Respiratory-syncytial virus immunoprophylaxis on asthma symptoms development in prematurity with bronchopulmonary dysplasia.

Background: Infants with respiratory-syncytial virus bronchiolitis hospitalization are more likely to develop wheezing and subsequent asthma. Reportedly, palivizumab prophylaxis effectively prevents respiratory-syncytial virus hospitalization in high-risk children-such as premature infants or infants with bronchopulmonary dysplasia (BPD). Objective: We sought to explore the effect of respiratory-syncytial virus immunoprophylaxis on the risk of asthma development in premature infants with BPD in subtropical areas. Methods: This case-control study included preterm children with BPD born at Mackay Memorial Hospital, Taipei, Taiwan, from 1999 to 2015. Overall, medical records of 616 eligible participants were retrospectively collected from their birth to the time they attained an age of 5 to 20 years. The primary outcome was onset of active asthma. Results: Overall, 576 consecutive cases met the inclusion criteria. Of these, 306 (53.2%) patients had palivizumab exposure and 191 (33.2%) were diagnosed with asthma. Patients with history of respiratory-syncytial virus bronchiolitis hospitalization had a higher risk of developing asthma in the future (adjusted odds ratio, 3.77; 95% CI, 2.30-6.20, P < .001; hazard ratio, 2.56; 95% CI, 1.81-3.62, P < .001). Palivizumab prophylaxis reduced future asthma development through the inhibition of respiratory-syncytial virus bronchiolitis hospitalization (coefficient, -0.021; 95% CI, -0.031 to -0.011, P = .027). Asthmatic children who received palivizumab immunoprophylaxis had a lesser active asthma duration than those who did not (P = .005). Conclusions: Children with BPD with hospitalization for respiratory-syncytial virus bronchiolitis had higher risk of developing asthma compared with those without respiratory-syncytial virus infection. Prophylactic palivizumab might reduce later asthma development through inhibition of respiratory-syncytial virus bronchiolitis hospitalization. For those already developing asthma, palivizumab could reduce active asthma duration.

Differentially expressed microRNAs in peripheral blood cell are associated with downregulated expression of IgE in nonallergic childhood asthma.

Childhood asthma is a heterogeneous disease characterized by chronic airway inflammation, leading to a broad range of clinical presentations. Nonallergic asthma is asthma without allergic sensitization. Both clinical manifestations and immunopathological mechanisms of nonallergic childhood asthma were rarely investigated. We aimed to compare the clinical features between nonallergic and allergic childhood asthma and apply microRNA to explore the underlying mechanism of nonallergic childhood asthma. We enrolled 405 asthmatic children (76 nonallergic, 52 allergic with total IgE < 150 IU/mL and 277 allergic with total IgE > 150 IU/mL). Clinical characteristics were compared between groups. Comprehensive miRNA sequencing (RNA-seq) was performed using peripheral blood from 11 nonallergic and 11 allergic patients with elevated IgE, respectively. Differentially expressed miRNA (DEmiRNA) were determined with DESeq2. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed to determine functional pathways involved. Publicly available mRNA expression data was applied to investigate the predicted target mRNA networks via Ingenuity Pathway Analysis (IPA). The average age of nonallergic asthma was significantly younger (5.614 ± 2.743 vs 6.676 ± 3.118 years-old). Higher severity and worse control were more common in nonallergic asthma (two-way ANOVA, P < 0.0001). Long-term severity was higher, and intermittent attacks persisted in nonallergic patients. We identified 140 top DEmiRNAs based on false discovery rate (FDR) q-value < 0.001. Forty predicted target mRNA gene were associated with nonallergic asthma. The enriched pathway based on GO included Wnt signaling pathway. IgE expression was predicted to be downregulated by a network involving simultaneous interaction with IL-4, activation of IL-10 and inhibition of FCER2. Nonallergic childhood asthma were distinct in their younger age, higher long-term severity and more persistent course. Differentially expressed miRNA signatures associate with downregulation of total IgE expression and predicted target mRNA genes related molecular networks contribute to canonical pathways of nonallergic childhood asthma. We demonstrated the negative role of miRNAs involved in regulating IgE expression indicating differences between asthma phenotypes. Identification of biomarkers of miRNAs could contribute to understand the molecular mechanism of endotypes in nonallergic childhood asthma, which can potentially allow delivery of precision medicine to pediatric asthma.

