Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze.

BACKGROUND: Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits. OBJECTIVE: To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW). METHODS: A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months. RESULTS: Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively). CONCLUSION: Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV. TRIAL REGISTRATION: This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

Characterization of gut microbiome profile in children with confirmed wheat allergy.

BACKGROUND: Food allergies pose serious health risks, including life-threatening anaphylactic reactions, increased morbidity, and reduced quality of life. Wheat allergy is a common concern in Asia. There is growing interest in understanding the potential association between dysregulation of the gut microbiome and the development of food allergies. OBJECTIVE: This study aimed to explore the gut microbiome of Thai children with wheat allergy and its potential association with allergic responses. METHODS: Microbial abundance was assessed using Quantitative Insights into Microbial Ecology 2 (QIIME2) microbiome analysis based on 16S rDNA data. The correlation between microbial richness and relevant parameters was evaluated using the Spearman correlation analysis. Additionally, the microbial community functions were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2). RESULTS: The gut microbiome analysis revealed significant differences between the two groups at the phylum and genus levels. Firmicutes (p = 0.012) and Verrucomicrobia (p < 0.001) were enriched in wheat-allergic children, whereas specific gut microbes such as Megamonas (p = 0.04), Romboutsia (p < 0.001), Fusobacterium (p < 0.001), Clostridium senso stricto1 (p < 0.001), and Turicibacter (p < 0.001) were more abundant in healthy children. Anaerostripes (p = 0.011), Erysipelatoclostridium (p < 0.001), Prevotella 2 (p < 0.001), Ruminiclostridium 5 (p < 0.001), and Clostridium innnocuum (p < 0.001) were enriched in children with a confirmed wheat allergy. Functional analysis indicated disparities in the pathways related to arginine and polyamine biosynthesis. CONCLUSION: These findings offer valuable insights into the gut microbiome of children with wheat allergy and its potential impact on symptom severity, laying the groundwork for further research and interventions aimed at addressing this health concern.

Anaphylaxis in children: Effect of age and atopic status.

BACKGROUND: Anaphylaxis is a life-threatening allergic reaction with rising incidence worldwide. Young children's limited ability to express symptoms adds unique diagnostic challenges. OBJECTIVE: To study on anaphylaxis in children, including triggers, symptoms, treatment, atopic status impact, and adrenaline injection time intervals. METHODS: In-patient medical records of children who were diagnosed with anaphylaxis during 2014-2021 were reviewed. RESULTS: One hundred thirty-three anaphylaxis events were identified. Food (47%) was the most common trigger, followed by drugs (31%), blood components (17%), insects (3%), and idiopathic causes (2%). Ten cases of refractory anaphylaxis, 2 cases of biphasic reactions, and 1 case of persistent anaphylaxis were found. There were no reported fatalities. The most common presentations involved the skin (94%), followed by the respiratory (73%), gastrointestinal (47%), and cardiovascular (42%) systems. In atopic patients, wheezing was more prominent than in those without atopy (p-value = 0.017). In the non-atopic patients, there was a higher incidence of cardiovascular symptoms, particularly hypotension (p-value = 0.001), compared to individuals with atopy. Children under 5 years old with mild-moderate anaphylaxis required more time to reach the hospital (147.0 vs. 45.0 minutes, p = 0.033) and to receive adrenaline injections (35.0 vs. 9.0 minutes, p-value = 0.017) than those with severe anaphylaxis. CONCLUSION: Childhood anaphylaxis is prevalent. Children with mild-moderate anaphylaxis experienced delays in hospital visits and adrenaline administration. Education on allergies is needed to improve the identification and prompt response to anaphylactic reactions, especially in young children.

Benefits of mobile messenger application in caregivers of food allergy children.

