Children are affected by a broad spectrum of acute and chronic respiratory disorders. The number of children with respiratory disease is increasing, as are the complexity of disease pathophysiology and the management demands on pediatric pulmonologists. Despite slowing increasing numbers of board-certified pediatric pulmonologists, large areas of the country are underserved and there is a perception of an impending workforce crisis. There are multiple reasons for these concerns. A joint effort between the Pediatric Pulmonology Division Directors Association and Pediatric Pulmonary Training Directors Association was undertaken to address these issues.

Abstract. Pseudomonas aeruginosa and Staphylococcus aureus are bacterial pathogens frequently associated with pulmonary complications and disease progression in cystic fibrosis (CF) patients. However, these bacteria increasingly show multiple resistance to antibiotics, necessitating novel management strategies. One possibility is phage therapy, where lytic bacteriophages (phages; bacteria-specific viruses) are administered to kill target bacterial pathogens. Recent publication of case reports of phage-therapy treatment of antibiotic-resistant lung infections in CF has garnered significant attention. These cases exemplify the renewed interest in phage therapy, as an older concept that is newly updated to include rigorous collection and analysis of patient data to assess clinical benefit, while informing the development of clinical trials. As outcomes of these trials become public, the results will valuably gauge the potential usefulness of phage therapy to address the rise in antibiotic-resistant bacterial infections. In addition, we highlight the further need for basic research on accurately predicting the different responses of target bacterial pathogens when phages are administered alone, sequentially or as mixtures (cocktails), and whether within-cocktail interactions among phages hold consequences for the efficacy of phage therapy in patient treatment.

Abstract INTRODUCTION: Effective Airway Clearance Techniques (ACT) is the key step in the management of Bronchiectasis. The aim of this study was to evaluate the efficacy of 3% Hypertonic Saline (HS) pre-medication in ACT in children with non Cystic Fibrosis (non-CF) bronchiectasis. METHODS: Five to 15 year old children with non-CF bronchiectasis were randomized either to receive 200µg of inhaled salbutamol followed by hypertonic saline nebulization (test) or only 200µg of inhaled salbutamol, prior to chest physiotherapy which is the conventional ACT (controls) for 8 weeks. After completion of first phase both groups went through one month washout period, before being crossed over to the opposite arms in the second phase. Spirometric parameters were recorded at the end of each phase. RESULTS: Fifty two children completed the study. Baseline characteristics of the two groups were similar. A significantly higher mean improvement was seen in predicted Forced Expiratory Volume in one second(FEV1) in the HS arm during phase 1 [HS=14.15±5.50 vs. conventional =5.04±5.55, p=0.001] and phase II [HS =10.81±5.51 vs. conventional =3.54 ±5.13, p=0.001]. HS arm showed a significantly higher mean improvement in predicted Forced Vital Capacity(FVC) in phase I[HS=13.77±5.73 vs. conventional= 7.54±4.90, p=0.001] and phase II, [HS=9.42±7.00 vs. conventional =4.42±4.00, p=0.003). Mean number of exacerbations experienced by a single child during phase I (2 months) were significantly less (p=0,001) in HS group compared to that of conventional group. CONCLUSIONS: Incorporating HS nebulization into ACT is an effective strategy to improve dynamic lung volumes and morbidity in children with non-CF bronchiectasis.

Background: Several studies have explored the predictive value of impulse oscillometry (IOS) for asthma exacerbations in childhood, but its specific parameters are still unclear. Therefore, we designed this meta-analysis to determine the related indicators of acute asthma attacks. Methods: A comprehensive literature search was performed in July 2020 based on Pubmed, Embase, and Web of science database. Weighted mean differences (WMD) were calculated using Fixed-or random-effects models. Results: A total of 615 patients from 6 trials were included in this analysis. IOS may be a useful tool to predict asthma exacerbations. And the results showed that R5 (WMD = − 1.21, 95%CI: −1.55 to −0.87, P＜0.001), Fres (WMD = − 1.34, 95%CI: −2.03 to −0.65,P=0.018) and AX (WMD = − 7.35, 95%CI: −9.94 to −4.76,P＜0.001) had significant correlation with asthma exacerbations. In addition, X5 may also predict the acute attack of asthma (WMD =0.81, 95%CI: 0.56 to 1.01, P＜0.001). Conclusion: R5, AX, Fres, and X5 may be able to identify the risk of an acute attack of asthma. Besides, our research further demonstrated that peripheral airway injury may play an important role in the acute attack of asthma.

