Pulmonary function characteristics in children with suspected asthma: implications for asthma diagnosis.

BACKGROUND: In children suspected of asthma, diagnosis is confirmed via variable expiratory airflow limitation. However, there is no single gold standard test for diagnosing asthma. OBJECTIVE: This study aimed to evaluate the pulmonary function characteristics in children suspected of asthma without bronchodilator response (BDR) and bronchial hyperresponsiveness (BHR). METHODS: We utilized two separate real-world retrospective observational cohorts of children who underwent both spirometry and bronchial provocation testing for asthma. Spirometry parameters were collected and compared between definite asthma, probable asthma, and non-asthma groups. The original cohort comprised 1199 children who visited the Severance Hospital (Seoul, Korea) between January 2017 and December 2019. The external cohort included 105 children who visited the Gangnam Severance Hospital between January 2019 and December 2019. RESULTS: Probable asthma accounted for 16.8% and 32.4% of the original and external cohorts, respectively. This group showed a significantly higher FeNO level and prevalence of allergic sensitization. Baseline forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF25-75), and FEF75 showed stepwise decrements from non-asthma, probable asthma, to definite asthma patients (P < 0.001). The probable asthma group showed significantly higher odds of abnormal FEV1/FVC (OR, 2.24 [95%CI, 1.43-3.52])and FEF25-75 (2.05 [1.13-3.73]) than the non-asthma group and lower odds of abnormal FEV1(0.05 [0.01-0.19]),FEV1 /FVC (0.27 [0.18-0.41]), FEF25-75 (0.17 [0.11-0.28]), and FEF75 (0.14 [0.08-0.24]) compared to the definite asthma group. The external cohort was consistent with the original cohort. CONCLUSION: We show evidence of airway dysfunction in children for whom a high clinical suspicion of asthma exists without evidence of BDR and BHR. Repeated pulmonary function tests that closely monitor for subtle lung function impairments and active utilization of additional tests, such as allergic screening and FeNO, should be considered to close the gap in diagnosing asthma.

Factors influencing the quality of life in children with atopic dermatitis in Korea: A multicenter cross-sectional study.

Background: There is a lack of studies about which factors affect the quality of life (QoL) in children with atopic dermatitis (AD), although it is well known that AD has considerably negative effects on their QoL. Objective: This study aimed to measure the QoL in children with AD and identify the factors that affect their QoL. Methods: A questionnaire derived from the Children's Dermatology Life Quality Index (CDLQI) was used to measure QoL. Family history, allergic comorbidities, exacerbation-related factors, time of exacerbation, and previous and current treatment were also evaluated. The total immunoglobulin E (IgE) level and specific IgE sensitization were determined by the multiple allergen simultaneous test, allergy test, or skin-prick test. AD severity was categorized into mild, moderate, and severe based on treatments. Results: In total, 254 children (46.4 months, 53% boys) from seven hospitals completed the survey. The mean CDLQI score was 7.2 ± 5.5 (total score range of 0-30). The respondents were divided into three groups according to their QoL score distribution, with 0 - 4 points (n = 84), 5 - 9 points (n = 90), and ≥10 points (n = 80) representing good, fair, and poor QoL, respectively. The more severe AD showed the higher CDLQI score significantly (p = 0.001). Compared with other groups, children with poor QoL were more sensitized to inhalant allergens (odds ratio [OR] 1.29 [95% confidence interval {CI}], 1.03 - 1.62) and had more exacerbating factors (OR 1.26 [95% CI, 1.04 - 1.54]), which included inhalation allergen-related exacerbating factors (OR 2.54 [95% CI, 1.23 - 5.23), even after adjusting for age, total IgE, body mass index, severity, and use of moisturizer. The concordance between animal sensitization and an exacerbating factor, including dog and cat, was fair, with 0.39 κ and 0.85 accuracy. Conclusion: This study showed that impaired QoL in children with AD is associated with inhalant allergen sensitization and inhalant allergen-related exacerbation factors. Especially, dog and cat sensitization was a significant exacerbating factor. The inhalation-related exacerbation factors, including animal allergens, might be addressed to improve AD management in children.

Predicting the Outcome of Pediatric Oral Food Challenges for Determining Tolerance Development.

