Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age.

BACKGROUND: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze. METHODS: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25-75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age. RESULTS: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment. CONCLUSIONS: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci. Clinical trial registration ClinicalTrials.gov, NCT01723696 and NCT03203603.

[Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)].

The methacholine challenge test (MCT) is a standard evaluation method of assessing airway hyperresponsiveness (AHR) and its severity, and has significant clinical value in the diagnosis and treatment of bronchial asthma. A consensus working group consisting of experts from the Pulmonary Function and Clinical Respiratory Physiology Committee of the Chinese Association of Chest Physicians, the Task Force for Pulmonary Function of the Chinese Thoracic Society, and the Pulmonary Function Group of Respiratory Branch of the Chinese Geriatric Society jointly developed this consensus. Based on the "Guidelines for Pulmonary Function-Bronchial Provocation Test" published in 2014, the issues encountered in its use, and recent developments, the group has updated the Standard technical specifications of methacholine chloride (methacholine) bronchial challenge test (2023). Through an extensive collection of expert opinions, literature reviews, questionnaire surveys, and multiple rounds of online and offline discussions, the consensus addressed the eleven core issues in MCT's clinical practice, including indications, contraindications, preparation of provocative agents, test procedures and methods, quality control, safety management, interpretation of results, and reporting standards. The aim was to provide clinical pulmonary function practitioners in healthcare institutions with the tools to optimize the use of this technique to guide clinical diagnosis and treatment.Summary of recommendationsQuestion 1: Who is suitable for conducting MCT? What are contraindications for performing MCT?Patients with atypical symptoms and a clinical suspicion of asthma, patients diagnosed with asthma requiring assessment of the severity of airway hyperresponsiveness, individuals with allergic rhinitis who are at risk of developing asthma, patients in need of evaluating the effectiveness of asthma treatment, individuals in occupations with high safety risks due to airway hyperresponsiveness, patients with chronic diseases prone to airway hyperresponsiveness, others requiring assessment of airway reactivity.Absolute contraindications: (1) Patients who are allergic to methacholine (MCh) or other parasympathomimetic drugs, with allergic reactions including rash, itching/swelling (especially of the face, tongue, and throat), severe dizziness, and dyspnea; (2) Patients with a history of life-threatening asthma attacks or those who have required mechanical ventilation for asthma attacks in the past three months; (3) Patients with moderate to severe impairment of baseline pulmonary function [Forced Expiratory Volume in one second (FEV1) less than 60% of the predicted value or FEV1<1.0 L]; (4) Severe urticaria; (5) Other situations inappropriate for forced vital capacity (FVC) measurement, such as myocardial infarction or stroke in the past three months, poorly controlled hypertension, aortic aneurysm, recent eye surgery, or increased intracranial pressure.Relative contraindications: (1) Moderate or more severe impairment of baseline lung function (FEV1%pred<70%), but individuals with FEV1%pred>60% may still be considered for MCT with strict observation and adequate preparation; (2) Experiencing asthma acute exacerbation; (3) Poor cooperation with baseline lung function tests that do not meet quality control requirements; (4) Recent respiratory tract infection (<4 weeks); (5) Pregnant or lactating women; (6) Patients currently using cholinesterase inhibitors (for the treatment of myasthenia gravis); (7) Patients who have previously experienced airway spasm during pulmonary function tests, with a significant decrease in FEV1 even without the inhalation of provocative.Question 2: How to prepare and store the challenge solution for MCT?Before use, the drug must be reconstituted and then diluted into various concentrations for provocation. The dilution concentration and steps for MCh vary depending on the inhalation method and provocation protocol used. It is important to follow specific steps. Typically, a specified amount of diluent is added to the methacholine reagent bottle for reconstitution, and the mixture is shaken until the solution becomes clear. The diluent is usually physiological saline, but saline with phenol (0.4%) can also be used. Phenol can reduce the possibility of bacterial contamination, and its presence does not interfere with the provocation test. After reconstitution, other concentrations of MCh solution are prepared using the same diluent, following the dilution steps, and then stored separately in sterile containers. Preparers should carefully verify and label the concentration and preparation time of the solution and complete a preparation record form. The reconstituted and diluted MCh solution is ready for immediate use without the need for freezing. It can be stored for two weeks if refrigerated (2-8 ℃). The reconstituted solution should not be stored directly in the nebulizer reservoir to prevent crystallization from blocking the capillary opening and affecting aerosol output. The temperature of the solution can affect the production of the nebulizer and cause airway spasms in the subject upon inhaling cold droplets. Thus, refrigerated solutions should be brought to room temperature before use.Question 3: What preparation is required for subjects prior to MCT?(1) Detailed medical history inquiry and exclusion of contraindications.(2) Inquiring about factors and medications that may affect airway reactivity and assessing compliance with medication washout requirements: When the goal is to evaluate the effectiveness of asthma treatment, bronchodilators other than those used for asthma treatment do not need to be discontinued. Antihistamines and cromolyn have no effect on MCT responses, and the effects of a single dose of inhaled corticosteroids and leukotriene modifiers are minimal, thus not requiring cessation before the test. For patients routinely using corticosteroids, whether to discontinue the medication depends on the objective of the test: if assisting in the diagnosis of asthma, differential diagnosis, aiding in step-down therapy for asthma, or exploring the effect of discontinuing anti-inflammatory treatment, corticosteroids should be stopped before the provocation test; if the patient is already diagnosed with asthma and the objective is to observe the level of airway reactivity under controlled medication conditions, then discontinuation is not necessary. Medications such as IgE monoclonal antibodies, IL-4Rα monoclonal antibodies, traditional Chinese medicine, and ethnic medicines may interfere with test results, and clinicians should decide whether to discontinue these based on the specific circumstances.(3) Explaining the test procedure and potential adverse reactions, and obtaining informed consent if necessary.Question 4: What are the methods of the MCT? And which ones are recommended in current clinical practice?Commonly used methods for MCT in clinical practice include the quantitative nebulization method (APS method), Forced Oscillalion method (Astograph method), 2-minute tidal breathing method (Cockcroft method), hand-held quantitative nebulization method (Yan method), and 5-breath method (Chai 5-breath method). The APS method allows for precise dosing of inhaled Methacholine, ensuring accurate and reliable results. The Astograph method, which uses respiratory resistance as an assessment indicator, is easy for subjects to perform and is the simplest operation. These two methods are currently the most commonly used clinical practice in China.Question 5: What are the steps involved in MCT?The MCT consists of the following four steps:(1) Baseline lung function test: After a 15-minute rest period, the subjects assumes a seated position and wear a nose clip for the measurement of pulmonary function indicators [such as FEV1 or respiratory resistance (Rrs)]. FEV1 should be measured at least three times according to spirometer quality control standards, ensuring that the best two measurements differ by less than 150 ml and recording the highest value as the baseline. Usually, if FEV1%pred is below 70%, proceeding with the challenge test is not suitable, and a bronchodilation test should be considered. However, if clinical assessment of airway reactivity is necessary and FEV1%pred is between 60% and 70%, the provocation test may still be conducted under close observation, ensuring the subject's safety. If FEV1%pred is below 60%, it is an absolute contraindication for MCT.