M2-like macrophages polarized by Foxp3- Treg-of-B cells ameliorate imiquimod-induced psoriasis.

Our group have demonstrated that splenic B cells contributed to the CD4+ CD25- naive T cells conversion into CD4+ CD25+ Foxp3- regulatory T cells without adding appended cytokines, named Treg-of-B cells which were potent suppressors of adaptive immunity. We like to investigate whether Treg-of-B cells could promote alternatively activated macrophage (M2 macrophages) polarization and alleviate inflammatory disease, psoriasis. In this study, we co-cultured the bone marrow-derived macrophages (BMDMs) with Treg-of-B cells under LPS/IFN-γ stimulation and analyzed the M2-associated gene and protein using qPCR, western blotting, and immunofluorescence staining. We also examined the therapeutic effect of Treg-of-B cell-induced M2 macrophage for skin inflammation using imiquimod (IMQ)-induced psoriatic mouse model. Our results showed that BMDMs co-cultured with Treg-of-B cells upregulated typical M2-associated molecules, including Arg-1, IL-10, Pdcd1lg2, MGL-1, IL-4, YM1/2 and CD206. In an inflammatory environment, TNF-α and IL-6 production by macrophages co-cultured with Treg-of-B cells was decreased significantly. The molecular mechanism revealed that Treg-of-B cells promoted M2 macrophage polarization via STAT6 activation in a cell contact-dependent manner. Moreover, the treatment with Treg-of-B cell-induced M2 macrophages attenuated the clinical manifestations of psoriasis, such as scaling, erythema and thickening in the IMQ-induced psoriatic mouse model. T cell activation in draining lymph nodes was decreased in the Treg-of-B cell-induced M2 macrophage group after IMQ application. In conclusion, our findings suggested that Foxp3- Treg-of-B cells could induce alternatively activated M2 macrophages through STAT6 activation, providing a cell-based therapeutic strategy for psoriasis.

Risk factors for subsequent lupus nephritis in patients with juvenile-onset systemic lupus erythematosus: a retrospective cohort study.

BACKGROUND: Lupus nephritis (LN) is a crucial organ involvement in systemic lupus erythematosus (SLE). Patients with LN have higher morbidity and mortality rates than those without. Among all patients with LN, 20-40% had delayed onset, but the data for patients with juvenile-onset SLE (jSLE), who have a higher percentage of LN than patients with adult-onset SLE (aSLE), were limited. This study aimed to determine the risk factors for subsequent LN in patients with jSLE. METHODS: A retrospective cohort study was conducted between 2008 and 2018 in a single tertiary medical centre. Patients with diagnosed jSLE were reviewed. We investigated those without LN at diagnosis and whether they developed LN afterward. The primary outcome was the development of subsequent LN. Clinical manifestations at diagnosis, serial laboratory data, and treatments were reviewed during follow-up periods. RESULTS: Among the 48 patients with jSLE without initial LN, 20 developed subsequent LN later (Group 1), whereas 28 remained free of LN (Group 2). There was no difference in the percentage of initial manifestations except for more discoid rashes in Group 2 patients. In the Cox regression model, elevated average anti-double-stranded DNA (dsDNA) antibody, low average serum complements, and high average erythrocyte sedimentation rate (ESR) levels during follow-up were predictors of subsequent LN. After adjusting for these factors in multivariable analyses, only high average anti-dsDNA antibody and high average ESR levels remained predictive of subsequent LN. For every 100 IU/ml increase in anti-dsDNA antibody, the risk for subsequent LN in jSLE increases by 1.29 times (hazard ratio = 1.29, 95% confidence interval 1.055-1.573). CONCLUSION: Persistently high anti-dsDNA antibody and ESR levels during the follow-up period were risk factors for subsequent LN in patients with jSLE.

