Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

Primary health care utilization and hospital readmission in children with asthma: a multi-site linked data cohort study.

OBJECTIVES: To (1) describe primary health care utilization and (2) estimate the effect of primary care early follow-up, continuity, regularity, frequency, and long consultations on asthma hospital readmission, including secondary outcomes of emergency (ED) presentations, asthma preventer adherence, and use of rescue oral corticosteroids within 12 months. METHODS: An Australian multi-site cohort study of 767 children aged 3-18 years admitted with asthma between 2017 and 2018, followed up for at least 12 months with outcome and primary care exposure data obtained through linked administrative datasets. We estimated the effect of primary care utilization through a modified Poisson regression adjusting for child age, asthma severity, socioeconomic status and self-reported GP characteristics. RESULTS: The median number of general practitioner (GP) consultations, unique GPs and clinics visited was 9, 5, and 4, respectively. GP care was irregular and lacked continuity, only 152 (19.8%) children visited their usual GP on more than 60% of occasions. After adjusting for confounders, there was overall weak indication of effects due to any of the exposures. Increased frequency of GP visits was associated with reduced readmissions (4-14 visits associated with risk ratio of 0.71, 95% CI 0.50-1.00, p = 0.05) and ED presentations (>14 visits associated risk ratio 0.62, 95% CI 0.42-0.91, p = 0.02). CONCLUSIONS: Our study demonstrates that primary care use by children with asthma is often irregular and lacking in continuity. This highlights the importance of improving accessibility, consistency in care, and streamlining discharge communication from acute health services.

Modifiable factors associated with pediatric asthma readmissions: a multi-center linked cohort study.

OBJECTIVES: To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use. METHODS: We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively. RESULTS: Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47, p = 0.05. None of the hospital or home environmental factors appeared to be associated with hospital readmissions. CONCLUSIONS: Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

Novel approaches to the prediction and diagnosis of pulmonary complications in the paediatric haematopoietic stem cell transplant patient.

PURPOSE OF REVIEW: Haematopoietic stem cell transplant (HSCT) remains the only curative treatment option for many children with relapsed leukaemia, primary immunodeficiencies and haemoglobinopathies. Unfortunately, infectious and noninfectious pulmonary complications following HSCT continue to cause significant morbidity and mortality. This review will focus on recent advances in the field that enhance clinically available diagnostic tools and the role of novel diagnostic techniques. RECENT FINDINGS: Research continues to highlight the role of standard diagnostic modalities, including imaging using computed topography chest and Fluorodeoxyglucose-positron emission tomography (FDG-PET) in the diagnosis of posttransplant pulmonary infections. Similarly, bronchoalveolar lavage using bronchoscopy to obtain samples for microbiological analysis remains an important tool in the clinical and diagnostic algorithm for these children. The application of more novel diagnostic techniques such as metagenomic next-generation sequencing and the use of specific biomarkers remain potential future tools in children in whom the aetiology of posttransplant lung disease is unknown. The impact of the pulmonary microbiome on infectious and noninfectious pulmonary disease post HSCT is a future research direction. SUMMARY: Pulmonary infectious complications post HSCT remain a devastating complication for children and their families. Despite improvements in standard and novel diagnostic modalities, the aetiology of pulmonary disease remains unknown for many patients. There is an urgent need for ongoing collaborative research to bridge this critical knowledge gap and lead to better patient outcomes.

Fissure adjacent partial lobe atelectasis in primary ciliary dyskinesia.

AIM: Establishing the underlying cause in a child with chronic suppurative lung disease (CSLD) allows for targeted treatment and screening for associated complications. One cause of CSLD is primary ciliary dyskinesia (PCD). Testing for PCD requires specialist expertise which is not widely available. Computed tomography (CT) scans are commonly performed when assessing CSLD. Identifying PCD-specific signs on CT would help clinicians in deciding when to refer for specialist testing. One potential PCD-specific sign we have observed is fissure adjacent partial lobe atelectasis (FAPLA). We aimed to assess if FAPLA is commonly found in CT of PCD patients. METHODS: Fifty-eight CT scans from 42 adult and child PCD patients were analysed. The presence and distribution of FAPLA were noted, and its association to sputum culture and other signs commonly seen in CSLD (bronchiectasis, bronchial wall thickening, air trapping and mucus plugging). RESULTS: FAPLA was found in 13 of 40 participants in their earliest CT scan. The prevalence of FAPLA was similar in children and adults. FAPLA involved the right middle lobe in all 13 cases and was systematically associated with ≥1 other structural change. There was no association between FAPLA and bacterial isolation from sputum. CONCLUSION: FAPLA was found in 32.5% PCD scans, without difference between children and adults in terms of frequency. Future work will determine if it is a PCD-specific sign by assessing whether it is also found in other CSLD processes and analysing more scans from children with PCD to determine how early this sign develops.