(2) Inhalation of diluent and repeat lung function test for control values: the diluent, serving as a control for the inhaled MCh, usually does not significantly impact the subject's lung function. the higher one between baseline value and the post-dilution FEV1 is used as the reference for calculating the rate of FEV1 decline. If post-inhalation FEV1 decreases, there are usually three scenarios: ①If FEV1 decreases by less than 10% compared to the baseline, the test can proceed, continue the test and administer the first dose of MCh. ②If the FEV1 decreases by≥10% and<20%, indicating a heightened airway reactivity to the diluent, proceed with the lowest concentration (dose) of the provoking if FEV1%pred has not yet reached the contraindication criteria for the MCT. if FEV1%pred<60% and the risk of continuing the challenge test is considerable, it is advisable to switch to a bronchodilation test and indicate the change in the test results report. ③If FEV1 decreases by≥20%, it can be directly classified as a positive challenge test, and the test should be discontinued, with bronchodilators administered to alleviate airway obstruction.(3) Inhalation of MCh and repeat lung function test to assess decline: prepare a series of MCh concentrations, starting from the lowest and gradually increasing the inhaled concentration (dose) using different methods. Perform pulmonaryfunction tests at 30 seconds and 90 seconds after completing nebulization, with the number of measurements limited to 3-4 times. A complete Forced Vital Capacity (FVC) measurement is unnecessary during testing; only an acceptable FEV1 measurement is required. The interval between two consecutive concentrations (doses) generally should not exceed 3 minutes. If FEV1 declines by≥10% compared to the control value, reduce the increment of methacholine concentration (dose) and adjust the inhalation protocol accordingly. If FEV1 declines by≥20% or more compared to the control value or if the maximum concentration (amount) has been inhaled, the test should be stopped. After inhaling the MCh, close observation of the subject's response is necessary. If necessary, monitor blood oxygen saturation and auscultate lung breath sounds. The test should be promptly discontinued in case of noticeable clinical symptoms or signs.(4) Inhalation of bronchodilator and repeat lung function test to assess recovery: when the bronchial challenge test shows a positive response (FEV1 decline≥20%) or suspiciously positive, the subject should receive inhaled rapid-acting bronchodilators, such as short-acting beta-agonists (SABA) or short-acting muscarinic antagonists (SAMA). Suppose the subject exhibits obvious symptoms of breathlessness, wheezing, or typical asthma manifestations, and wheezing is audible in the lungs, even if the positive criteria are not met. In that case, the challenge test should be immediately stopped, and rapid-acting bronchodilators should be administered. Taking salbutamol as an example, inhale 200-400 µg (100 µg per puff, 2-4 puffs, as determined by the physician based on the subject's condition). Reassess pulmonary function after 5-10 minutes. If FEV1 recovers to within 10% of the baseline value, the test can be concluded. However, if there is no noticeable improvement (FEV1 decline still≥10%), record the symptoms and signs and repeat the bronchodilation procedure as mentioned earlier. Alternatively, add Ipratropium bromide (SAMA) or further administer nebulized bronchodilators and corticosteroids for intensified treatment while keeping the subject under observation until FEV1 recovers to within 90% of the baseline value before allowing the subject to leave.Question 6: What are the quality control requirements for the APS and Astograph MCT equipment?(1) APS Method Equipment Quality Control: The APS method for MCT uses a nebulizing inhalation device that requires standardized flowmeters, compressed air power source pressure and flow, and nebulizer aerosol output. Specific quality control methods are as follows:a. Flow and volume calibration of the quantitative nebulization device: Connect the flowmeter, an empty nebulization chamber, and a nebulization filter in sequence, attaching the compressed air source to the bottom of the chamber to ensure airtight connections. Then, attach a 3 L calibration syringe to the subject's breathing interface and simulate the flow during nebulization (typically low flow:<2 L/s) to calibrate the flow and volume. If calibration results exceed the acceptable range of the device's technical standards, investigate and address potential issues such as air leaks or increased resistance due to a damp filter, then recalibrate. Cleaning the flowmeter or replacing the filter can change the resistance in the breathing circuit, requiring re-calibration of the flow.b. Testing the compressed air power source: Regularly test the device, connecting the components as mentioned above. Then, block the opening of the nebulization device with a stopper or hand, start the compressed air power source, and test its pressure and flow. If the test results do not meet the technical standards, professional maintenance of the equipment may be required.c. Verification of aerosol output of the nebulization chamber: Regularly verify all nebulization chambers used in provocation tests. Steps include adding a certain amount of saline to the chamber, weighing and recording the chamber's weight (including saline), connecting the nebulizer to the quantitative nebulization device, setting the nebulization time, starting nebulization, then weighing and recording the post-nebulization weight. Calculate the unit time aerosol output using the formula [(weight before nebulization-weight after nebulization)/nebulization time]. Finally, set the nebulization plan for the provocation test based on the aerosol output, considering the MCh concentration, single inhalation nebulization duration, number of nebulization, and cumulative dose to ensure precise dosing of the inhaled MCh.(2) Astograph method equipment quality control: Astograph method equipment for MCT consists of a respiratory resistance monitoring device and a nebulization medication device. Perform zero-point calibration, volume calibration, impedance verification, and nebulization chamber checks daily before tests to ensure the resistance measurement system and nebulization system function properly. Calibration is needed every time the equipment is turned on, and more frequently if there are significant changes in environmental conditions.a. Zero-point calibration: Perform zero-point calibration before testing each subject. Ensure the nebulization chamber is properly installed and plugged with no air leaks.b. Volume calibration: Use a 3 L calibration syringe to calibrate the flow sensor at a low flow rate (approximately 1 L/s).c. Resistance verification: Connect low impedance tubes (1.9-2.2 cmH2O·L-1·s-1) and high impedance tubes (10.2-10.7 cmH2O·L-1·s-1) to the device interface for verification.d. Bypass check: Start the bypass check and record the bypass value; a value>150 ml/s is normal.e. Nebulization chamber check: Check each of the 12 nebulization chambers daily, especially those containing bronchodilators, to ensure normal spraying. The software can control each nebulization chamber to produce spray automatically for a preset duration (e.g., 2 seconds). Observe the formation of water droplets on the chamber walls, indicating normal spraying. If no nebulization occurs, check for incorrect connections or blockages.Question 7: How to set up and select the APS method in MCT?The software program of the aerosol provocation system in the quantitative nebulization method can independently set the nebulizer output, concentration of the methacholine agent, administration time, and number of administrations and combine these parameters to create the challenge test process. In principle, the concentration of the methacholine agent should increase from low to high, and the dose should increase from small to large. According to the standard, a 2-fold or 4-fold incremental challenge process is generally used. In clinical practice, the dose can be simplified for subjects with good baseline lung function and no history of wheezing, such as using a recommended 2-concentration, 5-step method (25 and 50 g/L) and (6.25 and 25 g/L). Suppose FEV1 decreases by more than 10% compared to the baseline during the test to ensure subject safety. In that case, the incremental dose of the methacholine agent can be reduced, and the inhalation program can be adjusted appropriately. If the subject's baseline lung function declines or has recent daytime or nighttime symptoms such as wheezing or chest tightness, a low concentration, low dose incremental process should be selected.Question 8: What are the precautions for the operation process of the Astograph method in MCT?