Neuromuscular respiratory medicine has traditionally focused on mechanically assisted lung ventilation and mucus clearance. These therapies have prolonged survival for patients with Duchenne muscular dystrophy (DMD). However, the field is rapidly evolving in a new direction: it is being revolutionized by molecular and genetic therapies. A good correlation between a patient’s dystrophin mutation and his cardiopulmonary phenotype would allow accurate prediction of patient prognosis and would facilitate the design of studies that assess new DMD therapies. Instead, patient prognosis and the design of valid therapeutic studies are complicated by cardiopulmonary phenotypic discordance and variability, by which a notable proportion of DMD patients have unexpectedly good or poor cardiopulmonary function. The likely cause of phenotypic variability and discordance is genetic modifiers. Once the modifiers that affect cardiopulmonary function are better understood, it should be possible to create a personalized genetic profile that accurately predicts the prognosis of each individual DMD patient. This would allow investigators to assess the effect of new therapies in the context of each patient’s particular cardiopulmonary natural history. Amplification of beneficial cardiopulmonary genetic modifiers and blocking of detrimental modifiers is a promising strategy for creating new DMD therapies. When patients with chronic respiratory failure are treated with assisted ventilation, cardiac function determines their survival. Therefore, prioritizing new cardiac therapies is most likely to prolong patient survival. By focusing on these topics we aim to move neuromuscular respiratory medicine beyond assisted ventilation and coughing and into the age of translational medicine.

Background: Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) and Transesophageal Bronchoscopic Ultrasound-guided fine-needle aspiration (EUS-B-FNA) are established modalities for evaluation of mediastinal/hilar lymphadenopathy in adults. Limited literature is available on the utility of these modalities in the pediatric population. Herein, we perform a systematic review and meta-analysis on the yield and safety of EBUS-TBNA and EUS-B-FNA in children. Methods: We performed a systematic search of the PubMed and EMBASE databases to extract the studies reporting the utilization of EBUS-TBNA/EUS-B-FNA in children (<18 years of age). Pooled diagnostic yield and sampling adequacy (proportions with 95% confidence intervals) were calculated using the random-effects model. Details of any procedure-related complications were noted. Results: The search yielded 12 relevant studies (five case series and seven case reports on EBUS-TBNA/EUS-B-FNA, 173 patients). Data from five case series (164 patients) were summarized for the calculation of sampling adequacy and diagnostic yield. Safety outcomes were extracted from all publications. The pooled sampling adequacy and combined diagnostic yield of EBUS TBNA/EUS-B-FNA were 98% (95% CI, 92-100%) and 61% (95% CI, 43-77%) respectively. A procedure-related major complication was reported in 1 patient (1/173, Major complication rate 0.6%), and minor complications occurred in 6 patients (6/173, Minor complication rate 3.5%). Conclusions: EBUS-TBNA and EUS-B-FNA are safe modalities for evaluation of mediastinal lymphadenopathy in the pediatric population. EBUS-TBNA/EUS-B-FNA may be considered as the first-line diagnostic modalities for this indication as they have a good diagnostic yield and can avoid the need for invasive diagnostic procedures.

Gene therapy is an attractive approach being intensively studied to prevent muscle deterioration in patients with Duchenne muscular dystrophy. While clinical trials are only in early stages, initial reports are promising for its effects on ambulation. Cardiopulmonary failure, however, is the most common cause of mortality in DMD patients, and little is known regarding the prospects for gene therapy on alleviating DMD-associated cardiomyopathy and respiratory failure. Here we review current knowledge regarding effects of gene therapy on DMD cardiomyopathy and discuss respiratory endpoints that should be considered as outcome measures in future clinical trials.

AIM: To report on the clinical, laboratory and radiological findings of adolescents who presented during the SARS-CoV-2 surge with symptoms of COVID-19, did not test positive for the infection and were diagnosed with e-cigarette and vaping product use associated lung injury (EVALI). Methods: A retrospective review of 12 cases of EVALI admitted to the Bristol Meyers Squibb Children’s Hospital between February 2020 and June 2020 was conducted. Results: The ages of the patients ranged from 14 to 19 years. There were 6 males and 6 females. Three patients had a past history of anxiety, depression or other psychiatric/mental health disorder, nine had prolonged coagulation profile (PT,PTT and/or INR) and eleven had elevated inflammatory markers. Eleven needed respiratory support. All 12 were negative for SARS-CoV-2 PCR. Four were tested for IgG Antibodies and were negative. As these cases were admitted to rule out COVID infection, initial treatment included hydroxychloroquine. Steroids were started only after SARS-CoV-2 PCR was shown to be negative. Urine THC was positive in all cases. CXR and CT findings showed ground glass opacities. CONCLUSIONS: Clinical and radiological features are similar in both EVALI and SARS-CoV-2 infection. Inflammatory markers are elevated in both conditions. A detailed social and substance use history in patients presenting with ‘typical’ COVID pneumonia like illness is important. EVALI should be ruled in early to start the appropriate treatment. Given the ongoing pandemic, pediatricians and other health care providers need to be aware of other conditions that can masquerade as SARS-CoV-2.