BACKGROUND: Unintentional exposure is common in children with food allergies. OBJECTIVE: To assess the benefits of newly developed food allergy application. METHODS: Caregivers of children with confirmed immediate reactions to food were enrolled to use the "Kinchew" application for one month. Kinchew provides the detail of food allergens after typing the name of specific food in the chat box. Then, the app provides the product image and detail of food allergens. Kinchew also has a menu for recording food diaries and videos on managing food allergies. Kinchew users were asked to assess their confidence in dealing with food allergies assessed by the questionnaire using 5 points Likert scale. The number of patients who experienced allergic reactions from unintentional food exposure was recorded after using Kinchew. RESULTS: Seventy caregivers were enrolled. Wheat was the most common causative food in 67% of the participants. All participants used Kinchew with a total use of 1,754 times, classified as food items searching 1080 times (62%), and recorded their food diary 674 times (38%). The number of patients who experienced allergic reactions from unintentional exposure significantly decreased from 61 (87%) to 31 (44%), p < 0.001.The user's confidence in choosing food improved significantly compared to the baseline score. In the subgroup analysis of the type of causative food, a significant improvement in confidence in food choosing was demonstrated in wheat and multiple food allergy groups. CONCLUSIONS: Well-designed food allergy mobile applications could improve caregivers' confidence in dealing with food allergies and reduce unintentional food exposure.

Effect of dyslipidemia, obesity, and atopic status on exhaled and alveolar nitric oxide in asthmatic children.

BACKGROUND: Dyslipidemia and obesity contribute to a pro-inflammatory state. Eosinophilic airway inflammation can be indirectly measured by fractional exhaled nitric oxide (FeNO) produced in the airways of asthmatic subjects. OBJECTIVE: To compare exhaled nitric oxide (NO) and alveolar NO in asthmatic children with and without dyslipidemia. METHODS: Asthmatic children (5-18 years old) had fasting serum low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) concentrations, and C-reactive protein (CRP) concentrations measured. FeNO was measured at constant flow rates of 20, 50, 100, and 300 ml/s by the chemiluminescence method. NO concentrations in tissue of the upper airways (CawNO) and the total flux of NO in the conducting airways (JawNO) were determined through FeNO at 20, 100, and 300 ml/s using a mathematical model. The atopic status was assessed using the skin prick test for aero-allergens. RESULTS: One hundred forty-one asthmatic children were enrolled with a mean (standard deviation) age of 11.82 (3.38) years. Sixty-four (45.4%) children had dyslipidemia and 20 (14.2%) were obese. Children with low HDL-C concentrations had significantly higher CawNO and JawNO than those with normal HDL-C concentrations (both p = 0.03). Asthmatic children with obesity had higher CRP concentrations than those with a normal weight (p < 0.001). Atopic children had a significantly higher FeNO, CawNO, and JawNO than non-atopic children (all p < 0.05). CONCLUSIONS: This study suggests an effect of HDL-C on CawNO and JawNO in asthmatic children. An intervention that normalizes HDL-C concentrations may be beneficial for airway inflammation in asthmatic children.

Skin prick test and serum specific IgE in predicting dust mite-induced allergic rhinitis diagnosed from nasal provocation test in chronic rhinitis children.

BACKGROUND: Allergen skin prick test (SPT) and serum specific immunoglobulin E (sIgE) are effective diagnostic tests in allergic rhinitis (AR), however, positive results may not always correlate with clinical allergies. A nasal provocation test (NPT) can identify the causative allergen for immunotherapy, but it's not routinely performed. OBJECTIVE: To establish the cutoff value for the house dust mite (HDM) SPT mean wheal diameter (MWD) and HDM sIgE level for identifying children with HDM-induced AR diagnosed from NPT. METHODS: Children aged 5 to 18 years old with chronic rhinitis were evaluated by HDM SPT, sIgE, and NPT. Children with positive NPT results indicated HDM-induced AR. The cutoff values of the HDM SPT and sIgE level for predicting positive NPT were determined using a receiver operating characteristic curve. RESULTS: A total of 245 children with a mean age of 9.53 ± 3 years were enrolled. HDM SPT results were positive (≥ 3 mm) in 160 (65.3%) children. HDM NPT results were positive in 176 (71.8%) children. Among children with positive HDM SPT (n = 160), 153 children (95.6%) were confirmed as having AR on NPT findings. The cutoff values for positive NPT responses were 6.6 mm for HDM SPT (yielding 100% specificity and 100% positive predictive value) and 17.0 kUA/L for sIgE (98.6% specificity and 99.2% positive predictive value). CONCLUSIONS: This study proposes HDM SPT and sIgE cutoff values for use in the diagnosis of HDM-induced AR based on NPT. These cutoff values can be used to identify HDM-induced AR children who might benefit from immunotherapy.