Characteristics, management and changing incidence of children with empyema in a paediatric intensive care unit.

AIM: Paediatric intensive care unit (PICU) admissions for empyema increased following the 13-valent pneumococcal conjugate vaccine (PCV13). We describe the clinical characteristics, management and outcomes for children with empyema and compare incidence before and after PCV13. METHODS: Retrospective study of patients <18 years admitted to The Royal Children's Hospital Melbourne PICU with empyema between January 2016 and July 2019. We investigated the incidence of empyema during two time periods: 2007-2010 (pre-PCV13) and 2016-2019 (post-PCV13). RESULTS: Seventy-one children (1.9% of all PICU admissions) were admitted to PICU with empyema between 2016 and 2019. Sixty-one (86%) had unilateral disease, 11 (16%) presented with shock and 44 (62%) were ventilated. Streptococcus pneumoniae and group A Streptococcus were the most commonly identified pathogens. Forty-five (63%) were managed with video-assisted thoracoscopic surgery (VATS). There was a 31% reduction in empyema hospitalisations as a proportion of all hospitalisations (IRR 0.69, 95% CI 0.59-0.8), but a 2.8-fold increase in empyema PICU admissions as a proportion of all PICU admissions (95% CI 2.2-3.5, P < 0.001). For the PICU cohort, this was accompanied by reduction in PIM2 probability of death (median 1% vs. 1.9%, P = 0.02) and duration of intubation (median 69 h vs. 126.5 h, P = 0.045). CONCLUSIONS: In children with empyema in PICU 62% required ventilation, 16% had features of shock and 63% received VATS. Empyema admissions, as a proportion of all PICU admissions, increased in the era post-PCV13 compared to pre-PCV13 despite no increase in illness severity at admission.

Telehealth and virtual health monitoring in cystic fibrosis.

PURPOSE OF REVIEW: At many institutions, the Covid-19 pandemic made it necessary to rapidly change the way services are provided to patients, including those with cystic fibrosis (CF). The purpose of this review is to explore the past, present and future of telehealth and virtual monitoring in CF and to highlight certain challenges/considerations in developing such services. RECENT FINDINGS: The Covid-19 pandemic has proven that telehealth and virtual monitoring are a feasible means for safely providing services to CF patients when traditional care is not possible. However, both telehealth and virtual monitoring can also provide further support in the future in a post-covid era through a hybrid-model incorporating traditional care, remote data collection and sophisticated platforms to manage and share data with CF teams. SUMMARY: We provide a detailed overview of telehealth and virtual monitoring including examples of how paediatric and adult CF services adapted to the need for rapid change. Such services have proven popular with people with CF meaning that co-design with stakeholders will likely improve systems further. In the future, telehealth and virtual monitoring will become more sophisticated by harnessing increasingly powerful technologies such as artificial intelligence, connected monitoring devices and wearables. In this review, we harmonise definitions and terminologies before highlighting considerations and limitations for the future of telehealth and virtual monitoring in CF.

Single-Cell Flow Cytometry Profiling of BAL in Children.

Childhood pulmonary diseases not only cause childhood morbidity and mortality but also can cause long-term pulmonary impairment. The clinical management of many childhood pulmonary diseases is hampered by a limited understanding of the underlying pathophysiological mechanisms. Flow cytometry, which can be used to phenotype individual cell populations or isolate cells for downstream analysis, represents a crucial technology that can help to elucidate the pathophysiology of these conditions. Here, we describe a flow cytometry-based method for purification and characterization of cell populations in BAL from children. This includes assessment of the effect of cryopreservation on cell phenotype and frequency, a knowledge gap recently identified by an American Thoracic Society report on flow cytometry in lung samples. To our knowledge, this is the first study to simultaneously quantify alveolar macrophages, T cells (CD4 and CD8), B cells, natural killer cells, dendritic cells, granulocytes, and monocytes (CD16+/CD16-) in the BAL of children. The protocols described can be used to advance investigation of the pathophysiology of childhood pulmonary diseases.

Utility of Endobronchial Ultrasound in Assessment of Intrathoracic Lesions in Paediatric Patients.