(1) Test equipment: The Astograph method utilizes the forced oscillation technique, applying a sinusoidal oscillating pressure at the mouthpiece during calm breathing. Subjects inhale nebulized MCh of increasing concentrations while continuous monitoring of respiratory resistance (Rrs) plots the changes, assessing airway reactivity and sensitivity. The nebulization system employs jet nebulization technology, comprising a compressed air pump and 12 nebulization cups. The first cup contains saline, cups 2 to 11 contain increasing concentrations of MCh, and the 12th cup contains a bronchodilator solution.(2) Provocation process: Prepare 10 solutions of MCh provocant with gradually increasing concentrations.(3) Operational procedure: The oscillation frequency is usually set to 3 Hz (7 Hz for children) during the test. The subject breathes calmly, inhales saline solution nebulized first, and records the baseline resistance value (if the subject's baseline resistance value is higher than 10 cmH2O·L-1·s-1, the challenge test should not be performed). Then, the subject gradually inhales increasing concentrations of methacholine solution. Each concentration solution is inhaled for 1 minute, and the nebulization system automatically switches to the next concentration for inhalation according to the set time. Each nebulizer cup contains 2-3 ml of solution, the output is 0.15 ml/min, and each concentration is inhaled for 1 minute. The dose-response curve is recorded automatically. Subjects should breathe tidally during the test, avoiding deep breaths and swallowing. Continue until Rrs significantly rises to more than double the baseline value, or if the subject experiences notable respiratory symptoms or other discomfort, such as wheezing in both lungs upon auscultation. At this point, the inhalation of the provocant should be stopped and the subject switchs to inhaling a bronchodilator until Rrs returns to pre-provocation levels. If there is no significant increase in Rrs, stop the test after inhaling the highest concentration of MCh.Question 9: How to interpret the results of the MCT?The method chosen for the MCT determines the specific indicators used for interpretation. The most commonly used indicator is FEV1, although other parameters such as Peak Expiratory Flow (PEF) and Rrs can also be used to assess airway hyperresponsiveness.Qualitative judgment: The test results can be classified as positive, suspiciously positive, or negative, based on a combination of the judgment indicators and changes in the subject's symptoms. If FEV1 decreases by≥20% compared to the baseline value after not completely inhaling at the highest concentration, the result can be judged as positive for Methacholine bronchial challenge test. If the patient has obvious wheezing symptoms or wheezing is heard in both lungs, but the challenge test does not meet the positive criteria (the highest dose/concentration has been inhaled), and FEV1 decreases between 10% and 20% compared to the baseline level, the result can also be judged as positive. If FEV1 decreases between 15% and 20% compared to the baseline value without dyspnea or wheezing attacks, the result can be judged as suspiciously positive. Astograph method: If Rrs rises to 2 times or more of the baseline resistance before reaching the highest inhalation concentration, or if the subject's lungs have wheezing and severe coughing, the challenge test can be judged as positive. Regardless of the result of the Methacholine bronchial challenge test, factors that affect airway reactivity, such as drugs, seasons, climate, diurnal variations, and respiratory tract infections, should be excluded.Quantitative judgment: When using the APS method, the severity of airway hyperresponsiveness can be graded based on PD20-FEV1 or PC20-FEV1. Existing evidence suggests that PD20 shows good consistency when different nebulizers, inhalation times, and starting concentrations of MCh are used for bronchial provocation tests, whereas there is more variability with PC20. Therefore, PD20 is often recommended as the quantitative assessment indicator. The threshold value for PD20 with the APS method is 2.5 mg.The Astograph method often uses the minimum cumulative dose (Dmin value, in Units) to reflect airway sensitivity. Dmin is the minimum cumulative dose of MCh required to produce a linear increase in Rrs. A dose of 1 g/L of the drug concentration inhaled for 1-minute equals 1 unit. It's important to note that with the continuous increase in inhaled provocant concentration, the concept of cumulative dose in the Astograph method should not be directly compared to other methods. Most asthma patients have a Dmin<10 Units, according to Japanese guidelines. The Astograph method, having been used in China for over twenty years, suggests a high likelihood of asthma when Dmin≤6 Units, with a smaller Dmin value indicating a higher probability. When Dmin is between 6 and 10 Units, further differential diagnosis is advised to ascertain whether the condition is asthma.Precautions:A negative methacholine challenge test (MCT) does not entirely rule out asthma. The test may yield negative results due to the following reasons:(1) Prior use of medications that reduce airway responsiveness, such as ß2 agonists, anticholinergic drugs, antihistamines, leukotriene receptor antagonists, theophylline, corticosteroids, etc., and insufficient washout time.(2) Failure to meet quality control standards in terms of pressure, flow rate, particle size, and nebulization volume of the aerosol delivery device.(3) Poor subject cooperation leads to inadequate inhalation of the methacholine agent.(4) Some exercise-induced asthma patients may not be sensitive to direct bronchial challenge tests like the Methacholine challenge and require indirect bronchial challenge tests such as hyperventilation, cold air, or exercise challenge to induce a positive response.(5) A few cases of occupational asthma may only react to specific antigens or sensitizing agents, requiring specific allergen exposure to elicit a positive response.A positive MCT does not necessarily indicate asthma. Other conditions can also present with airway hyperresponsiveness and yield positive results in the challenge test, such as allergic rhinitis, chronic bronchitis, viral upper respiratory infections, allergic alveolitis, tropical eosinophilia, cystic fibrosis, sarcoidosis, bronchiectasis, acute respiratory distress syndrome, post-cardiopulmonary transplant, congestive heart failure, and more. Furthermore, factors like smoking, air pollution, or exercise before the test may also result in a positive bronchial challenge test.Question 10: What are the standardized requirements for the MCT report?The report should include: (1) basic information about the subject; (2) examination data and graphics: present baseline data, measurement data after the last two challenge doses or concentrations in tabular form, and the percentage of actual measured values compared to the baseline; flow-volume curve and volume-time curve before and after challenge test; dose-response curve: showing the threshold for positive challenge; (3) opinions and conclusions of the report: including the operator's opinions, quality rating of the examination, and review opinions of the reviewing physician.Question 11: What are the adverse reactions and safety measures of MCT?During the MCT, the subject needs to repeatedly breathe forcefully and inhale bronchial challenge agents, which may induce or exacerbate bronchospasm and contraction and may even cause life-threatening situations. Medical staff should be fully aware of the indications, contraindications, medication use procedures, and emergency response plans for the MCT.