PURPOSE: Despite the risk of anaphylaxis, oral food challenges (OFCs) are performed clinically for various indications, particularly to confirm tolerance development. This study aimed to assess OFCs by relevant indications and build an outcome prediction model to help determine when to perform OFCs in children who are likely to have developed immune tolerance. METHODS: In total, 432 pediatric OFCs were retrospectively analyzed according to indications. Clinical characteristics, serum total immunoglobulin (Ig) E, blood eosinophils, and specific IgE and IgG4 levels for food allergens were noted and compared. Machine learning was utilized to select the most important variables in determining the passage of the OFCs, and prediction models were constructed using the selected variables. RESULTS: OFCs were most commonly performed to confirm tolerance development (number, %; 267, 61.8%). The most common food allergens tested were egg (191, 44.2%) and milk (135, 31.3%). Children who passed the egg challenges for confirming tolerance acquisition had significantly lower egg white-specific IgE level (P = 0.008). Similarly, those who passed milk challenges had significantly lower cow's milk-specific IgE (P = 0.002) and casein-specific IgE levels (P = 0.005). We developed a nomogram to predict the outcome of OFCs to determine the tolerance acquisition with the selected variables; lower food-specific IgE, higher total IgE, and younger age indicated a higher probability of passage. The area under the curve (95% confidence interval) was 0.623 (0.503-0.743) for egg and 0.734 (0.628-0.840) for milk. CONCLUSIONS: Serum total IgE and food-specific IgE combined with age showed trends toward passing OFCs for confirming tolerance development. The constructed model may be used by clinicians as a practical guide for minimizing the risks of OFCs and a timely reintroduction for children with food allergies.

TEV/FEV3 as a coherent metric of small airway dysfunction in childhood asthma.

Background: Spirometry is an unrivalled tool for determining asthma and asthma severity. The ratio of forced expiratory volume (FEV) in 1 second (FEV1) to forced vital capacity (FVC) and the forced expiratory flow between 25% and 75% of FVC (FEF25-75) are well-known markers of airway obstruction, but they are limited by low reproducibility, particularly in children. In this study, we defined terminal expiration volume (TEV) as FEV in 3 seconds forced expiratory volume in 3 seconds (FEV3) minus forced expiratory volume in 1 seconds (FEV1) and investigate whether TEV/FEV3 can function as a coherent marker to compensate for existing markers. Methods: This retrospective study comprised 980 children ages ≤ 18 years who underwent spirometry and the bronchial provocation testing. TEV/FEV3 was compared with regard to asthma presence and severity. The findings were verified with an external validation group (n = 105). Results: FEV3 was obtained in 837 children (85.4%). TEV/FEV3 was significantly higher in patients with asthma than in patients who did not have asthma (17.1 ± 5.5 versus 12.0 ± 4.4, p < 0.001). External validation with 73 patients showed similar results (18.0 ± 5.9 in asthma versus 10.2 ± 5.1 in non-asthma, p < 0.001). The discriminatory power of TEV/FEV3 for asthma was comparable with that of FEF25-75 (p = 0.804). TEV/FEV3 significantly increased with asthma severity (mild, 16.1 ± 5.4; moderate, 17.7 ± 5.4; severe, 22.0 ± 5.3; p < 0.001). For patients who could not achieve FEV3, FEF25-75 demonstrated no significant difference between mild and moderate asthma, and could not discriminate asthma or asthma severity. Conclusion: TEV/FEV3 is a new metric that may help diagnose and determine asthma severity by using conventional spirometry by assessing small airway dysfunction. TEV/FEV3 promotes a reassessment of the reliability of other spirometric parameters, particularly in young children. Caution is needed in interpreting the result of spirometry in children who cannot achieve FEV3.

Radiologic Assessment of Lung Edema Score as a Predictor of Clinical Outcome in Children with Acute Respiratory Distress Syndrome.

PURPOSE: The radiographic assessment of lung edema (RALE) score enables objective quantification of lung edema and is a valuable prognostic marker of adult acute respiratory distress syndrome (ARDS). We aimed to evaluate the validity of RALE score in children with ARDS. MATERIALS AND METHODS: The RALE score was measured for its reliability and correlation to other ARDS severity indices. ARDS-specific mortality was defined as death from severe pulmonary dysfunction or the need for extracorporeal membrane oxygenation therapy. The C-index of the RALE score and other ARDS severity indices were compared via survival analyses. RESULTS: Among 296 children with ARDS, 88 did not survive, and there were 70 ARDS-specific non-survivors. The RALE score showed good reliability with an intraclass correlation coefficient of 0.809 [95% confidence interval (CI), 0.760-0.848]. In univariable analysis, the RALE score had a hazard ratio (HR) of 1.19 (95% CI, 1.18-3.11), and the significance was maintained in multivariable analysis adjusting with age, ARDS etiology, and comorbidity, with an HR of 1.77 (95% CI, 1.05-2.91). The RALE score was a good predictor of ARDS-specific mortality, with a C-index of 0.607 (95% CI, 0.519-0.695). CONCLUSION: The RALE score is a reliable measure for ARDS severity and a useful prognostic marker of mortality in children, especially for ARDS-specific mortality. This score provides information that clinicians can use to decide the proper time of aggressive therapy targeting severe lung injury and to appropriately manage the fluid balance of children with ARDS.

