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.

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.

A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Frequent microbiological surveillance during inpatient cystic fibrosis pulmonary exacerbations has limited clinical value.

BACKGROUND: No evidence exists to guide the frequency of obtaining bacterial respiratory cultures during inpatient treatment of pediatric cystic fibrosis (CF) pulmonary exacerbations (PEx). At our institution, admission and weekly respiratory cultures are routinely collected to guide antimicrobial selection. This study evaluates the extent that this practice informs clinical management and the healthcare-related costs associated with routinely repeating cultures. METHODS: All children with CF with at least one hospital admission for IV antibiotics from January 2015 to December 2019 were included. Data collected included patient demographics, culture results, and antibiotic history. Respiratory cultures were numbered from the last clinic culture (`Culture 1'), culture on admission (`Culture 2'), and so on (`Cultures 3-6'). Outcomes assessed were microbiological results, frequency and timing of antibiotic change, and total microbiological laboratory costs. RESULTS: Seventy-eight children with 224 admissions and 695 bacterial cultures were analyzed. Repeated microbiology sampling revealed 118 new bacterial species in 82 admissions.  Culture 2 was most likely to identify a new bacterial species (91/115, 79.1 %) and most likely to be followed by a change in antibiotic (33/37; 89.2 %). The total cost of all cultures was $18,264.79. Eliminating Cultures 3-6 from routine practice could represent a 51 % cost-savings ($9,362.89), without significant impact on identification of new clinically relevant isolates. CONCLUSION: Ongoing bacterial surveillance during a CF PEx beyond admission culture provides minimal information, rarely impacts clinical management, and can increase healthcare costs. An optimized approach would be to routinely obtain admission cultures and to obtain further cultures only if clinically indicated.

Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective.

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.

Genetics of bronchopulmonary dysplasia: An update.

Bronchopulmonary dysplasia (BPD) is a multi-factorial disease that results from multiple clinical factors, including lung immaturity, mechanical ventilation, oxidative stress, pulmonary congestion due to increasing cardiac blood shunting, nutritional and immunological factors. Twin studies have indicated that susceptibility to BPD can be strongly inherited in some settings. Studies have reported associations between common genetic variants and BPD in preterm infants. Recent genomic studies have highlighted a potential role for molecular pathways involved in inflammation and lung development in affected infants. Rare mutations in genes encoding the lipid transporter ATP-binding cassette, sub-family A, member 3 (ABCA3 gene) which is involved in surfactant synthesis in alveolar type II cells, as well as surfactant protein B (SFTPB) and C (SFTPC) can also result in severe form of neonatal-onset interstitial lung diseases and may also potentially affect the course of BPD. This chapter summarizes the current state of knowledge on the genetics of BPD.

Multiple breath washout and oscillometry after allogenic HSCT: a scoping review.

Pulmonary chronic graft-versus-host disease (cGVHD) is a substantial cause of pulmonary morbidity and mortality post-haematopoietic stem cell transplantation (HSCT). Current spirometry-based monitoring strategies have significant limitations. Understanding the utility of novel peripheral airway function tests - multiple breath washout (MBW) and oscillometry - is critical in efforts to improve detection, facilitate earlier intervention and improve outcomes. In this scoping review, we identified 17 studies investigating MBW or oscillometry, or both, after allogenic HSCT. Despite small study numbers limiting the ability to draw firm conclusions, several themes were evident. Detectable peripheral airway abnormality in MBW occurred in a substantial proportion prior to HSCT. MBW indices post-HSCT were more frequently abnormal than spirometry when reporting group data and among those with extrapulmonary cGVHD and pulmonary cGVHD. Changes in MBW indices over time may be more indicative of pulmonary complications than absolute values at any given time point. Oscillometry indices were often normal at baseline, but more frequently abnormal in those who developed pulmonary cGVHD. Pooling currently available individual participant data across these studies may improve our ability to formally compare their respective sensitivity and specificity at specific time points and assess the trajectory of MBW and oscillometry indices over time.

Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ⩾6 Years with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Clinical Trial.

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).

Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2-5 Years with Cystic Fibrosis and at Least One F508del Allele.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L; 95% confidence interval [CI], -61.3 to -54.6; n = 69) and LCI2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).

Tracheal inflammatory myofibroblastic tumor presenting as an obstructive pediatric foreign body.

We describe an unusual presentation of a suspected pediatric foreign body (FB) aspiration which was found to be an occlusive inflammatory myofibroblastic tumor (IMT) of the distal trachea. These are rarely reported entities, with the potential for significant airway bleeds. Multidisciplinary discussion and involvement allowed for a safe patient outcome.

A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR.

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).

Heterogenous Disease Course and Long-Term Outcome of Children's Interstitial Lung Disease Related to Filamin A Gene Variants.

Rationale: Variable disease course and outcomes have been reported in children's interstitial lung disease associated with FLNA (Filamin A gene) variants. Objectives: To further delineate long-term respiratory outcomes and identify potential contributing factors to severe disease course. Methods: We retrospectively collected longitudinal data from three centers on nine cases (one male) with FLNA variants and early respiratory disease onset (within the first 24 mo of life). Clinical, radiographic, and histopathologic data were analyzed, focusing on cardiorespiratory disease course. Results: All required early respiratory support (three invasive ventilation, three noninvasive ventilation, three supplemental oxygen), and all experienced frequent severe infective respiratory exacerbations. Three died in infancy from refractory respiratory failure and pulmonary hypertension (PH). The six surviving individuals were 3, 10, 11, 15, 18, and 33 years old at time of reporting. The extent of functional respiratory impairment decreased with age; at last follow-up, there were no individuals on home invasive ventilation, one on nocturnal noninvasive ventilation, four on oxygen, and one on no respiratory support. Spirometry consistently demonstrated moderate to severe obstructive defects (forced expiratory volume in 1 s/forced vital capacity [FVC] z-score, -3.76 to -1.77; percent predicted FVC, 31.5% to 92.1%). Seven required PH treatment in early childhood (7/9), and three of the survivors (3/6) still receive treatment. Radiologic and histopathologic findings were consistent among cases. Conclusions: Early mortality was common, but many survivors stabilized even after severe symptoms in infancy. All survivors had persistent obstructive defects on spirometry, and half have persistent or recurrent PH. These typical findings are suggestive of this rare diagnosis and should prompt consideration of genetic testing.