Association of Prenatal Maternal and Infant Vitamin D Supplementation with Offspring Asthma.

Rationale: The role and timing of vitamin D supplementation in the prevention of asthma has not been fully elucidated. Objective: To describe the association between prenatal and postnatal vitamin D with offspring asthma outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial. Methods: We classified 748 mother-offspring pairs into four groups based on the mother's randomization to receive high-dose versus low-dose (4,400 IU vs. 400 IU) vitamin D supplementation during pregnancy and the offspring parent-reported high-dose versus low-dose (⩾400 IU vs. <400 IU) vitamin D supplementation as estimated by intake of vitamin D drops or infant formula. We used logistic regression to test the association of the four vitamin D exposure groups-"mother-low/infant-low (reference)," "mother-high/infant-high," "mother-high/infant-low," and "mother-low/infant-high"-with offspring asthma and/or recurrent wheeze at age 3 years, active asthma at age 6 years, and atopic asthma at age 6 years. Results: The risk of asthma and/or recurrent wheeze at 3 years was lowest in the mother-high/infant-low group (adjusted odds ratio vs. mother-low/infant-low, 0.39; 95% confidence interval, 0.16-0.88, P = 0.03). When stratifying by history of exclusive breastfeeding until age 4 months, the protective effect in the mother-high/infant-low group was seen only among exclusively breastfed infants (odds ratio vs. mother-low/infant-low, 0.19; 95% confidence interval, 0.04-0.68; P = 0.02). We did not observe any significant associations with active or atopic asthma at age 6 years. Conclusions: We observe that high-dose prenatal and low-dose postnatal vitamin D supplementation may be associated with reduced offspring asthma or recurrent wheeze by age 3 years, but this association may be confounded by the protective effect of breastfeeding.