Objectives. Although recent evidence suggests that management of viral bronchiolitis requires something other than guidelines-guided therapy, there is a lack of evidence supporting the economic benefits of phenotypic-guided bronchodilator therapy for treating this disease. The aim of the present study was to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. Methods: A decision‐analysis model was developed in order to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. The effectiveness parameters and costs of the model were obtained from electronic medical records. The main outcome was avoidance of hospital admission after initial care in the ED. Results: Compared to guidelines-guided strategy, treating patients with viral bronchiolitis with the phenotypic-guided bronchodilator therapy strategy was associated with lower total costs (US$250.99 vs US$263.46 average cost per patient) and a higher probability of avoidance of hospital admission (0.7902 vs 0.7638), thus leading to dominance. Results were robust to deterministic and probabilistic sensitivity analyses. Conclusions: Compared to guidelines-guided strategy, treating infants with viral bronchiolitis using the phenotypic-guided bronchodilator therapy strategy is a more cost-effective strategy, because it involves a lower probability of hospital admission at lower total treatment costs.

Obstructive airway disorders are common in infancy and early childhood. The leading example of such disorder is post-viral wheezing, predominantly the well characterized disorder that follows respiratory syncytial virus (RSV) infection and leads to intermittent, long-term wheezing. The underlying mechanisms of the airway reactivity related to RSV infection have been extensively studies and are associated with dysregulation of the nonadrenergic-noncholinergic (NANC) system, via upregulation of neurotransmitters, typically Substance P. Neuroendocrine hyperplasia of infancy (NEHI), while a less common entity, is a disorder of infancy characterized by more severe and long-term obstructive airway disease. NEHI is pathophysiologically characterized by abundance of neuroendocrine cells in the airways containing the neuroimmune mediator bombesin, the release of which is presumed to be the driver of the persistent small airway obstruction and functional air-trapping. Here we review the NANC and NEC neurotransmitter systems and their studied roles in pulmonary diseases with a focus on their role in lung development, and subsequent various pediatric lung diseases. We focus on the juxtaposition of the separate neuroimmune mechanisms underlying the pathogenesis of post-RSV recurrent wheezing and NEHI persistent small airway obstruction. We finally raise the question whether substance P is indeed specific to post-RSV infection and bombesin to NEHI and then propose a unifying concept of post-viral spectrum of respiratory disorders that may encompass these two entities and possibly others.

Introduction: Asthma is a disease with important morbidity and that can lead to death in childhood. The use of intravenous magnesium sulfate has been indicated in cases refractory to the initial management with inhaled bronchodilators and corticosteroids. Objective: To evaluate the use of magnesium sulfate in continuous infusion (50mg/kg/hour in 4 hours) in children with severe acute asthma. Location: 10-bed pediatric emergency room, university hospital. Patients: Children over 2 years old who received a continuous infusion of magnesium sulfate at a dose of 50mg/kg/hour in 4 hours. Methods and main findings: Cross-sectional, prospective study. All patients with severe acute asthma were included in a study protocol. A total of 40 patients met the inclusion criteria, 60% male, with a median age of 3.0 years (2.8-4.3). All patients were monitored and followed by an emergency pediatrician during the 4 hours of infusion. There was no description of adverse events related to the magnesium sulfate. The modified Wood-Downes clinical score was applied and compared before and after the infusion and a significant clinical improvement was observed (p<0.001). The serum magnesium levels at the end of the infusion ranged from 3.3-5.8 mg/dL, suitable as therapeutic and without toxicity (median 4.0). The median length of stay in pediatric emergency was 2 days. Only 2 patients (5%) were transferred to the PICU. Conclusions: On this study, the use of continuous magnesium sulfate proved to be well tolerated, leading to improved respiratory status, and can be considered as adjunctive therapy in the management of severe asthma.

Thromboembolic phenomena, especially pulmonary emboli, have been described in adult patients with COVID, but have been less evident in children. We describe a case of a teenager with bilateral pulmonary emboli leading to cardiovascular collapse in the setting of COVID and multisystem inflammatory syndrome in children (MIS-C).