Clinical features and outcomes of patients with chronic granulomatous disease in Taiwan.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by defective neutrophil killing of microbial pathogens and recurrent infections. We aimed to investigate the clinical, genetic features, treatment, and outcomes in patients with CGD. METHODS: Pediatric patients diagnosed with CGD from a medical center in Taiwan were enrolled from January 1999 to Oct 2021. RESULTS: Nine pediatric patients with CGD were enrolled: six X-linked (XL) CGD with CYBB gene mutations, three autosomal recessive (AR) CGD with two NCF1 and one CYBA gene mutations. The median age of onset and age of diagnosis was 0.92 and 2.64 years, respectively. Patients with XL-CGD had a younger age of onset (4.6 months vs. 1.83 years, P = 0.06) and age of diagnosis (1.71 vs. 8.86 years, P = 0.024) than AR-CGD patients. The most common sites of infections were skin and soft tissue abscesses. The most common pathogens were Staphylococcus, Serratia, and Salmonella spp. Prophylactic antibiotics, anti-fungal agents, and interferon-gamma (IFN-γ) were given in 9 (100%), 7 (77.8%), and 8 (88.9%) patients, respectively. The mean duration of IFN-γ usage was 5.15 years. One male patient with XL-CGD was successfully treated with hematopoietic stem cell transplantation at 2.2 years. The mortality rate was 11.1%, and the estimated overall survival at 20 years was 66.7%. CONCLUSION: Staphylococcus aureus, Serratia marcescens, and Salmonella infections are important in Taiwanese CGD patients. Patients with XL-CGD have early disease onset. IFN-γ prophylaxis and prophylactic anti-microbial agents might have an effect on alleviating the infection episodes in CGD patients.

Clinical, laboratory characteristics and growth outcomes of children with growing pains.

Growing pains (GP), a common and benign pain syndrome of unknown etiology, is characterized by bilateral recurrent leg pain in childhood. There are no standardized diagnostic criteria for GP, and the diagnosis is often made by exclusion. To identify clinical and laboratory features, we included patients < 12 years with GP at National Taiwan University Children's Hospital between April 2006 and April 2019 in a retrospective study. We also compared body weight and body height z-scores between diagnosis and up to 2 years post-diagnosis to determine if rapid growth was associated with GP. This cohort study included 268 patients with a mean age of 4.7 ± 2.2 years. The most common features of GP were bilateral leg pain, no limitation of activity, intermittent pain, normal physical examination, and being well physically. The average number of Walters' criteria fulfilled by the patients with GP was 6.7 ± 0.9. Elevated serum levels of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were observed in 37.5% and 15.6% of patients, respectively. Symptomatic medications were used in 33% of patients. Our study indicates that ALP and LDH may be biomarkers associated with GP. There was no significant association between GP and rapid growth within 2 years of diagnosis.

Clinical and Immunological Defects and Outcomes in Patients with Chromosome 22q11.2 Deletion Syndrome.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans and can present with highly variable clinical manifestations. Immune deficiencies occur because of thymic hypoplasia or aplasia. METHODS: This retrospective study included patients diagnosed with 22q11.2DS at a medical center between 2000 and 2021. We analyzed the association between clinical phenotypes, immunological abnormalities, age, and outcomes. RESULTS: Eighty-seven patients with 22q11.2DS had a median diagnostic age of 1.78 months. Patients presented with congenital heart disease (CHD; 86.2%), major infections (75.9%), and failure to thrive (FTT; 58.6%). Autoimmunity, neuropsychiatric disorders, and hypoparathyroidism were significantly associated. Neonatal seizures were associated with early diagnosis before 2 months (OR 8.56, 95% CI 1.21-60.58, P = 0.032). Immunological abnormalities included lymphopenia (93.1%), T lymphopenia (71.9%), CD4+ T lymphopenia (64.1%), a lack of hepatitis B vaccine antibodies (46.2%), and complete DiGeorge syndrome (cDGS) (2.3%). Severe lymphopenia and T lymphopenia improved at 3 years of age. Two patients with cDGS were treated with hematopoietic stem cell transplantation, and one survived. The mortality rate was 12.8% and the estimated 35-year survival probability was 77.5%. Major infections experienced > four times were significantly associated with a decreased survival rate of 60%. Patients with CHD without FTT or recurrent infections had a better 20-year survival rate (96.2%). CONCLUSIONS: CHD, major infection, and FTT were common manifestations and poor prognostic factors. Autoimmunity, neuropsychiatric disorders, and hypoparathyroidism were significantly associated. Although T lymphopenia may improve with age, patients with 22q11.2DS require lifelong monitoring for immune dysregulation.