Characterization of changes in the intestinal microbiome following combination therapy with zinc preparation and conventional treatment for children with rotavirus enteritis.

Background: Rotavirus (RV) is one of the most common pathogens causing diarrhea in infants and young children worldwide. Routinely, antiviral therapy, intestinal mucosa protection, and fluid supplementation are used in clinic, however this is not efficacious in some severe cases. Zinc supplementation has previously been shown to improve resolution of symptoms from infectious diarrhea. Methods: In this study differences in response rate, duration of hyperthermia, vomiting, and diarrhea, and the persistence time of cough and lung rales in groups were compared. 16SrDNA gene sequencing technology was used to analyze and compare changes in the intestinal microflora of children with RV enteritis who received the conventional treatment with or without the zinc preparation. In addition, the correlations between the differential bacterial species and the related inflammatory factors were determined. Results: Conventional therapy combined with the zinc preparation significantly shortened the duration of hyperthermia, vomiting, and diarrhea compared with the conventional treatment alone. In addition, the time to symptom relief showed that the absorption time of cough and lung rales was significantly shorter in the combination treatment group than that in the conventional treatment group in the children with pneumonia. Further, compared with the conventional treatment, the combined treatment significantly increased the diversity and abundances of florae as compared with the conventional treatment. This combination therapy containing zinc preparation markedly increased the abundances of Faecalibacterium, Bacteroidales, Ruminoccoccoccus, and Lachnospiraceae at the genus level. The LEfSe analysis suggested that Clostridiumbolteae were most significantly altered after the combination therapy. In addition, a correlation analysis revealed significantly negative correlations between the inflammatory factors especially IL-6, TNF-a, CRP and some intestinal florae such as Bacteroides, Faecalibacterium, Blautia, Parabacteroides, Subdoligranulum, and Flavonifractor. Conclusion: Compared with the conventional therapy alone, the combined therapy with the zinc preparation significantly improves symptoms caused by RV. The combination therapy containing the zinc preparation significantly increases the diversity and abundances of some beneficial groups of bacteria. Further, The presence of these groups was further negatively correlated with relevant inflammatory factors. More importantly, this combination therapy containing the zinc preparation provides a reference for the clinical management of children with RV enteritis.

[Effects of blistering cupping combined with thunder-fire moxibustion on the efficacy and airway remodeling of cold-wheezing syndrome in bronchial asthma].

OBJECTIVE: To investigate the clinical efficacy of the combined application of blistering cupping with thunder-fire moxibustion in treating bronchial asthma of cold-wheezing syndrome, and its influences on airway remodeling, inflammatory factors, lung function, and quality of life on the base of conventional western medicine treatment. METHODS: A total of 76 patients with bronchial asthma of cold-wheezing syndrome were randomly divided into an observation group and a control group, 38 cases in each group. In the control group, the basic treatment was used, i.e. budesonide formoterol powder inhalation. In the observation group, on the basis of the treatment as the control group, blistering cupping combined with thunder-fire moxibustion was supplemented, Dazhui (GV 14), Danzhong (CV 17) and bilateral Feishu (BL 13), Gaohuang (BL 43), and Zhongfu (LU 1) were selected; blistering cupping was administered once a day and thunder-fire moxibustion was given twice a day. One course of treatment was composed of 7 days in both groups, and 2 courses of treatment were required. Before and after treatment, the airway remodeling indexes (matrix metalloproteinase-9 [MMP-9], tissue inhibitor of matrix metalloproteinase-1 [TIMP-1], and transforming growth factor-ß1 [TGF-ß1]) and inflammatory indexes (interleukin [IL] -1ß、IL-25) were detected by using radioimmunoassay in the patients of the two groups. The lung function, traditional Chinese medicine symptom score, and asthma quality of life questionnaire (AQLQ) score were observed in the patients of the two groups. RESULTS: After treatment, the serum levels of MMP-9, TIMP-1, TGF-ß1, IL-1ß, IL-25, peak expiratory flow (PEFR), traditional Chinese medicine symptom scores, and AQLQ scores were decreased compared with those before treatment in the patients of the two groups (P<0.05), and the results in the observation group were lower than those in the control group (P<0.05). After treatment, the first second forced expiratory volume (FEV1) and peak expiratory flow rate (PEF) were increased compared with those before treatment in the two groups (P<0.05), and the results in the observation group were higher than those in the control group (P<0.05). CONCLUSION: On the basis of the conventional western medicine treatment, the combination of blistering cupping with thunder-fire moxibustion can effectively ameliorate the clinical symptoms of patients, reduce inflammatory levels, inhibit airway remodeling and improve the lung function and quality of life in the patients with bronchial asthma.

Maternal vitamin D-related metabolome and offspring risk of asthma outcomes.

BACKGROUND: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS: In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

Maternal fish oil and/or probiotics intervention: Allergic diseases in children up to two years old.

BACKGROUND: As n-3 long-chain polyunsaturated fatty acids and probiotics possess immunomodulatory properties, theoretically they could lower the risk of allergic diseases. But their effects remain controversial. We aimed to study the effects of fish oil and probiotics separately or in combination from early pregnancy onwards to lower the risk of allergic diseases in the infants. METHODS: In this double-blind trial, women (n = 439) in early pregnancies were randomized into four intervention groups: fish oil + placebo, probiotics + placebo, fish oil + probiotics, and placebo + placebo. Fish oil (1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid) and probiotic (Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each) supplements were provided for daily consumption from randomization up to 6 months postpartum. All analyses were adjusted with pet ownership. RESULTS: No difference between the infants in the four intervention groups were found regarding physician-diagnosed food allergy, atopic eczema, or atopy at the age of 12 or 24 months (all p > .05). The probiotic intervention was associated with lower odds of recurrent wheezing at 24 months (OR 0.39, 95% CI 0.18-0.84, p = .017), but not at 12 months. CONCLUSIONS: The use of fish oil and/or probiotics from early pregnancy onwards did not lower the odds of childhood allergic diseases or atopy, with the exception of the probiotic intervention which decreased the risk of recurrent wheezing when the infants were two years old. This suggests that the incidence of asthma could also decrease later in childhood and thus these outcomes need to be clarified in further investigations.