Improvement of inattentive and hyperactive symptoms after real-life rhinitis treatment in school-aged children.

OBJECTIVES: Rhinitis treatment may improve attention-deficit/hyperactivity symptoms in children. The current study evaluated changes in inattentive and hyperactive symptoms after treatment in children with chronic rhinitis. METHODS: Children aged 5-18 years with chronic rhinitis were enrolled in a 3-month prospective study. The nasal provocation test for house dust mites (HDM) and evaluation of allergen sensitization, including the skin prick test and the Phadiatop test, were performed. The severity of rhinitis was assessed according to the ARIA guideline. The total nasal symptom score and the Vanderbilt ADHD Diagnostic Rating Scale (VADRS) score for assessing inattentive and hyperactive symptoms were recorded at baseline and at 1 and 3 months after rhinitis treatment. Children with rhinitis were classified into the following two groups: HDM-induced allergic rhinitis (AR group) and non-allergic rhinitis to HDM (NAR group) based on the NPT. RESULTS: Overall, 83 children completed the 3-month prospective study, and they had a mean age of 9.12 ± 2.89 years and 44.6% were boys. After rhinitis treatment, VADRS scores assessed by the parents and teachers were significantly decreased compared with those at baseline (p = 0.005). In subgroup analysis, 61 (73.49%) children had AR, and 22 (26.5%) children had NAR. No significant difference in the baseline VADRS score was found between the AR and NAR groups. After treatment, VADRS scores assessed by the parents and teachers were significantly decreased only in the AR group (p < 0.001). Forty-five (54.2%) children had moderate persistent rhinitis, 29 (34.9%) had mild persistent rhinitis, and 9 (10.8%) had mild intermittent symptoms. There were no differences in baseline VADRS scores assessed by the parents and teachers among children with mild intermittent, mild persistent, or moderate persistent symptoms. The total nasal symptom score and VADRS score were significantly decreased after treatment for all severities of rhinitis compared with those at baseline. A greater baseline VADRS score was associated with substantial improvement of inattentive and hyperactive symptoms after treatment. CONCLUSION: Early treatment for rhinitis may improve inattentive and hyperactive symptoms in school-aged children.

Association of Dyslipidemia and Respiratory Resistance Assessed by the Forced Oscillation Technique in Asthmatic Children.

PURPOSE: This study aimed to evaluate the associations between dyslipidemia and pulmonary function parameters assessed by spirometry and the forced oscillation technique in asthmatic children. METHODS: Asthmatic children (5-18 years old) had fasting serum lipid profiles including low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) concentrations, and C-reactive protein (CRP) measured. Pulmonary function tests were assessed by spirometry and the forced oscillation technique (FOT). RESULTS: One hundred forty-one asthmatic children were enrolled with a mean (SD) age of 11.82 (3.38) years. Eighty-eight (62.4%) children were boys, 64 (45.4%) had dyslipidemia, and 20 (14.2%) were obese. Among the children with dyslipidemia, a high LDL-C concentration (65.6%) was the most common form of dyslipidemia, followed by high TC (57.8%), high TG (35.9%), and low HDL-C concentrations (15.6%). Multivariable analysis showed significant associations between HDL-C concentrations and respiratory resistance at 5 Hz (R5) and respiratory resistance at 20 Hz (R20), and TC concentrations were modestly associated with reactance at 5 Hz (X5), the frequency of resonance (Fres), and the area of reactance (ALX). Asthmatic children who had high LDL-C concentrations had a significantly higher expiratory phase R5, whole breath R20, and expiratory phase R20 than those in children with normal LDL-C concentrations. CONCLUSION: This study suggests an association of blood cholesterol, especially HDL-C and LDL-C, and respiratory resistance measured by the FOT, irrespective of the obesity status. An intervention for improving LDL-C and HDL-C concentrations may be beneficial on lung function parameters in asthmatic children. CLINICAL TRIAL REGISTRATION: TCTR20200305005; date of registration: 03-04-2020 (retrospectively registered).

