Bronchoalveolar Lavage in Children: Still the Gold StandardShivanthan Shanthikumar1,2,3 and Sarath C Ranganathan1,2,3Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne, AustraliaRespiratory Diseases, Murdoch Children’s Research Institute, Melbourne, AustraliaDepartment of Paediatrics, University of Melbourne, Melbourne, AustraliaCorresponding Author; Dr Shivanthan Shanthikumar; Respiratory Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia; email@example.comAcknowledgements; The authors have no conflicts of interest to declareDear Editor,We read with great interest the recent article by Craven et al , entitled “High levels of inherent variability in microbiological assessment of bronchoalveolar lavage samples from children with persistent bacterial bronchitis and healthy controls .”1 In a small study of 18 children, funded by GlaxoSmithKline, the authors demonstrate variability in the results of bronchoalveolar lavage (BAL) collected from controls and children with protracted bacterial bronchitis (PBB). Specifically, they show that when the BAL was divided and sent to two laboratories the results were discordant in terms of both the organisms isolated and their relative abundance. From these data the authors draw conclusions which include questioning “assumptions about this procedure being the gold standard .” Whilst these data are of interest, there are significant limitations to their value especially when considering existing literature.One of the key findings of the study is the discordant results between laboratories. A lack of detail regarding the methods used at each site is a major limitation. It is recognised that laboratory processes can affect the yield of samples collected from patients with chronic airway infection, and the need for a consistent approach has led to disease specific consensus guidelines on this topic.2 The discordant results seen in the study could result from different laboratory handling of specimens, and hence the findings of this study could purely be explained by a difference in practice between two centres, not least of which was the transport of samples to the second laboratory in STGG. Molecular studies have identified that even media considered sterile can contain numerous organisms albeit in low densities.3 We note that it was laboratory 2 where additional bacteria were cultured from the BAL.Hare et al analysed BAL samples from 655 children collected and analysed at two different sites compared with 18 samples in the study of Craven et al .4 They compared bacterial pathogen load (control, negative, 102 colony forming units per ml (CFU/ml), 103 CFU/ml, 104 CFU/ml, 105 CFU/ml) and inflammatory markers to determine an appropriate definition for infection. They found that a bacterial pathogen load of ≥104 CFU/ml was associated with increased markers of inflammation and hence an appropriate threshold for defining infection. This was in keeping with previous studies.4 Whilst the authors contend the current paper does not support the use of ≥104 CFU/ml, given it only includes 13 children with PBB an explanation of the findings of Hareet al in their considerably larger study and other studies needs explanation.Another key finding of the study was the limited correlation between semiquantitative and quantitative methods of measuring bacterial pathogen load. Whilst there has not been direct comparison of different methods of determining bacterial pathogen load in PBB and other paediatric suppurative disorders, a large amount of data speaks to the validity of using a semiquantitative or qualitative approach. For instance, the previously discussed Hare et al study utilised a semiquantitative approach, and was able to clearly identify a threshold for lower airway infection that was associated with inflammation. In addition, the qualitative approach used by AREST CF (the long running study of CF patients cited in the article) to define infection is supported by the fact that this definition is associated with important clinical outcomes. For example, in a recent AREST-CF study analysing 1161 BAL from 265 children with CF, the presence of early life infection using the AREST-CF definition, was associated with future risk of structural lung disease severity.5Further, we have used molecular studies to assess the microbiome in CF and shown considerable agreement between pathogen-dominated microbiota and routine laboratory bacterial culture even though these samples were assessed by two different techniques, in two laboratories in different continents and analysed two decades apart in time.6Despite the data that contradicts the findings of their study, and while not discussed by the authors themselves, we do contend that use of both quantitative and semi-quantitative microbiologic cultures are likely problematic given that bacterial density is influenced by the dilution from the 0.9% saline used to lavage the target lobe. Dilution further depends on the volume of return retrieved on suctioning. The consensus has been that standardising for this dilution is not required but data supporting this are few.In summary, there are significant issues that limit the value of the key findings of the study by Craven et al . A large amount of published data in PBB and cystic fibrosis support the use of BAL as a biological specimen associated with important clinical outcomes. These studies have been conducted in multiple centres, over many years, and included many children. While the findings of Craven et alhighlight there can be inconsistencies in results, this potentially speaks to the methods used by the laboratories involved in handing the small number of samples. When these findings are compared to the large amount of evidence already generated, they should prompt evaluation of local practices and not just a reconsideration of whether BAL is the gold standard method of sampling the lower airway of children with suppurative lung disease. While we believe that BAL remains the gold standard for the detection of lower respiratory infection we do not believe it is a perfect test and its use and many limitations need to be considered and minimised.Therefore, we agree with the authors that interpretation of microbial culture results utilizing BAL samples can be challenging. However, we disagree that assumptions about this procedure being the “gold standard” fail to take into account its many limitations as despite these BAL remains the best test to detect endobronchial infection that is associated with lower respiratory inflammation especially in CF.