[Review and perspective of clinical research involving chest tightness variant asthma in China].

Chest tightness variant asthma (CTVA) was first reported and named by Chinese scholars in 2013. It is a new clinical type of asthma characterized by chest tightness as the only or primary symptom, without typical asthma manifestations such as recurrent wheezing and shortness of breath, and without wheezing sounds heard during lung auscultation. The overall epidemiological data on CTVA is currently unavailable. Its pathogenesis is similar to that of typical asthma, involving eosinophilic airway inflammation. Due to the lack of typical clinical manifestations, insufficient knowledge of this disease in some clinicians and some other reasons, CTVA is susceptible to misdiagnosis or missed diagnosis. Currently, the diagnostic criteria for CTVA are: chest tightness as the only or primary symptom, without typical asthma symptoms and signs such as wheezing and shortness of breath, and with any one of the objective indicators of variable airflow limitation. Effective anti-asthma treatment is required, and other diseases that cause chest tightness, such as cardiovascular, digestive, nervous, muscular, and mental diseases should be excluded. CTVA treatment follows that of typical asthma, but the specific treatment duration is uncertain and may require long-term management. Traditional Chinese medicine has shown some therapeutic effects on CTVA. Most CTVA patients have a good prognosis after active anti-asthma treatment. This paper analyzes and summarizes the research of CTVA in China from 2013 and provides new perspectives for further exploration of CTVA.

Pollen and asthma morbidity in Atlanta: A 26-year time-series study.

BACKGROUND: Compared to many environmental risk factors, the relationship between pollen and asthma is understudied, including how associations may differ by pollen type and between subgroups, and how associations may be changing over time. OBJECTIVES: We evaluated the association between ambient pollen concentrations and emergency department (ED) visits for asthma and wheeze in Atlanta, Georgia during 1993-2018. We estimated overall associations for 13 individual pollen taxa, as well as associations by decade, race, age (5-17, 18-64, 65+), and insurance status (Medicaid vs non-Medicaid). METHODS: Speciated pollen data were acquired from Atlanta Allergy & Asthma, a nationally certified pollen counting station. ED visit data were obtained from individual hospitals and from the Georgia Hospital Association. We performed time-series analyses using quasi-Poisson distributed lag models, with primary analyses assessing 3-day (lag 0-2 days) pollen levels. Models controlled for day of week, holidays, air temperature, month, year, and month-by-year interactions. RESULTS: From 1993 to 2018, there were 686,259 ED visits for asthma and wheeze in the dataset, and the number of ED visits increased over time. We observed positive associations of asthma and wheeze ED visits with nine of the 13 pollen taxa: trees (maple, birch, pine, oak, willow, sycamore, and mulberry), two weeds (nettle and pigweed), and grasses. Rate ratios indicated 1-8% increases in asthma and wheeze ED visits per standard deviation increases in pollen. In general, we observed stronger associations in the earliest period (1993-2000), in younger people, and in Black patients; however, results varied by pollen taxa. CONCLUSIONS: Some, but not all, types of pollen are associated with increased ED visits for asthma/wheeze. Associations are generally higher in Black and younger patients and appear to have decreased over time.

Relationship between vitamin D and asthma from gestational to adulthood period: a meta-analysis of randomized clinical trials.

BACKGROUND: Despite numerous studies investigating vitamin D, its impact on asthma is still unknown. The aim of our meta-analysis is to analyze the vitamin D supplementation influence on asthma prevention and treatment ranging from gestational to adulthood period. METHODS: Fifteen randomized clinical trials were included after database search. Studies contained the analyzed endpoints: the number of asthma and wheezing occurrence in gestational and infantile periods, the change of childhood/adult asthma control test score and forced expiratory volume in one second (FEV1) in childhood and adulthood periods. Random effects model was used to calculate effect sizes. RESULTS: Supplementation by women during pregnancy period decreased the wheezing occurrence in their children by 23% (RR = 0.77; 95% CI [0.64; 0.92]; p < 0.0049, I2 = 0%); whereas had no effect on given asthma parameters during the infantile period. Moreover, vitamin D administration had negative effect on the FEV1 change in children (MD = -3.84; 95% CI [-7.68; -0.01]; p = 0.0497; I2 = 95%), but had positive effect on the change of ACT score in adults (MD = 1.80; 95% CI [0.12; 3.49]; p = 0.0359; I2 = 99%). CONCLUSIONS: Our meta-analysis showed the varying results depending on patient's life period. It is important to further investigate the role of vitamin D supplementation in asthma management.

The Impact of Baseline 25-Hydroxyvitamin D Level and Gestational Age on Prenatal Vitamin D Supplementation to Prevent Offspring Asthma or Recurrent Wheezing.

BACKGROUND: Prenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive. OBJECTIVES: We aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing. METHODS: We conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10-18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation. RESULTS: An inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32-38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D-deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9-12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82). CONCLUSIONS: Pregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy. This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621.

The Role of Lung Function in Determining Which Children Develop Asthma.