Azithromycin to Prevent Recurrent Wheeze Following Severe Respiratory Syncytial Virus Bronchiolitis.

BACKGROUND: Early-life severe respiratory syncytial virus (RSV) bronchiolitis is a risk factor for childhood asthma. Because azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated whether it would reduce the occurrence of post-RSV recurrent wheeze. METHODS: We prospectively enrolled 200 otherwise healthy 1- to 18-month-old children hospitalized with RSV bronchiolitis in this single-center, double-blind, placebo-controlled study and randomly assigned them to receive oral azithromycin (10 mg/kg daily for 7 days, followed by 5 mg/kg daily for 7 days) or placebo. Randomization was stratified by recent open-label antibiotic use. The primary outcome was the occurrence of recurrent wheeze, defined as a third episode of post-RSV wheeze over the following 2 to 4 years. RESULTS: As an indication of the biologic activity of azithromycin, nasal wash interleukin-8 levels, at day 14 after randomization, were lower among azithromycin-treated participants (P<0.01). Despite evidence of biologic activity, azithromycin did not reduce the risk of post-RSV recurrent wheeze (47% in the azithromycin group vs. 36% in the placebo group; adjusted hazard ratio, 1.45; 95% confidence interval [CI], 0.92 to 2.29; P=0.11). Azithromycin also did not modify the risk of recurrent wheeze among participants already receiving other antibiotic treatment at the time of enrollment (hazard ratio, 0.94; 95% CI, 0.43 to 2.07). There was a potential signal among antibiotic-naïve participants who received azithromycin to have an increased risk of recurrent wheeze (hazard ratio, 1.79; 95% CI, 1.03 to 3.1). CONCLUSIONS: Azithromycin therapy for 14 days during acute severe RSV bronchiolitis did not reduce recurrent wheeze occurrence over the following 2 to 4 years. Our data suggest no benefit of azithromycin administration with the goal of preventing recurrent wheeze in later life. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02911935.).

Serum Periostin Predicts Wheezing Exacerbation: A Prospective Study in Preschool Children with Recurrent Wheezing.

INTRODUCTION: Wheezing is a common problem in preschool children. Currently, there are no reliable biomarkers that can predict subsequent wheezing in preschool children. This study aimed to compare serum periostin levels between preschool children with and without recurrent wheezing and investigate its utility for predicting acute wheezing exacerbation. METHODS: Children aged 2-5 years with recurrent wheezing and healthy control children were enrolled. They were evaluated for serum periostin level at enrollment and subsequently followed for wheezing episodes in a 1-year prospective study. RESULTS: A total of 122 children were enrolled. Children in the recurrent wheezing group (n = 80) had a greater median serum periostin level (1,122.32 pg/mL [<10-6,978.93]) than that of the healthy control group (n = 40) (<10 pg/mL [<10-2,116.69]), p value = 0.006. After 1-year follow-up, subjects who experienced subsequent wheezing exacerbation episodes had a greater median of periostin level (5,321 pg/mL) compared with those with no exacerbation (<10 pg/mL), p value = 0.014. ROC curve analysis revealed that the level of serum periostin >1,200 pg/mL, corresponding to 78.9% sensitivity and 64.6% specificity, with an AUC of 0.701, p value = 0.009, could be a predictor for acute wheezing exacerbation within 1 year. Besides, subjects with serum periostin >1,200 pg/mL had greater odds of subsequent wheezing episodes compared with those with lower levels of serum periostin (adjusted odds ratio 10.0, 95% confidence interval: 2.3-43.5). CONCLUSIONS: Preschool children with recurrent wheezing have a greater serum periostin level than healthy control. Serum periostin may be a valuable biomarker for predicting acute wheezing exacerbations in the following year.

Airway Nitric Oxide in Children with HDM-Induced Allergic Rhinitis.

