erythematosus (SLE), an autoimmune disease, is characterized by the overproduction of autoantibodies. Anti-neutrophil cytoplasmic antibodies (ANCAs) have been recognized in SLE for decades. To date, their association with SLE disease activity, especially in pediatric-onset SLE (pSLE) patients, is limited. We conducted a retrospective case-control study of pSLE patients with ANCAs from 2010 to 2020. Clinical characteristics, laboratory data, renal histological features, treatment and outcomes were analyzed. A total of 70 pediatric-onset SLE patients (9 ANCA-positive vs. 61 ANCA-negative) with a median age of 12.23 years (age ranging from 4 years to 18 years) at diagnosis were enrolled. Among patients with ANCAs, MPO-ANCA was found in seven and PR3-ANCA in two of those cases. Patients with ANCAs had a tendency to have hematuria compared with those without ANCAs (66 vs. 24.6%, respectively; = 0.026). Of the 70 SLE patients, 8 with ANCAs and 44 without ANCAs underwent renal biopsies. Patients with ANCAs (25%, 2/8) were more likely to lack the typical full-house pattern in their renal immunofluorescence (IF) staining. pSLE patients with ANCAs tend to have hematuria and an absence of typical IF histology. However, patients with and without ANCAs showed no difference in their clinical presentations and treatment outcomes.
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http://dx.doi.org/10.3389/fmed.2021.647510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085249PMC
April 2021

Effect of Hydrocortisone on Angiotensinogen () Mutation-Causing Autosomal Recessive Renal Tubular Dysgenesis.

Cells 2021 Apr 1;10(4). Epub 2021 Apr 1.

Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei 114, Taiwan.

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.
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http://dx.doi.org/10.3390/cells10040782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065467PMC
April 2021

Palmitoleic and Dihomo-γ-Linolenic Acids Are Positively Associated With Abdominal Obesity and Increased Metabolic Risk in Children.

Front Pediatr 2021 9;9:628496. Epub 2021 Apr 9.

Chang Gung University College of Medicine, Taoyuan, Taiwan.

The impact of abdominal obesity (AO) on plasma fatty acid changes and cardiometabolic risk in children who are obese and overweight has rarely been investigated. This study determined whether plasma fatty acid composition differed between children with AO and those without AO and its relationship with metabolic risk, particularly in the obese and overweight groups. A total of 181 schoolchildren (aged 7-18 years) were included. Anthropometric and biochemical data and plasma fatty acid profiles were analyzed, and the indices of desaturase activity were estimated. Children were categorized based on their body weight and AO status. A continuous metabolic risk score was calculated using the sum of the z-scores of metabolic variables. A one-way analysis of variance test was used to compare the composition ratio of fatty acids between children with and without AO in the obese and overweight groups and normal-weight controls. Pearson analysis was also used to explore significant fatty acid and desaturase indicators associated with metabolic abnormalities. Children who were obese and overweight ( = 126) displayed higher dihomo-γ-linolenic acid (20:3n-6) and γ-linolenic acid (18:3n-6) proportions than normal-weight controls ( = 55), but lower heptadecanoic acid (17:0) proportion, regardless of the AO status of each individual. Obese and overweight children with AO ( = 89), but not their non-AO counterparts ( = 37), exhibited a significantly higher proportion of palmitoleic acid (16:1n-7) than the remaining study groups. Pearson analysis showed that high proportions of palmitoleic acid and dihomo-γ-linolenic acid, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities, are strongly correlated with weight-height ratio, homeostasis model of assessment values for insulin resistance, hypertriglyceridemia, and continuous metabolic risk scores. Higher palmitoleic acid and dihomo-γ-linolenic acid proportions, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities are associated with AO and increased metabolic risk in children who are obese and overweight.
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http://dx.doi.org/10.3389/fped.2021.628496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062925PMC
April 2021

Cord blood soluble Fas ligand linked to allergic rhinitis and lung function in seven-year-old children.

J Microbiol Immunol Infect 2021 Apr 9. Epub 2021 Apr 9.

Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, and College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background: Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated.

Methods: The Prediction of Allergies in Taiwanese Children birth cohort study recruited healthy newborns upon delivery. At birth, blood was collected from the umbilical cords of these children, and the cord blood soluble Fas ligand levels were measured. At the age of seven years, the allergic outcome of each child was diagnosed by pediatric allergists and pulmonologists. Tests were conducted to measure the specific immunoglobulin E, fractional exhaled nitric oxide (FeNO), and pulmonary function levels of each child.

