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.

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.

Benchmarking single-cell hashtag oligo demultiplexing methods.

Sample multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells' RNA to determine their sample of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to samples. In this study, we critically assess the performance of seven HTO demultiplexing tools: hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFF (bimodal flexible fitting) and HashSolo. The comparison uses data sets where each sample has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic 'ground truth'. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal count distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in an scRNA-seq experiment.

Telehealth use in Australian cystic fibrosis centers: Clinician experiences.

BACKGROUND: Telehealth has been rapidly adopted by cystic fibrosis (CF) centers and ongoing use in routine CF care is endorsed by CF consumers. However, data describing CF clinician perceptions regarding telehealth are scarce. We aimed to describe clinician experiences and attitudes towards telehealth in CF care among health professionals across Australia. METHODS: CF multidisciplinary health professionals from all CF clinics in Australia were sent an anonymous electronic survey. RESULTS: Eighty-five responses were received representing 15 of 23 (65%) centers. Most clinicians reported using telehealth for routine clinic visits, and a range of other clinical encounters (69.9%). Telehealth was widely perceived as acceptable (91.8%), and clinicians were comfortable/very comfortable (81.2%) integrating telehealth into future CF care. Despite this, 64.1% of respondents considered telehealth clinics to be much worse than face-to-face clinics and 57.5% reported quality of care was somewhat/much worse using telehealth. Home spirometry was available in 73.7% of centers, however, only 26.7% of clinics could provide spirometers for >75% eligible patients. Growth and microbiology assessments were often missed in telehealth clinics and 75.7% reported a technical issue had prevented a telehealth consultation from occurring. CONCLUSIONS: Telehealth for CF in Australia is considered feasible and acceptable by CF clinicians, although use of telehealth varies widely between centers. Concerns exist around the impact of telehealth on health outcomes, especially given core assessments are frequently omitted. Guidelines may help ensure the benefits of telehealth are realized for people with CF without compromising the standard of care.

Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease.

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.

Telehealth in Cystic Fibrosis. A systematic review incorporating a novel scoring system and expert weighting to identify a 'top 10 manuscripts' to inform future best practices implementation.

The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice.

Effectiveness of asthma preventer dispensing for preventing childhood asthma readmissions: a multisite cohort linkage study.

OBJECTIVES: To (1) describe the dispensing of asthma preventers at hospital discharge and estimate its effect on hospital readmissions, and (2) estimate the effect of community asthma preventer dispensing on readmissions for the subgroup of children who were not prescribed an asthma preventer at discharge. DESIGN: Multisite cohort study with linked administrative data. PARTICIPANTS: Children aged 3-18 years admitted with asthma to a tertiary paediatric, mixed paediatric and adult, or regional hospital between 2017 and 2018. MAIN OUTCOME MEASURE: Hospital readmission for asthma within 12 months. RESULTS: Of the 767 participants, 201 (26.2%) were newly prescribed or requested to continue with asthma preventers. Of these, only 91 (45.3%) dispensed their discharge prescription within 3 days or had an active prescription. There was no evidence for a protective effect of discharge asthma preventer dispensing on asthma hospital readmissions within 12 months (OR 1.17, 95% CI 0.69 to 1.97, p=0.57). Of the 566 children who were not prescribed asthma preventers at discharge, 269 (47.5%) had one or more prescriptions dispensed in the community within 12 months. Participants who were in the protected period (asthma preventer dispensed) had reduced risk of an asthma hospital readmission (HR 0.61, 95% CI 0.36 to 1.02, p=0.06), including preschool children (HR 0.48, 95% CI 0.25, 0.93, p=0.03) on subgroup analysis. CONCLUSIONS: There was a low rate for prescribing and dispensing of hospital discharge asthma preventers and no protective effect was found for its impact on readmissions. A protective effect on readmissions was found for community asthma preventer dispensing.

Virtual monitoring in CF - the importance of continuous monitoring in a multi-organ chronic condition.

Cystic Fibrosis (CF) is a chronic life-limiting condition that affects multiple organs within the body. Patients must adhere to strict medication regimens, physiotherapy, diet, and attend regular clinic appointments to manage their condition effectively. This necessary but burdensome requirement has prompted investigations into how different digital health technologies can enhance current care by providing the opportunity to virtually monitor patients. This review explores how virtual monitoring has been harnessed for assessment or performance of physiotherapy/exercise, diet/nutrition, symptom monitoring, medication adherence, and wellbeing/mental-health in people with CF. This review will also briefly discuss the potential future of CF virtual monitoring and some common barriers to its current adoption and implementation within CF. Due to the multifaceted nature of CF, it is anticipated that this review will be relevant to not only the CF community, but also those investigating and developing digital health solutions for the management of other chronic diseases.