Longitudinal studies have demonstrated that altered indices of airway function, assessed shortly after birth, are a risk factor for the subsequent development of wheezing illnesses and asthma, and that these indices predict airway size and airway wall thickness in adult life. Pre- and postnatal factors that directly alter early airway function, such as extreme prematurity and cigarette smoke, may continue to affect airway function and, hence, the risks for wheeze and asthma. Early airway function and an associated asthma risk may also be indirectly influenced by immune system responses, respiratory viruses, the airway microbiome, genetics, and epigenetics, especially if they affect airway epithelial dysfunction. Few if any interventions, apart from smoking avoidance, have been proven to alter the risks of developing asthma, but vitamin C supplementation to pregnant smokers may help decrease the effects of in utero smoke on offspring lung function. We conclude that airway size and the factors influencing this play an important role in determining the risk for asthma across the lifetime. Progress in asthma prevention is long overdue and this may benefit from carefully designed interventions in well-phenotyped longitudinal birth cohorts with early airway function assessments monitored through to adulthood.

Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial.

Importance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed. Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze. Design, Setting, and Participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021. Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment. Main Outcomes and Measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze. Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and Relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health. Trial Registration: ClinicalTrials.gov Identifier: NCT03203603.

Efficacy and Safety Analysis of Piperacillin Tazobactam in Combination With High Frequency Chest Wall Oscillation in Patients With COPD Coupled With Pneumonia.

Context: Chronic obstructive pulmonary disease (COPD) is a common, chronic inflammatory disease of the airway, and acute exacerbation of COPD (AE-COPD) refers to the manifestations of inflammation in the lungs that appear within a short period of time. Some patients contract pneumonia, and they can be prone to recurrent attacks of AE-COPD combined with pneumonia. The efficacy of conventional treatments isn't generally satisfactory. Objective: The study intended to investigate the effectiveness and safety of piperacillin tazobactam in combination with the use of high-frequency chest-wall oscillation (HFCWO) to produce expectoration for the treatment of pneumonia in patients with AE-COPD and to provide a reference for clinical treatment. Design: The research team designed a prospective, randomized controlled trial. Setting: The study took place at the Sixth Hospital of Wuhan of the Affiliated Hospital of Jianghan University in Wuhan, China. Participants: Participants were 92 patients who had been admitted to the hospital between January 2020 and November 2021 with AE-COPD combined with pneumonia. Intervention: Using the random number table method, the research team randomly assigned participants to one of two groups, an intervention group or a control group, each with 46 participants. The control group received conventional treatment with oxygen, antibiotics, antispasmodics, antiasthmatic drugs, and phlegmolytic drugs as well as HFCWO for sputum removal. In addition to those treatments, the intervention group received piperacillin tazobactam. Outcome measures: The research team measured the treatment's efficacy at one day postintervention. At baseline and at one day postintervention, the study also measured pulmonary function, laboratory indexes, and blood-gas-analysis indexes. In addition, the research team identified the time of disappearance of clinical symptoms, including the disappearance of cough, sputum, dyspnea, and pulmonary rales; calculated the length of hospital stay, and evaluated the treatment's safety. Results: Postintervention, the intervention group's clinical efficacy was significantly higher than that of the control group (P < .05), and the group's cough, coughing of sputum, dyspnea, disappearance time of pulmonary rales, and hospitalization times were all significantly lower than those in the control group (P < .05). The FEV1, FVC, FEV1% and FEV1/FVC levels were higher in both groups postintervention than at baseline and were significantly higher in the intervention group than in the control group (P < .05). Postintervention, the levels of IL-2, IL-10, TNF-α, CRP and PCT were lower in both groups than at baseline, and the intervention group's levels were significantly lower than those in the control group (P < .05). Postintervention, the PaCO2 level decreased and PaO2 and SaO2 levels increased in both groups compared to baseline; the intervention group's PaCO2 level was lower and PaO2 and SaO2 levels were higher than those in the control group. During the treatment, no adverse reactions occurred in the control group, and one participant had a decreased appetite in the intervention group; the incidence of adverse reactions in that group was 2.17% (1/46). That participant received no special treatment, and the condition improved after stopping the drug. Conclusion: Piperacillin tazobactam combined with HFCWO for sputum evacuation can effectively treat patients with pneumonia in acute exacerbation of COPD, with high safety. The treatment is worthy of clinical application.

Maternal dietary folate intake with folic acid supplements and wheeze and eczema in children aged 2 years in the Japan Environment and Children's Study.

Maternal intake of folic acid supplements is reportedly associated with the risk of early-onset allergies in offspring. However, only a few studies have considered the intake of both folic acid supplements and dietary folate. Here, the relationship between maternal intake of folic acid supplements and allergic symptoms such as wheeze and eczema in offspring was analyzed while considering dietary folate intake. We examined 84,361 mothers and 85,114 children in the Japan Environment and Children's Study. The participants were divided into three groups depending on maternal folic acid supplementation ("no use," "occasional use," and "daily use"). Each group was then subdivided into three groups based on total folic acid and dietary folate intake. Outcomes were determined considering the wheeze and eczema status of each child at the age of 2 years. The status was based on the International Study of Asthma and Allergies in Childhood. It was found that 22.1% of the mothers took folic acid supplements daily. In contrast, 56.3% of the mothers did not take these supplements. Maternal intake of folic acid supplements was not associated with wheeze and eczema in the offspring. In contrast, only dietary folate intake was positively associated with wheeze at the age of 2 (adjusted odds ratio, 1.103; 95% confidence interval, 1.003-1.212). However, there is no scientific evidence of a biological mechanism that clarifies this result. Potential confounders such as other nutrition, outdoor/indoor air pollution, and genetic factors may have affected the results. Therefore, further studies on the association between maternal intake of folic acid and allergic symptoms at the age of 3 or above are needed to confirm the results of this study. Trial registration UMIN Clinical Trials Registry (number: UMIN000030786).

A randomized clinical trial to assess the effect of zinc and vitamin D supplementation in addition to hypertonic saline on treatment of acute bronchiolitis.