Lower caprylate and acetate levels in the breast milk is associated with atopic dermatitis in infancy.

BACKGROUND: Atopic dermatitis (AD) occurs in exclusively breastfed infants. As fatty acids have some immunomodulatory effect, we aimed to investigate the influence of fatty acid compositions in breast milk (BM) on the development of AD in exclusively breastfed infants. METHODS: We enrolled two- to four-month-old exclusively breastfed infants. The objective SCORing Atopic Dermatitis (objSCORAD) was evaluated. The lipid layer of BM was analyzed by gas chromatography for fatty acid levels. Medical charts were reviewed. RESULTS: Forty-seven AD infants and 47 healthy controls were enrolled. The objSCORAD was 20.5 ± 1.7 (shown as mean ± SEM) in the AD group. The age, sex, parental atopy history, and nutrient intake of mothers were not significantly different between two groups. The palmitate and monounsaturated fatty acid (MUFA) levels in BM positively correlated with objSCORAD, while caprylate, acetate, and short-chain fatty acid (SCFA) levels negatively correlated with objSCORAD (p = .031, .019, .039, .013, .022, respectively). However, the butyrate levels in BM were not significantly different. The caprylate and acetate levels in BM were significantly associated with the presence of infantile AD (p = .021 and .015, respectively) after adjusting for age, sex, parental allergy history, MUFA, palmitate, and SCFA levels in BM. ObjSCORAD in infancy was significantly associated with persistent AD (p = .026) after adjusting for age, sex, parental atopy history, caprylate, palmitate, MUFA, acetate, and SCFA levels in BM. CONCLUSION: Caprylate and acetate levels in BM for exclusively breastfed infants were negatively associated with objSCORAD. Lower caprylate and acetate in BM might be the risk factors for infantile AD, while butyrate in BM was not associated with infantile AD.

Predictive characteristics to discriminate the longitudinal outcomes of childhood asthma: a retrospective program-based study.

BACKGROUND: Childhood asthma is an inflammatory disease with heterogeneous outcomes. We sought to determine the impact of total IgE, blood eosinophil, allergen sensitization, and inhaled corticosteroid (ICS) on longitudinal outcomes and to identify characteristics for discriminating different outcomes. METHODS: We conducted a retrospective study in 383 childhood asthma patients and another 313 patients with blood eosinophil data only receiving regular program-based visits from September 1, 2004, to December 31, 2018. Peak expiratory flow (PEF) variability, PEF predicted %, asthma severity, and asthma control at each visit were assessed as clinical outcomes. RESULTS: Our data show that the percentage of blood eosinophils was significantly associated with increased asthma severity (OR: 1.043, 95% CI: 1.002-1.086, P = 0.0392). Mold sensitization was significantly associated with asthma severity (OR: 2.2485, 95% CI: 1.3253-3.8150, P = 0.0027). Characteristics including sensitization status plus ICS dosage had the best area under the receiver operating characteristic curve (AUC) value for predicting longitudinal PEF predicted % (0.6609), PEF variability (0.6885), asthma severity (0.5918), and asthma control (0.6441), respectively. CONCLUSIONS: We showed that the risk for adverse clinical outcomes at follow-up differed between serum IgE, blood eosinophil, and allergen sensitization identified at baseline. Sensitization and ICS dosage were predictive characteristics of long-term clinical outcomes. IMPACT: The unique aspects of the study are its longitudinal assessment of patients receiving guideline-based asthma management program to help characterize the stability of the clinical outcomes over time. Characteristics including allergen sensitization and ICS dosage demonstrated an improved capability for distinguishing between better and worse clinical outcomes. Through longitudinal serial assessment, this study indicates the risk for adverse clinical outcomes differed between children with serum IgE/blood eosinophil/allergen sensitization characterized at baseline.

CTLA-4 gene mutation and multiple sclerosis: A case report and literature review.

We reported a patient with autoimmunity (multiple sclerosis), immunodeficiency (hypogammaglobulinemia with severe infections), enteropathy (diarrhea with intestinal inflammation), splenomegaly, lymphadenopathy and lymphocytic infiltration of non-lymphoid organs (lung, gut and brain). The patient was found to have a heterozygous mutation in cytotoxic T lymphocyte antigen-4, and had excellent response to abatacept.