Results: Cord blood soluble FasL levels were higher in seven-year-old children with allergic rhinitis (Odds ratio [OR] = 2.41, p = 0.012) and expiratory airway obstruction (the highest forced expiratory volume in 1 second/forced vital capacity < 90%, OR = 2.11, p = 0.022). The FeNO and Dermatophagoides pteronyssinus-specific immunoglobulin E levels of seven-year-old children were positively correlated with cord blood soluble FasL levels (p = 0.006 and 0.02, respectively).

Conclusion: In this birth cohort, the cord blood soluble FasL levels were associated with allergic rhinitis, obstructive-type lung function, FeNO, and house dust mite sensitization in 7-year-old children. The cord blood soluble FasL level might be used as a predictor for allergic diseases in children who are 7 years old.
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http://dx.doi.org/10.1016/j.jmii.2021.03.016DOI Listing
April 2021

Association of Oral Corticosteroid Bursts With Severe Adverse Events in Children.

JAMA Pediatr 2021 Apr 19. Epub 2021 Apr 19.

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Importance: The adverse effects from the long-term use of oral corticosteroids are known, but, to our knowledge, few studies have reported the risk of corticosteroid bursts, particularly among children.

Objective: To quantify the associations of corticosteroid bursts with severe adverse events, including gastrointestinal (GI) bleeding, sepsis, pneumonia, and glaucoma, in children.

Design, Setting, And Participants: This cohort study used data derived from the National Health Insurance Research Database in Taiwan from January 1, 2013, to December 31, 2017, on children younger than 18 years of age and used a self-controlled case series design. Data were analyzed from January 1 to July 30, 2020.

Exposure: Oral corticosteroid bursts (defined as oral corticosteroid use for ≤14 days).

Main Outcomes And Measures: Incidence rates were calculated of 4 severe adverse events (GI bleeding, sepsis, pneumonia, and glaucoma) in children who did or did not receive corticosteroid bursts. Conditional fixed-effect Poisson regression was used to estimate incidence rate ratios (IRRs) of severe adverse events within 5 to 30 days and 31 to 90 days after initiation of corticosteroid bursts.

Results: Among 4 542 623 children, 23% (1 064 587; 544 268 boys [51.1%]; mean [SD] age, 9.7 [5.8] years) were prescribed a single corticosteroid burst. The most common indications were acute respiratory tract infections and allergic diseases. The incidence rate differences per 1000 person-years between children administered a single corticosteroid burst and those not prescribed corticosteroids were 0.60 (95% CI, 0.55-0.64) for GI bleeding, 0.03 (95% CI, 0.02-0.05) for sepsis, 9.35 (95% CI, 9.19-9.51) for pneumonia, and 0.01 (95% CI, 0.01-0.03) for glaucoma. The IRRs within 5 to 30 days after initiating corticosteroid bursts were 1.41 (95% CI, 1.27-1.57) for GI bleeding, 2.02 (95% CI, 1.55-2.64) for sepsis, 2.19 (95% CI, 2.13-2.25) for pneumonia, and 0.98 (95% CI, 0.85-1.13) for glaucoma; the IRRs within the subsequent 31 to 90 days were 1.10 (95% CI, 1.02-1.19) for GI bleeding, 1.08 (95% CI, 0.88-1.32) for sepsis, 1.09 (95% CI, 1.07-1.11) for pneumonia, and 0.95 (95% CI, 0.85-1.06) for glaucoma.

Conclusions And Relevance: This study suggests that corticosteroid bursts, which are commonly prescribed for children with respiratory and allergic conditions, are associated with a 1.4- to 2.2-fold increased risk of GI bleeding, sepsis, and pneumonia within the first month after initiation of corticosteroid therapy that is attenuated during the subsequent 31 to 90 days.
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http://dx.doi.org/10.1001/jamapediatrics.2021.0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056312PMC
April 2021

Complement Factor I Mutation May Contribute to Development of Thrombotic Microangiopathy in Lupus Nephritis.

Front Med (Lausanne) 2020 5;7:621609. Epub 2021 Feb 5.

Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Renal thrombotic microangiopathy (TMA) is associated with complement overactivation and poor outcome in patients with lupus nephritis (LN). The role of genetic makeup of complement system in these patients remains to be elucidated. The clinical and laboratory characteristics of 100 patients with LN during 2010-2017 were retrospectively analyzed. LN patients with renal TMA and condition-matched LN patients without renal TMA were studied. Twenty normal subjects were also enrolled for comparison. Whole exome sequence followed by Sanger sequence was used in our study cohort. Eight patients with renal TMA and eight condition-matched patients were enrolled from 100 LN patients with mean age 11.2 ± 2.0 years. Compared with condition-matched LN patients without renal TMA, LN patients with renal TMA exhibited statistically higher serum urea. Although most patients with renal TMA responded to plasma exchange, they had significantly higher relapse rate of nephritis, lower remission rate, and higher risk of end-stage renal disease and mortality. Compared with patients without renal TMA and normal subjects, those with renal TMA had significantly lower serum complement factor H (CFH) and plasma ADAMTS13 activity. Molecular analysis of all 100 patients with LN uncovered that three patients with renal TMA harbored mutations, two missense and non-sense, on and . The non-sense mutation, E302X, on may impair its interaction C3b/CFH complex by loss of the heavy chain of complement factor I on simulation model. In addition to low serum CFH level and plasma ADAMTS13 activity, defects in genes responsible for complement regulatory proteins may contribute to the development of renal TMA in patients with LN.
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http://dx.doi.org/10.3389/fmed.2020.621609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892619PMC
February 2021

Longitudinal analysis of total serum IgE levels with allergen sensitization and atopic diseases in early childhood.

Sci Rep 2020 12 4;10(1):21278. Epub 2020 Dec 4.

Division of Pediatric Pulmonology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyüan, Taiwan.

There are few studies addressing the longitudinal analysis of serum IgE levels and its impact to the development of atopic diseases in early childhood. We investigated 170 children who regularly followed up at our clinic for 4 years in a birth cohort study with at least 3 time-points of serum samples. The pattern of total serum IgE levels from 6 months to 4 years of age was clustered using K-means method in R software. Specific immunoglobulin E antibodies against food (egg white and milk) and inhalant allergens (D. pteronyssinus and D. farinae) were measured at 0.5, 1, 1.5, 2, 3 and 4 years of age. By using K-means clustering, the dynamic changes in serum IgE levels was significantly stratified into 3 clusters (cluster A, < 100 kU/L, n = 106; cluster B, 100-200 kU/L, n = 35; cluster C, ≥ 200 kU/L, n = 29). A persistent total IgE levels higher than 100 kU/L appeared to be associated with higher prevalence of sensitization to food but not mite. However, a persistent IgE levels higher than 200 kU/L was not only remarkably related to increased prevalence of mite sensitization, but also risk of eczema at age 1 and allergic rhinitis and asthma at age 2, 3 and 4. In conclusion, a persistent total serum IgE level ≥ 200 kU/L since infancy is strongly associated with the presence of food and mite sensitization, as well as the development of eczema in infants, and rhinitis and asthma later in early childhood.
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http://dx.doi.org/10.1038/s41598-020-78272-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718260PMC
December 2020

Autosomal Recessive Renal Tubular Dysgenesis Caused by a Founder Mutation of Angiotensinogen.

Kidney Int Rep 2020 Nov 20;5(11):2042-2051. Epub 2020 Aug 20.

Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, National Defense Medical Center, Taiwan.

Introduction: Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in , , , and is a very rare but fatal disorder with an unknown prevalence.

Methods: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined.

Results: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in , which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels.

Conclusion: This mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.
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http://dx.doi.org/10.1016/j.ekir.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609895PMC
November 2020

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia.

Front Immunol 2020 4;11:2001. Epub 2020 Sep 4.

Division of Allergy, Asthma, and Rheumatology, Chang Gung University College of Medicine, Taoyuan, Taiwan.

X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase () gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for expression and genetic analysis. Nineteen (from 16 families) out of 29 patients had mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with mutations had obviously decreased expressions. sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.
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http://dx.doi.org/10.3389/fimmu.2020.02001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498534PMC
May 2021

Prenatal exposure to bisphenol - A is associated with dysregulated perinatal innate cytokine response and elevated cord IgE level: A population-based birth cohort study.

Environ Res 2020 12 6;191:110123. Epub 2020 Sep 6.

Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; Department of Pediatrics, New Taipei Municipal Tucheng Hospital, Chang Gung Memorial Hospital, Tucheng, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan. Electronic address:

Background: Reports on the relationship between prenatal exposure to bisphenol-A (BPA) and the development of childhood allergy have been conflicting. This study aimed to investigate the impact of prenatal BPA exposure on several objective outcomes such as cytokine profile, atopic sensitization, and infant lung function (ILF) tests in addition to clinical allergic symptoms.