P50 implies adverse clinical outcomes in pediatric acute respiratory distress syndrome by reflecting extrapulmonary organ dysfunction.

Hypoxemia and multiple organ dysfunction are significant contributors to mortality in patients with pediatric acute respiratory distress syndrome (PARDS). P50, the oxygen tension at which hemoglobin is 50% saturated, is a measure of hemoglobin-oxygen affinity, and its alteration might have implications for tissue hypoxia and organ dysfunction. The purpose of this single-center, retrospective study was to evaluate P50 levels in PARDS and to determine the association between P50 and clinical outcomes. The study included 212 children diagnosed with PARDS according to the Pediatric Acute Lung Injury Consensus Conference definition who required invasive mechanical ventilation and had arterial blood gas results of hemoglobin oxygen saturation < 97% at the time of diagnosis. P50 levels were calculated using Doyle's method, and organ dysfunction was assessed using the Pediatric Logistic Organ Dysfunction-2 score. Most patients exhibited more than one dysfunctional extrapulmonary organ at PARDS onset. P50 increased with increasing PARDS severity (mild (26.6 [24.9-29.6]), moderate (26.8 [25.0-29.5]), and severe PARDS (29.1 [26.1-32.4] mmHg; P = 0.025). Moreover, P50 demonstrated a significant positive association with extrapulmonary organ dysfunction score (ß = 0.158, P = 0.007) and risk of mortality (adjusted hazard ratio, 1.056; 95% confidence interval, 1.015-1.098; P = 0.007), irrespective of initial PARDS severity. The relationship between P50 and mortality was largely mediated by extrapulmonary organ dysfunction. A high P50 value at the time of PARDS diagnosis may be associated with mortality via dysfunctional extrapulmonary organs. Future studies should consider P50 as a potential candidate index for risk stratification of PARDS patients.

Genome-wide association study identifies BTNL2 associated with atopic asthma in children.

ABSTRACT: Asthma is a heterogeneous disease characterized by chronic airway inflammation with a genetic predisposition. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily that plays an important role in regulating T cell activation and immune homeostasis. Here, we aimed to investigate the association of the genetic variants of BTNL2 with childhood asthma and asthma-related traits by utilizing extreme asthma phenotypes and employing a genome-wide association study. Our study included 243 children with well-defined moderate to severe atopic asthma and 134 healthy children with no history of allergic diseases and allergic sensitization. DNA from these subjects was genotyped using AxiomTM Genome-Wide Array Plates. Although no single nucleotide polymorphisms (SNPs) reached a genome-wide threshold of significance, 3 SNPs, rs3817971, rs41355746, and rs41441651, at BTNL2 were significantly associated with moderate to severe atopic asthma after performing Bonferroni correction. These SNPs were also associated with the risk of allergic sensitization toward house dust mites and the presence and degree of bronchial hyperresponsiveness. Thus, we identified that BTNL2 was associated with atopic moderate to severe persistent asthma in Korean children, and this may play an important role in disease development and susceptibility.

Children with Heiner Syndrome: A Single-Center Experience.

Heiner syndrome is a rare cause of pulmonary hemosiderosis in children that is triggered by cow's milk allergy. Herein, we describe our experience with three recent cases of Heiner syndrome with diverse clinical courses. We recommend that clinicians should consider the possibility of Heiner syndrome in children who exhibit characteristics of idiopathic pulmonary hemosiderosis.

Multidisciplinary aerodigestive program at a children's hospital: A protocol for a prospective observational study.

BACKGROUND: Children with complex chronic multisystemic diseases frequently require care from multiple pediatric subspecialists. The aerodigestive program is a multidisciplinary program that diagnoses and treats pediatric patients with complex multi-systematic problems affecting airway, breathing, feeding, swallowing, or growth. The aim of this study is to present the protocol of the aerodigestive program of a children's hospital. METHODS AND DESIGN: This study is a prospective study to evaluate and compare the overall improvement of patients' objective and subjective conditions before and after the AeroDigestive Team (ADT) program. Among children from 1 month to 18 years of age, patients with complex problems of the airway, breathing, feeding, swallowing, or growth meeting at least two parameters of the inclusion criteria were enrolled. The overall process included referral based on the inclusion criteria, enrollment of ADT program with informed consents, interview and questionnaire for assessing patients' medical condition, prescheduling appointment, multi-specialists' evaluation, monthly team meetings, wrap-up discussion with the patients and family, therapeutic intervention, and follow-up at 6 months with the assessment of outcome measures. The outcome was evaluated objectively and subjectively. The objective outcome measure was divided into surgical or medical intervention, assessment of changes in medical condition, and follow-up study. Both caregiver interviews and questionnaires using a scoring system were used as subjective outcome measures before and after the ADT program. Children were scheduled to be followed-up at 6 months after the interventions or ADT meeting. DISCUSSION: The aerodigestive program is expected to provide comprehensive and multidisciplinary management of children with complex airway and digestive tract disorders.