All hands on deck: A multidisciplinary approach to SARS-CoV-2-associated MIS-C.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious complication of SARS-CoV-2 infection with overlapping features of Kawasaki disease and toxic shock syndrome. In May 2020, a provincial multidisciplinary working group was established in anticipation of emerging cases following the first wave of SARS-CoV-2 infections. Methodology: Our centre established a multidisciplinary working group for MIS-C cases in British Columbia. The group developed guidelines using the World Health Organization MIS-C case definition. Guidelines were updated using quality improvement methods as new reports and our local experience evolved. We included all children who were evaluated in person or had samples sent to our centre for MIS-C evaluation from May 2020 to April 2021. We prospectively collected patient demographics, clinical and laboratory characteristics, and treatment. Results: Fifty-two children were included. Eleven were diagnosed as confirmed MIS-C. Ten of the 11 MIS-C cases presented with shock. Gastrointestinal and mucocutaneous involvement were also prominent. Common laboratory features included elevated C-reactive protein, D-dimer, troponin, and brain natriuretic peptide. Four out of 11 (36%) had myocardial dysfunction and 3/11 (27%) had coronary artery abnormalities. All 11 patients had evidence of SARS-CoV-2 infection. Ten out of 11 (91%) received intravenous (IV) immunoglobulin and IV corticosteroids. Conclusion: Our provincial cohort of MIS-C patients were more likely to present with shock and cardiac dysfunction, require ICU admission, and be treated with corticosteroids compared to ruled out cases. Our working group's evolving process ensured children with features of MIS-C were rapidly identified, had standardized evaluation, and received appropriate treatment in our province.

Multiple Breath Washout Testing to Identify Pulmonary Chronic Graft Versus Host Disease in Children After Hematopoietic Stem Cell Transplantation.

Pulmonary chronic graft versus host disease (p-cGvHD) is a highly morbid, late complication of hematopoietic stem cell transplantation (HSCT). The 2014 National Institutes of Health cGvHD consensus criteria require a tissue biopsy or a drop in spirometry (with other features) to establish the diagnosis of p-cGvHD. Unfortunately, children are often incapable of performing spirometry, which can delay the diagnosis of this condition. Multiple breath washout testing (MBW) can detect abnormal pulmonary physiology in older children and adults after HSCT, but its feasibility and utility have not been assessed in younger children and in those who cannot perform spirometry. In this study, we assess the feasibility and sensitivity of MBW to detect p-cGvHD in children as young as 3 years of age after HSCT. We performed a cross-sectional analysis of children age 3 to 18 years, between 100 days and 5 years after allogenic HSCT. Participants were recruited from the HSCT population at BC Children's Hospital (Vancouver, Canada). All participants attempted nitrogen MBW, and children age 6 years and over attempted spirometry. Nonparametric statistical techniques were used; descriptive statistics used median (interquartile range [IQR]) and group medians were compared using Wilcoxon rank-sum test. Twenty-six children, median age 11.0 (range 3.6-18.5) years, were recruited a median of 26.4 (IQR 15.7, 51.8) months after HSCT. Six of the 26 children (23%) had a clinical diagnosis of p-cGvHD. MBW was successful in all (26/26, 100%) participants. The lung clearance index (LCI; the primary outcome of MBW) was higher in those with a history of p-cGvHD (median 11.8 [IQR 9.6, 18.7]) than in those with no history of cGvHD (median 7.7 [IQR 7.1, 8.0]; P = .001) or a history of extrapulmonary cGvHD (median 7.5 [IQR 6.9, 7.6], P = .007). A threshold LCI = 9 resulted in a sensitivity of 100% and specificity of 90% for the correct identification of clinically diagnosed p-cGvHD using MBW (area under the receiver operator characteristic curve is 0.97 [95% confidence interval 0.80, 0.99]). Spirometry was successful in most (17/26, 65%) participants. Similar to LCI, forced expiratory volume in 1 second (FEV1)/ forced vital capacity could distinguish between p-cGvHD and no cGvHD (P = .02) and extrapulmonary cGvHD (P = .01). FEV1 alone could not distinguish between either of these groups (P = .87, P = .24 respectively). MBW is feasible in young children after HSCT and in those who cannot perform spirometry. LCI has high discriminative power for correctly identifying p-cGvHD, but these preliminary results require confirmation in a larger validation cohort.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis.

Patients with pancreatic insufficient cystic fibrosis rarely develop acute pancreatitis due to insufficient acinar reserve. We describe a series of five patients under the age of 18 (range 8-16 years) with pancreatic insufficient cystic fibrosis who developed a phenotype in keeping with acute pancreatitis following initiation of CFTR modulator therapy. This occurred at a median of 30 months following CFTR modulator initiation. 3/5 of these patients also developed pancreatic sufficiency or at least an intermediary pancreas status, indicated by fecal elastases above 100 µg/g. This series highlights a mostly unrecognized potential side effect of this therapy as well as the potential of CFTR modulator therapies to improve exocrine pancreatic function, even in adolescent patients.

Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.