Maternal Nutritional Status and Development of Atopic Dermatitis in Their Offspring.

Atopic dermatitis (AD) is the leading chronic skin inflammatory disease and the initial manifestation of atopic march. Available evidence supports the notion that primary prevention early in life leads to a decreased incidence of AD, thus possibly decreasing the subsequent occurrence of atopic march. Nutritional status is essential to a proper functioning immune system and is valued for its important role in AD. Essential nutrients, which include carbohydrates, proteins, lipids, vitamins, and minerals, are transferred from the mother to the fetus through the placenta during gestation. Various nutrients, such as polyunsaturated fatty acids (PUFAs) and vitamin D, were studied in relation to maternal status and offspring allergy. However, no strong evidence indicates that a single nutrient or food in mothers' diet significantly affects the risk of childhood AD. In the light of current evidence, mothers should not either increase nor avoid consuming these nutrients to prevent or ameliorate allergic diseases in their offspring. Each essential nutrient has an important role in fetal development, and current government recommendations suggest specific intake amounts for pregnant women. This review discusses evidence on how various nutrients, including lipids (monounsaturated fatty acids, PUFAs, saturated fatty acids, and short-chain fatty acids), carbohydrates (oligosaccharides and polysaccharides), proteins, vitamins (A, B, C, D, and E), and trace minerals (magnesium, iron, zinc, copper, selenium, and strontium) in maternal status are associated with the development of AD and their possible mechanisms.

Aggressive corticosteroid treatment in childhood idiopathic pulmonary hemosiderosis with better outcome.

BACKGROUND/PURPOSE: Idiopathic pulmonary hemosiderosis (IPH) is a rare but fatal disease characterized by a triad of anemia, hemoptysis, and increased pulmonary infiltration. This study is aimed to review the clinical manifestations, diagnostic tools, medication and outcome of childhood IPH in Taiwan. METHODS: We retrospectively enrolled the patients less than 18 years old in National Taiwan University Hospital in the past 30 years. The clinical data were collected and analyzed. RESULTS: All of the twelve children diagnosed with IPH had anemia and increased pulmonary infiltration, eight had hemoptysis, and ten were confirmed with detection of hemosiderin-laden macrophages. The mean age at diagnosis were 4.9 (interquartile range 2.5-6.3) years old. Patients with high dose corticosteroid (CS, ≥ 1 mg/kg/day prednisolone equivalent) treatment had lower odds ratio for ICU admission and significant higher Hb recovery rate than those with mild disease activity not receiving high dose CS treatment (p = 0.011). The only factor that is significantly associated with persistent anemia is the usage of high dose CS (p < 0.001) after adjusting for hemoptysis, fulfilling triad, serum ferritin level, and ICU admission by multiple regression. The only factor that is significantly associated with ICU admission is the presence of microorganism yielded in sputum (p < 0.001) after adjusting for fever, serum ferritin level, usage of invasive MV, and high dose CS treatment days. CONCLUSION: The aggressive high dose CS therapy might prevent ICU admission and improve anemia. Aggressive high dose CS treatment is suggested in IPH patients regardless of the disease activity.

Differential parameters between activity flare and acute infection in pediatric patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients are vulnerable to infections. We aim to explore the approach to differentiate active infection from disease activity in pediatric SLE patients. Fifty pediatric SLE patients presenting with 185 clinical visits were collected. The associations between both clinical and laboratory parameters and the outcome groups were analyzed using generalized estimating equations (GEEs). These 185 visits were divided into 4 outcome groups: infected-active (n = 102), infected-inactive (n = 11), noninfected-active (n = 59), and noninfected-inactive (n = 13) visits. Multivariate GEE (generalized estimating equation) analysis showed that SDI, SLEDAI-2K, neutrophil-to-lymphocyte ratio (NLR), hemoglobin, platelet, RDW-to-platelet ratio (RPR), and C3 are predictive of flare (combined calculated AUC of 0.8964 and with sensitivity of 82.2% and specificity of 90.9%). Multivariate GEE analysis showed that SDI, fever temperature, CRP, procalcitonin (PCT), lymphocyte percentage, NLR, hemoglobin, and renal score in SLEDAI-2k are predictive of infection (combined calculated AUC of 0.7886 and with sensitivity of 63.5% and specificity of 89.2%). We can simultaneously predict 4 different outcome with accuracy of 70.13% for infected-active group, 10% for infected-inactive group, 59.57% for noninfected-active group, and 84.62% for noninfected-inactive group, respectively. Combination of parameters from four different domains simultaneously, including inflammation (CRP, ESR, PCT), hematology (Lymphocyte percentage, NLR, PLR), complement (C3, C4), and clinical status (SLEDAI, SDI) is objective and effective to differentiate flares from infections in pediatric SLE patients.