BACKGROUND: Rhinitis is a common problem in children. Airway nitric oxide (NO) was proposed to represent eosinophilic inflammation. OBJECTIVES: To evaluate airway NO level in children with house dust mite (HDM)-induced allergic rhinitis. METHODS: Children aged 5 to 18 years old with moderate-severe persistent rhinitis and positive result for the HDM nasal provocation test (NPT) was enrolled. The nasal symptoms evaluated by total nasal symptom score (TNSS) and visual analog scale (VAS) were recorded. Skin prick test (SPT) to common aeroallergens, fractional exhaled nitric oxide (FeNO), nasal nitric oxide (nNO), and blood test for specific IgE (sIgE) to HDM was measured. Rhinitis severity was categorized as severe if the VAS score > 7. RESULTS: Forty-eight children with HDM-induced allergic rhinitis with the mean age of 9.3 ± 2.4 years were enrolled. nNO levels and VAS score were significantly correlated (R = 0.398, P = .005). Children with severe rhinitis had significantly higher nNO levels than moderate rhinitis (1652.05 vs 941.30 parts per billion [ppb], P = .002), while there was no difference in FeNO level. ROC curve analysis demonstrated the cut-off value of nNO at 1350 ppb (AUC 0.764, 95% CI: 0.616-0.911, P = .002) for detecting severe HDM-induced allergic rhinitis with the sensitivity of 78% and the specificity of 71%. The level of FeNO in children who had HDM mean wheal diameter (MWD) > 8 mm was significantly higher than those with HDM MWD of 3 to 8 mm and those with a negative test (39.7 vs 14.3 vs 14.4 ppb; P = .006, respectively). Children who had sIgE to HDM < 0.35 KUA/L had significantly lower FeNO than those with sIgE to HDM 0.35 to 50 KUA/L and >50 KUA/L (9.5 vs 19.7 vs 40.4 ppb; P = .029, respectively). CONCLUSIONS: Cut-off value for the diagnosis of severe HDM-induced chronic rhinitis was proposed. Rhinitis children who had a higher degree of HDM sensitization had a higher level of FeNO.

The azithromycin to prevent wheezing following severe RSV bronchiolitis-II clinical trial: Rationale, study design, methods, and characteristics of study population.

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years. The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18-48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits. A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments. This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Skin Prick Test Versus Phadiatop as a Tool for Diagnosis of Allergic Rhinitis in Children.

BACKGROUND: Skin prick test (SPT) or Phadiatop, a multi-allergen IgE screening test, was used as a tool for detecting aeroallergen sensitization. OBJECTIVE: To compare SPT and Phadiatop as a tool for diagnosis allergic rhinitis (AR) using the nasal provocation test (NPT) as a comparative standard. METHODS: Children aged 5-18 years with rhinitis symptoms more than 6 times in the past year were enrolled. SPT to 13 common aeroallergens, serum for Phadiatop, and NPT to Dermatophagoides pteronyssinus (Der p) were performed. NPT to mixed cockroach (CR) were performed in children who had CR sensitization and negative NPT to Der p. Children who had a disagreement between the result of SPT and Phadiatop or having negative results were evaluated for specific IgE (sIgE) to common aeroallergens. RESULTS: One hundred-forty children were enrolled with the mean age of 9.8 ± 3 years, 56% were male. Of 92 children (65.7%) with positive SPT to any aeroallergens, 88 children (95.6%) were sensitized to house dust mite (HDM). NPT showed positive results in 97 children (69.3%). Of 48 children who showed negative SPT, 4 children (8.3%) had sIgE to aeroallergens but NPT was positive in 1 child. Eighty-eight children (62.9%) had positive tests for Phadiatop and 4 (4.5%) of them had negative results for NPT to Der p. Among 52 children who had negative results for Phadiatop, 4 children (7.6%) had sIgE to aeroallergens but NPT was positive in 2 children (3.8%). SPT and Phadiatop showed 94.2% agreement: with Kappa 0.876, p < 0.001. Using NPT as a comparative standard for diagnosis for AR, SPT showed a sensitivity of 89.6% and specificity of 88.3% and Phadiatop provided the sensitivity of 88.6% and specificity of 95.3%. CONCLUSIONS: SPT to aeroallergen and Phadiatop have good and comparable sensitivity and specificity for the diagnosis of AR in children.