INTRODUCTION: In adults, linear endobronchial ultrasound (EBUS) is the preferred modality to sample intrathoracic adenopathy and radial EBUS is a useful tool to biopsy peripheral pulmonary nodules. Utility in children is less well known. OBJECTIVES: The objective of this study was to review the EBUS experience of two specialist centres to better define the current role of EBUS in paediatric practice. METHODS: A retrospective record review of EBUS procedures undertaken in patients aged 0-17 years at the Royal Children's Hospital (Melbourne, Australia) and Thoraxklinik (Heidelberg, Germany) was performed. Data extracted included patient demographics, clinical presentation, bronchoscope (size and model), EBUS technique used, pathologic results, need for further invasive investigation, and complications. RESULTS: Between 2008 and 2017, ten EBUS procedures were performed (6 linear EBUS and 4 radial EBUS). No complications were reported. Linear EBUS was performed on subjects who were between 4 and 15 years old, with a 100% diagnostic yield. Radial EBUS was non-diagnostic in three cases of non-malignant disease. In one case, it was used successfully for imaging alone. CONCLUSION: Both linear and radial EBUS are safe and feasible in children. Diagnostic yield of linear EBUS was 100%. Radial EBUS did not demonstrate utility, likely reflecting the pathologies of underlying parenchymal masses in paediatric populations.

Pulmonary Mycobacterium abscessus complex in children with cystic fibrosis: A practical management guideline.

The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant.

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Pulmonary immune profiling reveals common inflammatory endotypes of childhood wheeze and suppurative lung disease.

Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management.

Eosinophilia and wheeze: thinking beyond asthma.

Primary idiopathic hypereosinophilic syndrome is a rare condition that can cause end-organ damage in multiple systems. The advent of targeted monoclonal antibodies, such as mepolizumab, provides a safe and effective steroid-sparing treatment. https://bit.ly/4bgDP1u.

Social deprivation and spatial clustering of childhood asthma in Australia.

BACKGROUND: Asthma is the most common chronic respiratory illness among children in Australia. While childhood asthma prevalence varies by region, little is known about variations at the small geographic area level. Identifying small geographic area variations in asthma is critical for highlighting hotspots for targeted interventions. This study aimed to investigate small area-level variation, spatial clustering, and sociodemographic risk factors associated with childhood asthma prevalence in Australia. METHODS: Data on self-reported (by parent/carer) asthma prevalence in children aged 0-14 years at statistical area level 2 (SA2, small geographic area) and selected sociodemographic features were extracted from the national Australian Household and Population Census 2021. A spatial cluster analysis was used to detect hotspots (i.e., areas and their neighbours with higher asthma prevalence than the entire study area average) of asthma prevalence. We also used a spatial Bayesian Poisson model to examine the relationship between sociodemographic features and asthma prevalence. All analyses were performed at the SA2 level. RESULTS: Data were analysed from 4,621,716 children aged 0-14 years from 2,321 SA2s across the whole country. Overall, children's asthma prevalence was 6.27%, ranging from 0 to 16.5%, with significant hotspots of asthma prevalence in areas of greater socioeconomic disadvantage. Socioeconomically disadvantaged areas had significantly higher asthma prevalence than advantaged areas (prevalence ratio [PR] = 1.10, 95% credible interval [CrI] 1.06-1.14). Higher asthma prevalence was observed in areas with a higher proportion of Indigenous individuals (PR = 1.13, 95% CrI 1.10-1.17). CONCLUSIONS: We identified significant geographic variation in asthma prevalence and sociodemographic predictors associated with the variation, which may help in designing targeted asthma management strategies and considerations for service enhancement for children in socially deprived areas.

Evaluation of a multiplex-qPCR for paediatric pleural empyema-An observational study in hospitalised children.

Pleural empyema is a serious complication of pneumonia in children. Negative bacterial cultures commonly impede optimal antibiotic therapy. To improve bacterial identification, we developed a molecular assay and evaluated its performance compared with bacterial culture. Our multiplex-quantitative PCR to detect Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae was assessed using bacterial genomic DNA and laboratory-prepared samples (n = 267). To evaluate clinical performance, we conducted the Molecular Assessment of Thoracic Empyema (MATE) observational study, enrolling children hospitalised with empyema. Pleural fluids were tested by bacterial culture and multiplex-qPCR, and performance determined using a study gold standard. We determined clinical sensitivity and time-to-organism-identification to assess the potential of the multiplex-qPCR to reduce the duration of empiric untargeted antibiotic therapy. Using spiked samples, the multiplex-qPCR demonstrated 213/215 (99.1%) sensitivity and 52/52 (100%) specificity for all organisms. During May 2019-March 2023, 100 children were enrolled in the MATE study; median age was 3.9 years (IQR 2-5.6). A bacterial pathogen was identified in 90/100 (90%) specimens by multiplex-qPCR, and 24/100 (24%) by bacterial culture (P <0.001). Multiplex-qPCR identified a bacterial cause in 68/76 (90%) culture-negative specimens. S. pneumoniae was the most common pathogen, identified in 67/100 (67%) specimens. We estimate our multiplex-qPCR would have reduced the duration of untargeted antibiotic therapy in 61% of cases by a median 20 days (IQR 17.5-23, range 1-55). Multiplex-qPCR significantly increased pathogen detection compared with culture and may allow for reducing the duration of untargeted antibiotic therapy.

Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.