Onset age is a risk factor for refractory pediatric IgA vasculitis: a retrospective cohort study.

BACKGROUND: Though outcome differences between children and adults with immunoglobulin A vasculitis (IgAV) has been well documented, it remains unclear if disease features in pediatric IgAV patients vary with onset age. We aimed to explore clinical features and prognosis of pediatric IgAV stratified by onset age. METHODS: We retrospectively reviewed records of patients under 18 years old diagnosed with IgAV from January 1999 to December 2018 in one tertiary medical center in Taiwan. Patients were grouped by onset age: ≤ 6 years old, 6-12 years old (> 6, ≤ 12), and 12-18 years old (> 12, < 18). Demographics, laboratory data, incidence of gastrointestinal, renal, and joint involvement, corticosteroid dependence, recurrence, and refractory disease were analyzed. Recurrence was defined as disease flare-up after complete remission and discontinuation of all medications for at least 3 months. Corticosteroid dependence was defined by more than 6 weeks of daily oral corticosteroid intake. Refractory disease was defined as not achieving complete remission 6 months after disease onset. Statistical analysis was performed using R software (v3.6.0). RESULTS: There were 484 IgAV patients, with an onset age of 6.10 (4.72-8.58) (median (IQR)) years old. There were 234 (48.3%) patients ≤6 years old, 210 (43.4%) 6-12 years old, and 40 (8.3%) 12-18 years old. One hundred and thirty (26.9%) patients had renal involvement, which was more frequent in older children (≤ 6 years old, 18.4%; 6-12 years old, 31.0%; 12-18 years old, 55.0%; p <  0.001). There were 361 patients (74.6%) with joint involvement; younger children were affected more frequently (≤ 6 years old, 82.1%; 6-12 years old, 71.9%; 12-18 years old, 45.0%; p <  0.001). Gastrointestinal involvement was present in 311 (64.3%) patients, showing no difference among age groups. There were 46 patients (9.5%) with recurrent IgA vasculitis, 136 (28.1%) with corticosteroid dependent and 76 (15.7%) with refractory disease. Corticosteroid dependence and refractory disease occurred more frequently as onset age increased (p <  0.001). CONCLUSION: Pediatric IgAV with different onset ages are associated with distinct clinical manifestations and outcomes. The risk of developing corticosteroid dependence, refractory disease and renal involvement increased with onset age.

Early-onset-early-resolving atopic dermatitis does not increase the risk of development of allergic diseases at 3 Years old.

BACKGROUND: Epidemiological findings showed the increased risk of allergic rhinitis (AR) and asthma in the children with preceding atopic dermatitis (AD). In this study, we aimed to observe the development of allergic diseases in infantile AD patients. METHODS: We followed up the prospective observational cohort enrolling two-to four-month-old exclusively breastfed infants. The presence of physician-diagnosed asthma, AR and AD at age 3 was recorded with the laboratory tests for atopic sensitization. RESULTS: Fifty infantile AD patients and 48 healthy controls were enrolled. The sex, age and parental atopy history were not significantly different between the two groups. At age 3, 21 (42%) patients had persistent AD in the infantile AD group while only 2 (4.2%) patients had newly diagnosed AD in the control group (p < 0.001). The early-onset-early-resolving AD (subsides before age 2) did not increase the risk of AR and asthma development, and the sensitization to allergens. However, the early-onset-persistent AD (persists after age 2) increased the risk of AR development and sensitization to inhalant allergens (adjusted odds ratio 2.83, 7.07, respectively). The parental atopy status was associated with any allergic disease at age 3 (p = 0.020). The maternal atopy history was the significant factor associated with AD, AR and eosinophilia at age 3 (p = 0.004, 0.014, 0.031, respectively). CONCLUSION: The early-onset-early-resolving AD was not associated with allergic diseases development at age 3. The parental atopy history and early-onset-persistent AD might be the risk factors for development of allergic diseases at age 3.