BACKGROUND: Bronchiolitis, the most common cause of hospitalization in infancy has not yet a definitive treatment. This study was conducted to assess the effect of Zinc and vitamin D on treatment of infants with bronchiolitis. METHODS: In this double blind, randomized clinical trial, 94 infants aged 2 to 23 months, admitted in Mousavi Hospital in Zanjan, Iran, with the diagnosis of acute bronchiolitis were randomly assigned into 3 groups. The control group was only treated with hypertonic saline. The two case groups received either 100 unit/kg/day of Vitamin D or 20 mg/day of zinc in addition to hypertonic saline. Wheezing, duration of hospital stay, cough, cyanosis, respiratory distress and the respiratory rate in the first, third and seventh day of hospitalization were evaluated. RESULTS: There was no significant difference between groups in terms of age, sex, weight, passive smoking, wheezing, oxygen saturation, cyanosis and type of delivery. On the third day of hospitalization, the respiratory rate/min in the control group, the groups receiving vitamin D and zinc were 45.2 ± 10.7, 37.8 ± 3.9 and 41.1 ± 9.1 respectively and the result of repeated measure analysis didn't show any significant difference between the 3 groups (P = 0.562). Duration of hospitalization in the group receiving Vitamin D or zinc and in controls were 4.2 ± 2.6, 4.4 ± 2.2 and 5.1 ± 2.4 days respectively and this difference was not significant. Zinc receiving patients did not differ from the control group regarding to respiratory rate, cyanosis and wheezing. CONCLUSION: Vitamin D or zinc administration was not effective in reducing respiratory rate in children with bronchiolitis. Trial registration This project was approved by the Institutional Ethics Committee (IR, ZUMS.REC.1396.50), and registered on IRCT (IRCT20131217015835N7).

Diagnosis and management of asthma in children.

Asthma is the the most common chronic respiratory condition of childhood worldwide, with around 14% of children and young people affected. Despite the high prevalence, paediatric asthma outcomes are inadequate, and there are several avoidable deaths each year. Characteristic asthma features include wheeze, shortness of breath and cough, which are typically triggered by a number of possible stimuli. There are several diagnostic challenges, and as a result, both overdiagnosis and underdiagnosis of paediatric asthma remain problematic.Effective asthma management involves a holistic approach addressing both pharmacological and non-pharmacological management, as well as education and self-management aspects. Working in partnership with children and families is key in promoting good outcomes. Education on how to take treatment effectively, trigger avoidance, modifiable risk factors and actions to take during acute attacks via personalised asthma action plans is essential.This review aimed to provide an overview of good clinical practice in the diagnosis and management of paediatric asthma. We discuss the current diagnostic challenges and predictors of life-threatening attacks. Additionally, we outline the similarities and differences in global paediatric asthma guidelines and highlight potential future developments in care. It is hoped that this review will be useful for healthcare providers working in a range of child health settings.

Addition of a nutraceutical to montelukast or inhaled steroid in the treatment of wheezing during COVID-19 pandemic: a multicenter, open-label, randomized controlled trial.

Background and aim Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy. Methods The multicenter, open-label study enrolled 84 children aged 2-6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif. Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician. Results Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups. Conclusions Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.

Primary Prevention of Pediatric Asthma through Nutritional Interventions.

Asthma is the most common chronic non-communicable disease in children, the pathogenesis of which involves several factors. The increasing burden of asthma worldwide has emphasized the need to identify the modifiable factors associated with the development of the disease. Recent research has focused on the relationship between dietary factors during the first 1000 days of life (including pregnancy)-when the immune system is particularly vulnerable to exogenous interferences-and allergic outcomes in children. Specific nutrients have been analyzed as potential targets for the prevention of childhood wheeze and asthma. Recent randomized controlled trials show that vitamin D supplementation during pregnancy, using higher doses than currently recommended, may be protective against early childhood wheezing but not school-age asthma. Omega-3 fatty acid supplementation during pregnancy and infancy may be associated with a reduced risk of childhood wheeze, although the evidence is conflicting. Data from observational studies suggest that some dietary patterns during pregnancy and infancy might also influence the risk of childhood asthma. However, the quality of the available evidence is insufficient to allow recommendations regarding dietary changes for the prevention of pediatric asthma. This review outlines the available high-quality evidence on the role of prenatal and perinatal nutritional interventions for the primary prevention of asthma in children and attempts to address unmet areas for future research in pediatric asthma prevention.

Dietary strategies for the prevention of asthma in children.

PURPOSE OF REVIEW: This review summarizes information relating to dietary intake during pregnancy, lactation and early life that may prevent childhood asthma. This review also summarizes how future studies may be improved. RECENT FINDINGS: Recent findings from observational studies suggest that eating according to certain dietary patterns during pregnancy, such as the dietary inflammatory index, Mediterranean diet and Maternal diet index, may reduce asthma and or wheeze in the child. Vitamin D supplementation with higher doses than recommended during pregnancy may be associated with reduced early transient childhood wheezing in the offspring. Higher levels of omega-3 fatty acids in breast milk may be protective against childhood asthma. Breastfeeding infants has been shown to offer many benefits to mother and child but a direct relationship between breastfeeding and the development of asthma has not been established. During childhood, infants and children may need to reduce their intake of advanced glycation end products, increase their food intake according to the traditional Mediterranean diet and increase the diversity of foods eaten. SUMMARY: Current evidence provides limited suggestions regarding dietary changes for preventing early transient childhood wheezing. In order to harmonize methods for future data collection and reporting, it is important to harmonize relevant definitions and other important factors. The aim of the considerations described here is to enable a better comparison of future studies and provide better guidance to patients and families.