The impact of telehealth based care on paediatric cystic fibrosis outcomes.

In response to the COVID-19 pandemic telehealth utilisation amongst the Cystic Fibrosis (CF) population increased. Our aim was to assess the impact of CF telehealth clinics on CF outcomes. We conducted a retrospective chart review of patients seen in the CF clinic at the Royal Children's Hospital (Victoria, Australia). In this review we compared spirometry, microbiology and anthropometry in the year preceding the pandemic to during the pandemic, and to the first in-person appointment in 2021. 214 patients were included. First in-person FEV1 was median 5.4% below individuals' best FEV1 in 12 months prior to lockdown and decreased by >10% in 46 (31.9%) patients. There were no significant findings with regards to microbiology or anthropometry. The reduction in FEV1 observed on return to in-person appointments highlights the importance of ongoing improvement of telehealth-based care along with continued face-to-face review for the paediatric CF population.

A scoping review of lung function in children and adolescents living with HIV in the era of antiretroviral treatment.

BACKGROUND: Human immunodeficiency virus (HIV) in children and adolescents remains an important health challenge in many countries and is commonly associated with lung disease. The introduction of antiretroviral therapy (ART) has greatly improved survival but chronic lung disease is a common ongoing challenge. We conducted a scoping review of studies that have reported lung function in school-aged children and adolescents living with HIV. METHODS: A systematic literature search was performed by searching Medline, Embase, and PubMed databases, limited to articles published between 2011 and 2021 in English language. Inclusion criteria were studies involving participants living with HIV aged 5-18 years and having spirometry data. The primary outcome was lung function as measured by spirometry. RESULTS: Twenty-one studies were included in the review. Most study participants were living in the sub-Saharan African region. The prevalence of reduced forced expiratory volume in 1 s (FEV1 ) ranged from 25.3% to 73% across studies, reduced forced vital capacity (FVC) ranged from 10% to 42% and reduced FEV1 /FVC ranged from 3% to 26%. The mean z-score of FEV1 ranged from -2.19 to -0.73, mean zFEV1 /FVC ranged from -0.74 to 0.2, and mean FVC ranged from -1.86 to -0.63. CONCLUSION: There is a high prevalence of lung function impairment in children and adolescents living with HIV, which persists in the ART era. Further studies are needed of interventions that might improve lung function in these vulnerable populations.

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.

Exploring gaps and opportunities in primary care following an asthma hospital admission: a multisite mixed-methods study of three data sources.

OBJECTIVE: Explore gaps and opportunities in primary care for children following a hospital admission for asthma. DESIGN: Exploratory mixed-methods, using linked hospital and primary care administration data. SETTING: Eligible children, aged 3-18 years, admitted to one of three hospitals in Victoria, Australia between 2017 and 2018 with a clinical diagnosis of asthma. RESULTS: 767 caregivers of eligible children participated, 39 caregivers completed a semistructured interview and 277 general practitioners (GPs) caring for 360 children completed a survey. Over 90% (n=706) of caregivers reported their child had a regular GP. However, few (14.1%, n=108) attended a GP in the 24 hours prior to index admission or in the 7 days after (35.8%, n=275). Children readmitted for asthma (34.2%, n=263), compared with those not readmitted (65.8%, n=504), were less likely to have visited a GP in the non-acute phase of their asthma in the 12 months after index admission (22.1% vs 42.1%, respectively), and their GP was more likely to report not knowing the child had an asthma admission (52.8% vs 39.2%, respectively). Fewer GPs reported being extremely confident managing children with poorly controlled asthma (11.9%, n=43) or post-discharge (16.7%, n=60), compared with children with well-controlled asthma (36.4%, n=131), with no difference by child readmission status. CONCLUSIONS: Given the exploratory design and descriptive approach, it is unknown if the differences by child readmission status have any causal relationship with readmission. Nonetheless, improving preventative patterns of primary care visits, timely communication between hospitals and primary care providers, and guideline concordant care by GPs are needed.

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.

Persistent pleuritic chest pain in a patient with cystic fibrosis.

Pleural effusion is rare in cystic fibrosis. Infection leading to pleural effusion is likely to be polymicrobial, including contributory fungal infection; microbiology of pleural fluid is commonly discordant with sputum. https://bit.ly/3MJXrhk.

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.