Methods: A subset of 274 children from the PATCH cohort study with available cord BPA data were followed until 3 years of age. Total and specific IgE level and Toll-like receptor (TLR) stimulated cytokine production were assessed yearly since birth. ILF such as tidal volume, Vmax, airway resistance and compliance were performed at least once before the age of 2 years. Allergic outcome was determined by questionnaires and physician's assessment.

Results: There was significant association between BPA concentration and IgE level in the cord blood (p < 0.01), but the correlation was no longer significant at ages 1 through 3 years. In addition, cord BPA concentration was associated with dysregulated TLR stimulated TNF-α and IL-6 production, but the correlation was significant only at birth. No relationship was found between cord BPA concentration and ILF measurements or allergic symptoms (wheezing, rhino-conjunctivitis, or eczema) throughout early childhood.

Conclusion: Results showed that prenatal exposure to BPA was not associated with increased risk of childhood allergy or impaired ILF. However, with its impact on biomarkers for allergy such as alterations in perinatal cytokine profile and elevated cord IgE level, the potential role of prenatal BPA exposure on the development of allergy cannot be disregarded.
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http://dx.doi.org/10.1016/j.envres.2020.110123DOI Listing
December 2020

Longitudinal investigation of nasopharyngeal pneumococcal carriage in early childhood: The PATCH birth cohort study.

PLoS One 2020 20;15(8):e0237871. Epub 2020 Aug 20.

Chang Gung University College of Medicine, Taoyuan, Taiwan.

Streptococcus pneumoniae is a common cause of infectious diseases such as pneumonia and sepsis. Its colonization is thought to be the first step in the development of invasive pneumococcal diseases. This study aimed to investigate pneumococcal colonization patterns in early childhood. A longitudinal birth cohort study was conducted for investigating nasopharyngeal colonized pneumococci at 1, 6, 12, 18, 24, and 36 months of age, particularly focusing on the serotype distribution and antimicrobial susceptibilities. Pneumococcal conjugate vaccine (PCV) effect on nasopharyngeal colonization was also assessed. During 2013-2017, 855 infants were enrolled and a total of 107 isolates were recovered from 95 infants during the first three years of life. In this period, the prevalence of pneumococcal colonization increased, with values ranging from 0.2% (2/834) at 1 month of age to 5.9% (19/323) at 36 months of age. The investigation of serotype revealed that 81.1% (73/90) belonged to the non-PCV13 serotypes-23A, 15A, 15C, and 15B. Moreover, PCV13 serotypes significantly decreased during 2014-2015, when routine PCV13 vaccination was initiated in Taiwan. PCV13 introduction may lead to the reduction in the rates of pneumococcal isolates resistant (R) to penicillin. Under conditional PCV13 vaccination, pneumococcal isolates primarily belonged to non-PCV13 serotypes. This non-PCV13 serotype replacement exhibited lower rates of penicillin R isolates, suggesting that PCV13 administration may reduce the antibiotic-nonsusceptible pneumococcal disease burden and antibiotic use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237871PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446878PMC
October 2020

Clinical significance of herpes virus entry mediator expression in hepatitis B virus-related hepatocellular carcinoma.

Oncol Lett 2020 Oct 16;20(4):19. Epub 2020 Jul 16.

Key Laboratory of Carcinogenesis and Cancer Invasion, Department of Liver Surgery and Transplantation, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.

Herpes virus entry mediator (HVEM) is overexpressed in several malignancies, including hepatocellular carcinoma (HCC). However, to the best of our knowledge, the clinical significance of HVEM in hepatitis B virus (HBV)-related HCC remains unclear. Thus, the present study aimed to explore the clinical significance of HVEM in HBV-related HCC. In the present study, HVEM expression was evaluated in HCC cell lines and HCC frozen samples. The prognostic value of HVEM was assessed in a cohort of 221 patients with HBV-related HCC, following radical resection. B- and T-lymphocyte attenuator (BTLA) expression in subsets of CD8 T cells was determined via flow cytometry analysis. The results demonstrated high HVEM expression in HCC cell lines, and in HCC tissues compared with paired non-cancerous liver tissues. HVEM expression was demonstrated to be significantly associated with tumor encapsulation and vascular invasion. Furthermore, tumor HVEM status was significantly associated with infiltration of regulatory T cells, but not with CD8 T cells. Notably, high HVEM expression in HCC was determined to be an independent predictor of an unfavorable outcome of patients with HCC following radical resection. Higher BTLA expression (the receptor of HVEM) was observed in both HCC-infiltrating CD8 effector memory (CCR7 CD45RA) and CD45RA effector memory (CCR7 CD45RA) T cells in HCC tissues and blood compared with those in paired peritumor tissues or peripheral blood. Taken together, the results of the present study suggest that HVEM may serve a critical role in HBV-related HCC, most likely by promoting tumor progression and tumor immune evasion, thus the HVEM/BLTA signaling pathway may be a potential target in tumor immunotherapy.
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http://dx.doi.org/10.3892/ol.2020.11880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406888PMC
October 2020

Lower T Regulatory and Th17 Cell Populations Predicted by RT-PCR-Amplified and γ Genes Are Not Rare in Patients With Primary Immunodeficiency Diseases.