Introduction This study investigates drivers of childhood pulmonary tuberculosis (PTB) using a childhood ecosystem approach in South Africa. An ecosystem approach towards identifying risk factors for PTB may identify new directions for intervention. Methods Data were collected as part of a prospective cohort study of children presenting at a primary care facility or tertiary hospital with suspected TB. Characterization of the childhood ecosystem included proximal, medial and distal determinants. Proximal determinants included child characteristics that could impact PTB outcomes. Medial determinants included relational factors such as caregiver health that might impact interactions with the child. Distal determinants included macro-level determinants of disease such as socioeconomic status and food insecurity. Children started on TB treatment were followed for up to 6 months. Multivariate regression models tested independent associations between factors associated with PTB in children. Results Of 1,738 children enrolled in the study, 242 (20%) of children had confirmed PTB, 756 (63%) were started on TB treatment, and 444 (37%) had respiratory conditions other than TB. In univariate analyses, childhood malnutrition and caregiver smoking were associated with treated or confirmed PTB. In multivariate analyses, proximal factors such as male gender and hospitalization and low socio-economic status as a distal factor were associated with PTB. Conclusions Interventions may need to target subgroups of children and families at elevated risk for PTB. Screening for risk factors such caregiver health may guide targeting, and provision of social protection programs to bolster economic security may be important interventions for attenuating childhood exposure to risk factors.

Background Prenatal origins of wheezing are not fully understood. This study develops a model of mechanisms linking perinatal stress exposure to wheeze phenotypes in children. Methods Data were obtained from 1,849 mother-child dyads participating in ELSPAC-CZ birth cohort. Wheeze phenotypes assessed between birth and age seven years included “never wheeze”, “early-onset transient (EOT) wheeze,” “early-onset persistent (EOP) wheeze,” and “late-onset (LO) wheeze.” Prenatal and postnatal maternal stress exposures were assessed in mid-pregnancy and six months post-delivery, respectively, using an inventory of 42 life events. Results In adjusted models, children in the highest tercile (high) vs. lowest tercile (low) of prenatal life events had a 44% higher risk of EOT wheeze (relative risk ratio [RRR]=1.44, 95% confidence interval [CI]=1.06-1.95, p=0.02) and 69% higher risk of LO wheeze (RRR=1.69, 95% CI=1.13-2.52, p=0.01). High vs. low exposure to postnatal life events predicted a 74% increase in the risk of EOT wheeze (RRR=1.74, 95% CI=1.27-2.38, p<0.001) and 101% increase for EOP wheeze (RRR=2.01, 95% CI=1.23-3.26, p=0.005). Postnatal life events partially mediated between prenatal life events and any wheeze (high vs. low life events: indirect effect OR=1.13, 95% CI=1.06-1.21, p<0.001). Lower respiratory tract infections and secondary smoke partially mediated between postnatal life events and any wheeze (indirect effects OR=1.06, 95% CI=1.02-1.09, p=0.002 and OR=1.02, 95% CI 1.001-1.05, p=0.035, respectively). Conclusions Exposures to prenatal and postnatal life events are risk factors for development of wheezing. Prenatal stress contributes to wheeze directly and also through postnatal life events and respiratory infections.

Abstract Background and Objectives: Better phenotyping of the heterogenous bronchiolitis syndrome may lead to targeted future interventions. This study aims to identify severe bronchiolitis profiles among hospitalised Australian Indigenous infants, a population at high-risk of bronchiectasis, using Latent Class Analysis (LCA). Methods: We included prospectively collected clinical, viral and nasopharyngeal bacteria data from 164 Indigenous infants hospitalised with bronchiolitis. We undertook multiple correspondence analysis (MCA) followed by LCA. The best-fitting model for LCA was based on adjusted Bayesian information criteria and entropy R2. Results: We identified five clinical profiles. Profile-A’s (23.8% of cohort) phenotype was previous preterm (90.7%), low birth-weight (89.2%) and weight-for-length z-score <-1 (82.7% from combining those with z-score between -1 and -2 and those in the z-score of <-2 group) previous respiratory hospitalisation (39.6%) and bronchiectasis on chest high-resolution computed tomography scan (35.4%). Profile-B (25.3%) was characterised by oxygen requirement (100%) and marked accessory muscle use (45.5%). Infants in profile-C (7.0%) had the most severe disease, with oxygen requirement and bronchiectasis in 100%, moderate accessory muscle use (85% vs 0-51.4%) and bacteria detected (93.1% vs 56.7-72.0%). Profile-D (11.6%) was dominated by rhinovirus (49.4%), mild accessory muscle use (73.8%) and weight-for-length z-score <-2 (36.0%). Profile-E (32.2%) included bronchiectasis (13.8%), RSV (44.0%), rhinovirus (26.3%) and any bacteria (72%). Conclusions: Using LCA in Indigenous infants with severe bronchiolitis, we identified 5 clinical profiles with one distinct profile for bronchiectasis. LCA can characterise distinct phenotypes for severe bronchiolitis and infants at risk for future bronchiectasis, which may inform future targeted interventions.