Spirometry, a gold standard technique for measuring lung functions, has been restricted to a select cohort of patients in current COVID-19 pandemic due to the enhanced risk of disease dissemination. To monitor pulmonary functions in various obstructive (e.g., asthma) and restrictive diseases (e.g., COVID-19 pneumonia) on in- and out-patients serially, there is an urgent requirement of an alternate reliable test. Impulse Oscillometry (IOS) measures lung functions by working at tidal volumes and thus reduces the risk of potential aerosol generation. Feasibility of IOS in smaller children and its ability to detect parenchymal and peripheral airway involvement are other advantages over conventional spirometry. IOS could be a potential solution to periodically monitor lung functions in current pandemic situation to keep a check on diseases affecting lung functionality.
Pediatric pulmonologists, and, indeed, general pediatricians, are exposed to the causative virus of Covid-19 , SARS-CoV2, in their daily outpatient practices from both symptomatic and asymptomatic patients. This risk naturally increases with multiple exposures over time. We have developed a simple equation to calculate the probability of a practitioner remaining Covid free over a specified time interval, given the local population prevalence of virus, the transmissibility of the organism or “attack rate,” the mitigating effects of personal protective equipment (PPE), and the number of patients seen over the time interval. The equation can be used to construct a Kaplan Meier -like plot for remaining Covid free. Since studies of transmission of SARS-CoV2 suggest a spectrum between droplet and aerosol spread, even in asymptomatic patients and absence of aerosol generating procedures, the type of masks protection worn by medical practitioners may mitigate risk to different degrees. Eye protection may mitigate the risk further. While the risk of acquiring Covid-19 in a year of practice is low, it is not negligible. However it can be minimized. These considerations may be helpful in deciding local risk to the practitioner according to practice volume and in choosing the level of PPE that would result in minimizing that risk.
Rationale: Aerosolized albuterol is widely used, but its safety and efficacy in infants with severe bronchopulmonary dysplasia (sBPD) is not well established. Objectives: To compare the tolerability and efficacy of two dose levels of aerosolized albuterol to saline placebo in infants with sBPD. Methods: Single-center, multiple-crossover trial in 24 ventilated very preterm infants with sBPD. Albuterol (1.25mg, 2.5mg) and 3ml of normal saline were administered every 4 hours during separate 24-hour treatment periods assigned in random order with a 6-hour washout phase between periods. The primary outcome was the absolute change (post–pre therapy) in expiratory flow at 75% of exhalation (EF75). Secondary endpoints were changes in ventilator parameters, vital signs, and heart arrhythmia. Results: Average within subject EF75 values improved with each therapy: saline placebo (+0.45L/min 2.5, p=0.04), 1.25mg of albuterol (+0.70L/min 2.4, p<0.001), and 2.5mg of albuterol (+0.38L/min 2.4, p=0.06). However, 1.25mg of albuterol (0.26L/min; 95% CI -0.19, 0.72) and 2.5mg (-0.10L/min; 95% CI -0.77, 0.57) produced similar changes in EF75 when compared to saline. All secondary outcomes were similar between saline and 1.25mg of albuterol. Peak inspiratory pressure needed to deliver goal tidal volumes (7.5% relative decrease, 95% CI 2.6, 12.3) and heart rate (6.5% increase, 95% CI 2.2, 10.8) differed significantly between albuterol 2.5mg and saline. Conclusion: Albuterol at 1.25mg and 2.5mg, compared to aerosolized saline, did not affect EF75 in infants with sBPD receiving invasive ventilation. Greater improvement in inspiratory pressures with albuterol 2.5mg suggests benefit, but close heart monitoring is indicated.
A 12-year-old girl presented with chronic suppurative lung disease secondary to an old forgotten, foreign body (plastic whistle) in the right lower lobe bronchus, confirmed by Contrast enhanced computer tomography (CECT) chest. Rigid bronchoscopic removal was attempted twice but the foreign body could not be removed. Under general anesthesia, a flexible bronchoscope was inserted through the rigid bronchoscope and the foreign body was grasped and removed using rat-toothed forceps inserted through the suction channel of the flexible scope. Although there are a few reports of sequential use of flexible and rigid bronchoscopies, this report highlights the feasibility and utility of flexible through rigid bronchoscopy technique for foreign body removal in the distal airways.
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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.
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.
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.
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).
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.