Front Immunol 2020 25;11:1111. Epub 2020 Jun 25.

Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Deficiencies in T regulatory (Treg) and Th17 cells attenuate peripheral tolerance and the IL-17 family of cytokines, contributing to autoimmune disorders and opportunistic (fungal) infections, respectively. Because of limited blood samples from patients with primary immunodeficiency diseases (PIDs), a positive correlation/linear relationship between Treg and Th17 cells and their respective expressions of transcription factors forkhead box P3 (FOXP3) and retinoic acid-related orphan receptor γ (RORγt) by real-time PCR (RT-PCR) amplification, was used to predict the percentages of Treg and Th17 cells in peripheral blood. Compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, the percentages of Treg and Th17 cells were calculated as the linear relationship to the 2 value (cycle threshold). Among 91 PIDs patients, 68 and 78 had predicted Treg and Th17 percentages below 5% of the normal ranges (0.859 and 0.734%, respectively), which expanded different categories beyond obvious T cell deficiency. Notably, FOXP3 was undetectable in one patient (CVID), RORγt was undetectable in six patients (one CVID, one CID, two neutropenia, one WAS, and one CMC), and both were undetectable in four patients (two SCID, one STAT1, and one periodic fever). In contrast, two patients with auto-IFNγ antibodies had increased susceptibility to intracellular mycobacterial infections, interrupted Th1 development and subsequent elevation in the Th17 cells. Both predicted Treg and Th17 percentages in the PIDs patients were more independent of age (months) than in the controls. The predicted Th17/Treg ratio in the PIDs patients, overall, was lower than that in the healthy controls (0.79 ± 0.075 vs. 1.16 ± 0.208; = 0.038). In conclusion, lower predicted Treg and Th17 cell populations calculated by RT-PCR-amplified FOXP3 and RORγt in PIDs patients at diagnosis can explain the higher potential phenotypes of autoimmune disorders and opportunistic infections, although effective interventions in the early stage might have prevented such phenotypic development and caused a statistical bias in the comparisons.
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http://dx.doi.org/10.3389/fimmu.2020.01111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330141PMC
April 2021

Diminished toll-like receptor response in febrile infection-related epilepsy syndrome (FIRES).

Biomed J 2020 06 29;43(3):293-304. Epub 2020 May 29.

Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background: Defective human TLR3 signaling causes recurrent and refractory herpes simplex encephalitis/encephalopathy. Children with febrile infection-related epilepsy syndrome with refractory seizures may have defective TLR responses.

Methods: Children with febrile infection-related epilepsy syndrome were enrolled in this study to evaluate TLR1-9 responses (IL-6, IL-8, IL-12p40, INF-α, INF-γ, and TNF-α) in their peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs), compared to those with febrile seizures and non-refractory epilepsy with/without underlying encephalitis/encephalopathy.

Results: Adenovirus and enterovirus were found in throat cultures of enrolled patients (2-13 years) as well as serologic IgM elevation of mycoplasma pneumonia and herpes simplex virus, although neither detectable pathogens nor anti-neural autoantibodies in the CSF could be noted. Their PBMCs and MDDCs trended to have impaired TLR responses and significantly lower in cytokine profiles of TLR3, TLR4, TLR7/8, and TLR9 responses but not other TLRs despite normal TLR expressions and normal candidate genes for defective TLR3 signaling. They also had decreased naïve T and T regulatory cells, and weakened phagocytosis.

Conclusion: Children with febrile infection-related epilepsy syndrome (FIRES) could have impaired TLR3, TLR4, TLR7/8, and TLR9 responses possibly relating to their weakened phagocytosis and decreased T regulatory cells.
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http://dx.doi.org/10.1016/j.bj.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424096PMC
June 2020

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

J Asthma 2020 Sep 21:1-7. Epub 2020 Sep 21.

Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Objective: Air pollution is associated with the prevalence of respiratory diseases. This study aimed to evaluate the impacts of outdoor air pollutants and indoor 1 ( 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 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), for the recruited children met outdoor air quality standards set by the Taiwan Environmental Protection Agency. The lag effect of outdoor PM exposure was negatively associated with the forced expiratory volume in one second (FEV) [(Lag 1: =-0.771,  = 0.028), and O (Lag 1-7: =-2.02,  = 0.04, Lag 1-28: =-3.213,  = 0.029)]. Median pulmonary function parameters differed significantly in forced vital capacity (FVC) ( = 0.004) and FEV ( = 0.024) values between atopic asthmatic and non-asthmatic children. No association was found between the FeNO/EBC pH level and exposure to 1 allergen and air pollutants in the recruited children.

Conclusions: Outdoor PM and O exposure was associated with reduction in FEV in atopic asthmatic and non-asthmatic children.
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http://dx.doi.org/10.1080/02770903.2020.1788075DOI Listing
September 2020

Oxidative stress is associated with atopic indices in relation to childhood rhinitis and asthma.

J Microbiol Immunol Infect 2021 Jun 13;54(3):466-473. Epub 2020 Feb 13.

Community Medicine Research Centre, Chang Gung Memorial Hospital, Keelung, Taiwan; Division of Pediatric Pulmonology, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background: The association between oxidative stress and atopic diseases is uncertain. Several risk factors for atopic diseases have been identified, however, a comprehensive investigation of the relationship between oxidative stress markers and atopic indices related to atopic diseases is currently lacking.

Methods: We investigated 132 children who completed a 7-years follow-up in a birth cohort. Oxidative stress markers including plasma glutathione peroxidase (GPx), myeloperoxidase (MPO), total anti-oxidant capacity (TAC), and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were measured. Allergen-specific IgE levels, FeNO levels, and pulmonary function tests were also obtained.

Results: The activity of GPx and levels of MPO were inversely correlated to food (shrimp and crab) and house dust mite sensitization respectively. The 8-OHdG levels were strongly negatively correlated with FeNO levels (p < 0.01). A significant positive correlation was found between TAC levels and pre-and post-bronchodilator FVC % and FEV1% predicted (p < 0.05). All oxidative stress markers were not associated with the risk of atopic diseases. However, GPx-related crab sensitization and 8-OHdG related FeNO levels were significantly associated with increased risk of allergic rhinitis, while MPO-related mite sensitization and TAC-related pulmonary function parameters were strongly associated with risk of asthma (p < 0.01).

Conclusion: Oxidative stress is strongly correlated with allergic indices, potentially playing a role in the modulation of allergic responses contributing to atopic diseases.
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http://dx.doi.org/10.1016/j.jmii.2020.01.009DOI Listing
June 2021

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

Int J Environ Health Res 2020 Feb 19:1-11. Epub 2020 Feb 19.

Department of Information Management, Yuan Ze University, Taoyuan City, Taiwan.

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/m, 39.47 μg/m, 25.99 ppb, 2.19 ppb, and 11.23 ppb for PM, PM, O, SO, and NO, 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.
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http://dx.doi.org/10.1080/09603123.2020.1729964DOI Listing
February 2020

Correction to: Biomarkers associating endothelial dysregulation in pediatric-onset systemic lupus erythematous.

Pediatr Rheumatol Online J 2020 Feb 18;18(1):18. Epub 2020 Feb 18.

Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan.

Following publication of the original article [1], we have been notified that the colour representation of the graph is not correct in Figure 6 legend.
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http://dx.doi.org/10.1186/s12969-020-0405-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029457PMC
February 2020

Pregnancy outcomes and perinatal complications of Asian mothers with juvenile idiopathic arthritis - a case-control registry study.

Pediatr Rheumatol Online J 2020 Jan 23;18(1). Epub 2020 Jan 23.

Chang Gung University, College of Medicine, Taoyuan, Taiwan.

Backgrounds: In order to provide juvenile idiopathic arthritis (JIA) patients with better pre-conceptional and prenatal counselling, we investigated the obstetrical and neonatal outcomes among women with Asian descent.

Methods: Through the linkage of Taiwan National Health Insurance database and National Birth Registry, we established a population-based birth cohort in Taiwan between 2004 and 2014. In a case control study design, first children born to mothers with JIA are identified and matched with 5 non-JIA controls by maternal age and birth year. Conditional logistic regression was used to calculate odds ratios for maternal and neonatal outcomes crude and with adjustment.