Lower vitamin D levels in the breast milk is associated with atopic dermatitis in early infancy.

BACKGROUND: Our previous study showed that the discontinuation of breastfeeding could improve atopic dermatitis (AD) symptoms in exclusively breastfed infants. As vitamins A and D are influential on the immune system, we aimed to analyze the association of vitamin A and D levels in breast milk (BM) with AD. METHODS: We enrolled two- to four-month-old exclusively breastfed infants. The objective SCORing Atopic Dermatitis (objSCORAD) was evaluated. The lipid layer of BM was extracted and analyzed by liquid chromatography for vitamin A and D levels. Medical charts were reviewed for the clinical course of AD. RESULTS: Forty-five AD patients and 45 healthy controls were enrolled. The objSCORAD was 20.54 ± 1.73 (shown as mean ± SEM) in the AD group. The sex, parental atopy history, nutrient intake of mothers, and vitamin A levels in BM were not significantly different between the two groups. The 25-(OH) D3 level in BM was significantly lower in the AD group than in the control group (1.72 ± 0.30 and 3.95 ± 0.64 ng/mL, respectively; P = .001). The 25-(OH) D3 level negatively correlated with objSCORAD (P = .003). The only factor that is significantly associated with persistent AD is the objSCORAD in infancy (P = .003) after adjusting for age, sex, parental atopy history, and 25-(OH) D3 level by multiple regression. CONCLUSION: Vitamin D levels in BM for exclusively breastfed infants were negatively associated with objSCORAD. Lower vitamin D levels in BM might be a risk factor for infantile AD.

Tai Chi Chuan Exercise Improves Lung Function and Asthma Control through Immune Regulation in Childhood Asthma.

BACKGROUND: Tai Chi Chuan (TCC) is an exercise of low to moderate intensity with key features of mindfulness, structural alignment, and flexibility to relax the body and mind in adults. Our previous study showed that TCC could improve the quality of life (QoL), pulmonary function, and fractional exhaled nitric oxide in asthmatic children. We further investigated whether the benefits induced by TCC were associated with immune regulation. METHOD: Six- to twelve-year-old children diagnosed with mild to severe persistent asthma for at least one year according to the Global Initiative for Asthma guidelines were enrolled from a tertiary pediatric allergy center in Taiwan. Asthmatic children were divided into two groups based on their choice: (1) the TCC group had a 60-minute TCC exercise session once weekly led by an instructor and (2) the control group kept their original activity levels. All other exercises were encouraged as usual. Pulmonary function tests, laboratory tests, standardized pediatric asthma QoL questionnaire (PAQLQ(S)), and childhood asthma control test (C-ACT) were performed before and after the TCC program (12 weeks). Data on medications and exacerbations were collected from medical records. RESULTS: There were no differences between the TCC (n = 25) and control (n = 15) groups at baseline, except that the C-ACT showed significantly lower results in the TCC group (p=0.045). After 12 weeks, the number of leukocytes (p=0.041) and eosinophils (p=0.022) decreased, while regulatory T cells increased significantly (p=0.008) only in the TCC group. Lung functions (FEV1 and PEFR) were significantly improved in both the TCC (p < 0.001) and control (p=0.045 and 0.019, respectively) groups, while the PAQLQ(S) and C-ACT (p < 0.001) showed improvement only in the TCC group. Moreover, compared to the control group, the exacerbations within 12 weeks after the study were significantly decreased in the TCC group (p=0.031). After multiple regression by a conditional forward method, the factors that were significantly associated with exacerbation within 12 weeks after study is the practice of TCC and exacerbation within 24 weeks before study (p=0.013 and 0.015, respectively) after adjusting for age, sex, asthma severity, PEF, FEV1, C-ACT, PAQLQ(S), and medication score at baseline. CONCLUSION: TCC exercise may improve pulmonary functions, asthma control, and QoL and prevent exacerbations in asthmatic children through immune regulation. Further research on detailed mechanisms is mandated.