Introduction Childhood cancer survivors (CSs) might face an increased lifelong risk of lung function impairment. The Lung Clearance Index (LCI) has been described as being more sensitive than spirometry in the early stages of some lung diseases. The aim of this study was to evaluate this index in a cohort of patients with a history of childhood cancer for the first time. Materials and Methods We evaluated 57 off-treatment CSs aged 0–18 years old and 50 healthy controls (HCs). We used the multiple breath washout (MBW) method to study LCI and spirometry. Results CSs did not show any differences from the controls in ventilation homogeneity (LCI 6.78 ± 1.35 vs. 6.32 ± 0.44, P: ns) or lung function (FEV1 99.9 ± 11.3% vs. 103.0 ± 5.9% of predicted, P: ns; FVC 98.2 ± 10.3% vs. 101.1 ± 3.3% of predicted). LCI significantly correlated with the number of years since the last chemotherapy (r = 0.35, P < 0.05). Conclusions Our study describes the trend of LCI in a cohort of CSs and compares it with the results obtained from healthy controls. The results show that patients maintain both good values of respiratory function and good homogeneity of ventilation during childhood. Moreover, the LCI identifies the tendency toward pulmonary fibrosis, which is typical of adult CSs, at an earlier time than spirometry.

Background: High frequency (HF) oscillatory ventilation has been shown to improve CO2 clearance in premature infants. In a previous in vitro lung model with normal lung mechanics we demonstrated significantly improved CO2 washout by HF oscillation of bubble CPAP (BCPAP). Objective: To examine CO2 clearance in a premature infant lung model with abnormal lung mechanics via measurement of end-tidal CO2 levels (EtCO2) while connected to HF oscillated BCPAP. Design/Methods: A 40mL premature infant lung model with either: normal lung mechanics (NLM): compliance 1.0 mL/cmH2O, airway resistance 56 cmH2O/(L/s); or abnormal lung mechanics (ALM): compliance 0.5 mL/cmH2O, airway resistance 136 cmH2O/(L/s), was connected to BCPAP with HF oscillation at either 4,6,8,10 or 12 Hz. EtCO2 was measured at BCPAPs of 4,6 and 8 cmH2O and respiratory rates (RR) of 40,60 and 80 breaths/min and 6mL tidal volume. Results: HF oscillation decreased EtCO2 levels at all BCPAPs, RRs, and oscillation frequencies for both lung models. Overall mean±SD EtCO2 levels decreased (p<0.001) from non-oscillated baseline by 19.3±10.2% for NLM vs. 14.1±8.8% for ALM. CO2 clearance improved for both lung models (p<0.001) as a function of oscillation frequency and RR with greatest effectiveness at 40-60 breaths/min and HF at 8-12 Hz. Conclusions: In this in-vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO2 clearance as compared to non-oscillated BCPAP for both NLM and ALM. The significant improvement in CO2 clearance in an abnormal lung environment is an important step towards clinical testing of this novel respiratory support modality.

Introduction: The prognosis of cystic fibrosis (CF) has dramatically changed over the past decade in France, mostly due to global improvements in specific care. Currently, the majority of French CF patients are adults, meaning they went through a transition process from a pediatric CF center to an adult CF center. To determine the impact of that transfer on clinical evolution, we report the transition procedure of our CF center in Lyon. Materials and Methods: From January 2006 to December 2016, 117 CF patients went through a standardized transition process from the pediatric to the adult CF center of Lyon. We compared the clinical evolution of the patients over 3 periods starting the year before transfer and ending the next year after transfer. Clinical data taken into account were FEV1%, BMI, pulmonary colonization, number of antibiotic courses, and number of days of hospitalization per year and outpatient visits per year. Results: No significant differences were observed between respiratory and nutritional status, pulmonary colonization, number of antibiotic courses, and numbers of hospitalizations and visits when comparing the 3 periods of observation (the year before, the year after and the next year after transfer) around transition. Conclusion: The standardized procedure of transition in Lyon is associated with the maintenance of a stable clinical status of our CF patients.