Results: Of the 2,100,143 newborn, 778 (0.037%) were born to JIA mothers. Among them, 549 first-born children were included in this research. Our result suggested that babies born to mothers with JIA were more likely to have low birth body weight, with an adjusted OR of 1.35(95% CI: 1.02 to 1.79) when compared to babies born to mothers without. No differences were observed in other perinatal complications between women with and without JIA including stillbirth, prematurity, or small for gestational age. The rate of adverse obstetrical outcomes such as caesarean delivery, preeclampsia, gestational diabetes, postpartum hemorrhage and mortality were also similar between the two.

Conclusions: Adverse obstetrical and neonatal outcomes were limited among Asian mothers with JIA. Intensive care may not be necessary for JIA mothers and their newborns.
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http://dx.doi.org/10.1186/s12969-020-0404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979350PMC
January 2020

Evolution and Determinants of Lung Function until Late Infancy among Infants Born Preterm.

Sci Rep 2020 01 16;10(1):490. Epub 2020 Jan 16.

Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan.

To investigate the evolution of lung function in preterm infants with and without bronchopulmonary dysplasia (BPD) and to determine the perinatal characteristics associated with indexes of lung function in later infancy. Longitudinal lung function assessments were performed at approximately 6, 12, 18, and 24 months of corrected age in preterm infants. Perinatal characteristics were further analyzed to ascertain the determinants of lung function indexes. Although all preterm infants (n = 121; 61 without BPD and 60 with BPD) exhibited decreased lung function in early infancy (6 months of age), after body length was adjusted for, only infants with BPD exhibited poor performance. Furthermore, the lung function of infants with mild to moderate BPD caught up gradually, but the generally poor lung function performance of infants with severe BPD, especially in forced expiratory flow, persisted until later age (24 months). Regarding perinatal characteristics, the z-score of body length at the time of examination and total number of days on positive-pressure ventilation are the major determinants of lung function in later infancy.
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http://dx.doi.org/10.1038/s41598-019-57359-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965604PMC
January 2020

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

J Allergy Clin Immunol 2020 05 12;145(5):1430-1437.e11. Epub 2020 Jan 12.

Food Allergy Center, Massachusetts General Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Massachusetts General Hospital, Boston, Mass. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaci.2020.01.001DOI Listing
May 2020

A Novel Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes.

Front Immunol 2019 19;10:2833. Epub 2019 Dec 19.

Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

The T-cell receptor (TCR)/CD3 complex is crucial for T-cell development and regulation. In humans, , and gene defects cause severe combined T- and B-cell immunodeficiency. However, mutations alone lead to a less severe condition, which is mainly characterized by autoimmunity. In the present study, we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation. This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period. Distinct from the previously reported mutations, which mainly present as autoimmunity, the novel deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression. However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia. A PubMed search for this rare disease entity revealed seven Turkish and two Spanish patients (five unrelated families). Among a total of 20 alleles, there were 14 splicing mutations (80(-1)G>C), two missense mutations (c.1G>A), two nonsense mutations (c.250A>T), and two deletions (c.del213A). Three patients presented with isolated AIT without significant infections. Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months. Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features ( = 0.0124, = 0.01, and = 0.0124, respectively). The patients with AIT had a significantly better prognosis ( = 0.0124) to those without AIT. Our patient with the novel mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function.
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http://dx.doi.org/10.3389/fimmu.2019.02833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930882PMC
November 2020

The influence of clinical features mimicking primary immunodeficiency diseases (mPID) on children with Langerhans cell histiocytosis (LCH) - Four with mPID among 39 LCH children from one referral center during 18-year period.

Immunobiology 2020 03 27;225(2):151877. Epub 2019 Nov 27.

Department of Pediatrics, Division of Hematology/Oncology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address:

Background: Recurrent or refractory infections can be a warning sign of primary immunodeficiency diseases (PID). Such mimicking PID (mPID) can occur in patients with Langerhans cell histiocytosis (LCH). Because some cases with refractory molluscum contagiosum-like lesions and persistent otorrhea are finally diagnosed with LCH, we wondered whether such mPID can occur in LCH children and affect on their prognosis.

Methods: We retrospectively reviewed all children with LCH at our institute from 2001 to 2018. A complete medical review of sex, age, symptoms, treatment course, and outcome comparison was performed.

Results: Of 39 enrolled LCH patients, three had persistent otorrhea and one had refractory molluscum contagiosum-like lesions despite aggressive antibiotic therapy. These four cases with mPID had significantly higher rates of multi-system involvement, recurrence and 5-month more lag time, but no risk organ (liver, spleen and bone marrow) involvement compared to those without mPID, although bone and skin were the most involved in both groups. Overall, the lag-time in multi-system was longer than that in single-system involvement (median 2.5 vs. 1.0 months; p = 0.003). The diagnosis-age of risk organ involvement was younger than those without (median 8 vs. 43 months; p = 0.004). There were no significant differences in diagnosis-age, single/multi-system and risk organ involvement between remission and recurrence groups. All were alive excluding four who were lost to follow-up.