Development of a Multidisciplinary Aerodigestive Program: An Institutional Experience.

We share our experience on the implementation of a multidisciplinary aerodigestive program comprising an aerodigestive team (ADT) so as to evaluate its feasibility. We performed a retrospective chart review of the patients discussed at the monthly ADT meetings and analyzed the data. A total of 98 children were referred to the ADT during the study period. The number of cases increased steadily from 3.5 cases per month in 2019 to 8.5 cases per month in 2020. The median age of patients was 34.5 months, and 55% were male. Among the chronic comorbidities, neurologic disease was the most common (85%), followed by respiratory (36%) and cardiac (13%) disorders. The common reasons for consultation were suspected aspiration (56%), respiratory difficulty (44%), drooling/stertor (30%), regurgitation/vomiting (18%), and feeding/swallowing difficulty (17%). Following discussions, 58 patients received active interventions, including fundoplication, gastrostomy, laryngomicrosurgery, tracheostomy, and primary dilatation of the airway. According to the questionnaire of the caregiver, the majority agreed that the main symptoms and quality of life of patients had improved (88%), reducing the burden on caregivers (77%). Aerodigestive programs may provide comprehensive and multidisciplinary management for children with complex airway and digestive tract disorders.

SpO2/FiO2 as a predictor of high flow nasal cannula outcomes in children with acute hypoxemic respiratory failure.

The high-flow nasal cannula (HFNC) is a useful treatment modality for acute hypoxemic respiratory failure (AHRF) in children. We compared the ability of the oxygen saturation to fraction of inspired oxygen ratio (S/F) and arterial oxygen partial pressure to fraction of inspired oxygen ratio (P/F) to predict HFNC outcomes in children with AHRF. This study included children treated with HFNC due to AHRF from April 2013 to March 2019 at the Severance Children's Hospital. HFNC failure was defined as the need for mechanical ventilation. Trends of S/F and P/F during HFNC were analyzed. To predict HFNC outcomes, a nomogram was constructed based on predictive factors. A total of 139 patients with arterial blood gas data were included in the S/F and P/F analyses. S/F < 230 at initiation showed high prediction accuracy for HFNC failure (area under the receiver operating characteristic curve: 0.751). Univariate analyses identified S/F < 230 at HFNC initiation and < 200 at 2 h (odds ratio [OR] 12.83, 95% CI 5.06-35.84), and hemato-oncologic disease (OR 3.79, 95% CI 1.12-12.78) as significant predictive factors of HFNC failure. The constructed nomogram had a highly predictive performance, with a concordance index of 0.765 and 0.831 for the exploratory and validation groups, respectively. S/F may be used as a predictor of HFNC outcomes. Our nomogram with S/F for HFNC failure within 2 h may prevent delayed intubation in children with AHRF.

Pediatric Home Mechanical Ventilation in Korea: the Present Situation and Future Strategy.

BACKGROUND: The number of children using home mechanical ventilation (HMV) has increased markedly in Europe and North America, but little is known about the situation in Korea. We described the clinical characteristics of children using HMV and investigated the current situation of HMV utilization in children. METHODS: Data on HMV prescriptions in year 2016 for children under the age of 19 was retrieved from the National Health Insurance Service for nationwide information. For more detailed information, data from year 2016 to 2018 was also retrieved from a tertiary center, Severance Children's Hospital. RESULTS: Nationwide, 416 children were prescribed with HMV in 2016, with an estimated prevalence of 4.4 per 100,000 children, of which 64.2% were male and mean age was 6-year-old. The estimated number of patients using invasive ventilators via tracheostomy was 202 (49%). Neuromuscular diseases were the most frequent cause (217; 52%), followed by central nervous system diseases (142; 34%), and cardiopulmonary diseases (57; 14%). In the tertiary center, a total of 62 children were prescribed with HMV (19 [31%] with non-invasive ventilation; 43 [69%] with invasive ventilation]. The number of children with HMV increased from 11 in 2016 to 29 in 2018. The mean age for initiation of HMV was 3.1 years and male patients comprised 65%. The most frequent diagnostic reason for HMV was central nervous system diseases (68%), followed by cardiopulmonary diseases (19%) and neuromuscular diseases (13%). Five patients died during the study period and five patients weaned from HMV. CONCLUSION: This study provides insights on the present situation of HMV utilization in Korean children.