Clinical manifestations and anti-TNF alpha therapy of juvenile Behçet's disease in Taiwan.

BACKGROUNDS: Behçet's disease (BD) is a rare vasculitic disorder affecting all sizes of vessels. Among BD patients, 4 to 25% of patients with diagnosed age younger than 16 years old are defined as juvenile BD (JBD). This study aimed to evaluate the clinical manifestations and treatments of patients with JBD, with a particular focus on the effectiveness and safety of anti-tumor necrosis factor (TNF)-alpha therapy. METHODS: We retrospectively reviewed data of all patients diagnosed with JBD at age of 16 years or younger in a tertiary hospital in Taiwan. The clinical manifestations, laboratory data, treatments, disease courses, and clinical outcomes were evaluated. The effectiveness of anti-TNF-alpha therapy was measured based on changes in Behçet's Disease Current Activity Form (BDCAF) scores, prednisolone dosages and the immunosuppression load scores. RESULTS: Fifty-five patients were included in the study. The median age at disease onset was 11 years. The most common clinical presentation was recurrent oral aphthous ulcers (100%), followed by genital ulceration (69.1%), skin lesions (36.4%), gastrointestinal symptoms (29.1%), ocular involvement (27.3%), and arthralgia (27.3%). Ninety-one percent of the patients fulfilled the International Criteria for Behçet's Disease, and 36.4% met the Paediatric Behçet's Disease criteria. The most frequently used medications were prednisolone (74.5%) and colchicine (54.5%). Six patients with refractory or severe JBD received anti-TNF-alpha therapy. These patients were diagnosed at a younger age compared with those who did not receive anti-TNF-alpha therapy (7.5 vs 13 years; P = 0.012), the BDCAF scores reduced significantly at the 1st month, the 6th month and 1 year after the treatment. They did not use steroids after the first year of treatment, and, after treatment for 6 months, their immunosuppression load scores reduced significantly. Due to the limited case numbers, literature reviews of anti-TNF-alpha therapy for refractory JBD were conducted, which had a total 18 JBD patients receiving anti-TNF-alpha therapy, of which fifteen patients had favorable outcomes after treatment with minimal side effects. CONCLUSIONS: Anti-TNF-alpha therapy may be necessary for JBD patients with refractory disease courses. Anti-TNF-alpha therapy was effective and safe in these patients, especially regarding its corticosteroid- and immunosuppressive drug-sparing effects.

The influence of breastfeeding in breast-fed infants with atopic dermatitis.

BACKGROUND: The aim of this study was to evaluate whether breastfeeding should be discontinued for exclusively breast-fed infants with atopic dermatitis (AD). METHODS: Eighty-seven exclusively breast-fed infants with AD were enrolled in a prospective observational study. The infants were divided into 3 groups: breastfeeding only (BM group), partial breastfeeding and partial partially hydrolyzed whey formula (pHF-W) (Partial group) and pHF-W only (DC group). The extent and severity of AD were evaluated with the Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD) index at enrollment and 3 and 6 months later. RESULTS: There were no significant differences in parental atopy history, PO-SCORAD scores, and medication scores at baseline. At month 3 and 6, the PO-SCORAD scores were significantly decreased in all groups. PO-SCORAD scores at month 3 and 6 and at the last time point when topical corticosteroids were given were significantly different among the groups. Stepwise multiple linear regression analysis showed that baseline PO-SCORAD scores and stopping breastfeeding were significantly associated with month 3 PO-SCORAD scores (p < 0.001), after adjusting for sex, age, baseline medication scores, partial breastfeeding and parental atopy history. In addition to baseline PO-SCORAD scores and stopping breastfeeding, partial breastfeeding was significantly associated with month 6 PO-SCORAD scores. Long-term follow-up showed that only stopping breastfeeding was significantly associated with the last time point when topical corticosteroids were given (p = 0.014). CONCLUSION: For exclusively breast-fed infants with AD, discontinuing breastfeeding and shifting to pHF-W might help to improve symptoms and shorten the duration of AD regardless of sex, age and parental atopy history.

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells.

T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.