Conclusions: The LCH children with mPID had greater lag time, multi-system involvement, recurrence and more refractory treatment including transplantation despite the ratio of bone and skin lesions equal to those without mPID.
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http://dx.doi.org/10.1016/j.imbio.2019.11.012DOI Listing
March 2020

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

Pediatr Res 2020 06 18;87(7):1251-1255. Epub 2019 Dec 18.

Division of Nephrology. Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking.

Methods: Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up.

Results: The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring.

Conclusions: Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.
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http://dx.doi.org/10.1038/s41390-019-0727-7DOI Listing
June 2020

Trajectory of vitamin D, micronutrient status and childhood growth in exclusively breastfed children.

Sci Rep 2019 12 13;9(1):19070. Epub 2019 Dec 13.

Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan.

This study aimed to compare the trajectory of serum 25(OH)D, micronutrient levels, and anthropometric measurements between exclusively breastfed and mixed-fed children. This is a prospective cohort study. Anthropometric measurements of the children were obtained during scheduled clinical visits. Tests for 25(OHD), ferritin, zinc and complete blood count were performed yearly until 3 years of age. Clinical records and questionnaires on dietary habits were obtained. The results showed that despite official recommendations on vitamin D/iron supplements for breastfed children, less than 10% of our exclusively breastfed children received regular supplements. Thus, after 1 year, the odds for having iron deficiency anemia and vitamin D insufficiency were 9 [95% CI, 4-19] and 6 [95% CI, 2-16], respectively. Longitudinal follow-up showed the prevalence of iron deficiency to decrease from 34% at 1 year to 2% at age 3 years. However, the prevalence of vitamin D insufficiency remained persistently high throughout the first three years of life (60% at 1 to 44% at 3 years). Very few children had zinc deficiency. Anthropometric measurements showed exclusively breastfed children to have lower mean z-scores for body weight and height when compared to mixed-fed children after 12 months. In conclusion, children who were exclusively breastfed for longer than 4 months without proper supplement were more likely to have transient iron deficiency anemia and persistent vitamin D insufficiency. Their growth became relatively slower after infancy. Whether this was associated with underlying inadequate serum vitamin D and iron level remains an important issue to be explored.
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http://dx.doi.org/10.1038/s41598-019-55341-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910939PMC
December 2019

Including Fibroblast Growth Factor-21 in Combined Biomarker Panels Improves Predictions of Liver Steatosis Severity in Children.

Front Pediatr 2019 30;7:420. Epub 2019 Oct 30.

Chang Gung University College of Medicine, Taoyuan, Taiwan.

Previous studies reported conflicting results regarding the association between fibroblast growth factor-21 (FGF-21) and non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the feasibility of combining FGF-21, obesity indices, and biochemical tests for predicting high-grade liver steatosis in children. A total of 203 children and adolescents aged 5-18 years were enrolled, and their anthropometric data, body composition, liver ultrasound score for NAFLD (range, 0-6), biochemical test results, and FGF-21, leptin, and adiponectin levels were analyzed. Children were categorized according to body mass index (BMI) and NAFLD scores. Univariate analysis and multivariate linear regression were used to identify independent predictors for the degree of liver steatosis. The accuracy of the models was also evaluated using a receiver-operating characteristic (ROC) curve. FGF-21 levels were significantly higher in subjects with high-grade liver steatosis ( < 0.001). In obese and overweight children, regression analysis indicated that higher BMI and higher gamma-glutamyl transferase (γ-GT), triglycerides (TG), and FGF-21 levels were independent risk factors strongly correlated with NAFLD scores. FGF-21 combined with any of the above parameters showed a larger area under the ROC (AUROC, 0.861-0.873) than either parameter used alone. Overall, the best performance was obtained by combing FGF-21, γ-GT, and TG, with an AUROC of 0.871, specificity of 82.54%, and sensitivity of 83.78% for predicting high-grade liver steatosis. BMI, FGF-21, γ-GT, and TG levels were strongly correlated with liver steatosis severity. Including FGF-21 in the biomarker panels may improve the accuracy for identifying obese and overweight children with high-grade liver steatosis.
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http://dx.doi.org/10.3389/fped.2019.00420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842980PMC
October 2019