Retrospective analysis of referrals for hypoxic challenge testing in children born preterm.

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may be at risk of hypoxaemia at altitude, such as during air travel. We have performed preflight hypoxic challenge testing (HCT) since 2006, incorporating British Thoracic Society (BTS) guidance since 2011, to determine which children may require oxygen during air travel. AIMS: We aimed to compare the outcome of HCTs in children with a history of BPD who met the 2011 BTS criteria and those who did not and, in addition to this, to interrogate the data for factors that may predict the outcome of HCT in this population. METHODS: We performed a retrospective analysis of data from HCTs of children with a history of BPD referred 2006-2020. Cases were excluded if the patient had a respiratory comorbidity, was still on oxygen therapy, if the test was a repeat or if the clinical record was incomplete. Descriptive and univariate analysis of the data was performed, and a binary logistic regression model was fitted. RESULTS: There were 79 HCTs, of which 24/79 (30%) did not meet BTS 2011 guidelines referral criteria. The analysis showed a greater proportion of desaturation in the group that did not meet criteria: 46% vs 27% (no statistical significance). Baseline oxygen saturations were higher in those who did not require oxygen during HCT and this variable was significant when adjusted for confounders. CONCLUSIONS: This study found that the current criteria for referral for preflight testing may incorrectly identify those most at risk and highlights the need for further investigation to ensure those most at risk are being assessed prior to air travel.

Diffuse alveolar haemorrhage in children: an international multicentre study.

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome. Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years. Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function. Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined.

Lung transplantation in an 18-month-old with donor specific antibodies - The use of intraoperative, targeted plasma exchange.

BACKGROUND: Sensitised patients undergoing Human Leukocyte Antigen-incompatible transplantation are at increased risk of hyperacute rejection and may be predisposed to antibody-mediated rejection, chronic lung allograft dysfunction and higher mortality. CASE: We present a case of primary lung transplantation in the setting of late identification of donor specific antibodies treated with intraoperative target plasma exchange. The patient was treated with fresh human plasma to a final volume of 1.5 times the patient's systemic circulation. From a pre-transplant mean fluorescence intensity of 5002, donor-specific antibodies were undetectable following plasma exchange on single antigen bead assay. CONCLUSIONS: This method represents a potential desensitisation technique for use in the intraoperative period.

Lung Clearance Index May Detect Early Peripheral Lung Disease in Sickle Cell Anemia.

Rationale: Chronic lung injury is common in sickle cell anemia (SCA) and worsens outcomes. Sensitive lung function tests might predict reversible disease that might benefit from therapeutic interventions. Objectives: To evaluate whether lung clearance index (LCI) (measuring global ventilation inhomogeneity), intraacinar ventilation inhomogeneity (Sacin), and conductive ventilation inhomogeneity (Scond) are more frequently abnormal than lung volumes in young people with SCA. Methods: Nitrogen multiple-breath washout, spirometry, and body plethysmography were cross-sectionally evaluated at steady state in subjects with SCA (hemoglobin SS) and healthy control subjects aged 8-21 years from London, United Kingdom. Results: Thirty-five patients (51% boys, mean ± SD age, 16.4 ± 3.5 yr) and 31 control subjects (48% boys; 16.2 ± 3.2 yr) were tested. There were significant differences between the study and control groups in mean LCI (mean difference, 0.42 units; 95% confidence interval [CI], 0.22 to 0.63; P = 0.0001), Sacin (mean difference, 0.014 units; 95% CI, 0.001 to 0.026; P = 0.04), forced expiratory volume in 1 second (FEV1) (mean difference, -0.79 z-scores; 95% CI, -1.28 to -0.30; P = 0.002), forced vital capacity (FVC) (mean difference, -0.80 z-scores; 95% CI, -1.28 to -0.31, P = 0.002), and total lung capacity (mean difference, -0.76 z-scores; 95% CI, -1.25 to -0.29, P = 0.002), but not in Scond and FEV1-to-FVC ratio. Whereas 29% (10 of 35) of patients had LCI > 95th percentile of control subjects, 23% (8 of 35) had abnormal FEV1 (<5th percentile of the reference population). Conclusions: LCI detected slightly more abnormalities than lung volumes in young people with SCA. Significant differences from control subjects in LCI and Sacin but not in Scond and FEV1-to-FVC ratio suggest that the lung function changes were most likely owing to patchy peripheral lung disease.

"You're on mute!" Does pediatric CF home spirometry require physiologist supervision?

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has accelerated the move towards home spirometry monitoring, including in children. The aim of this study is to determine whether the remote supervision of spirometry by a physiologist improves the technical quality and failure rate of the maneuvers. METHOD: Children with cystic fibrosis who had been provided with NuvoAir home spirometers were randomly allocated to either supervised or unsupervised home spirometry following a detailed training session. Home spirometry was performed every 2 weeks for 12 weeks. Tests were assigned a quality factor (QF) using our laboratory grading system as per American Thoracic Society/European Respiratory Society standards, with tests marked from A to D, or Fail. In our laboratory, we aim for QF A in all spirometry tests, but report results of QF B or C with a cautionary note. QF A was, therefore, the primary outcome, and QF A-C, the secondary outcome. RESULTS: Sixty-one patients were enrolled; 166 measurements were obtained in the supervised group, and 153 in the unsupervised group. Significantly more measurements achieved QF A in the supervised compared to unsupervised group (89% vs. 74%; p = <0.001), while proportions reaching Grade A-C were similar (99% vs. 95%; p = 0.1). All significant declines in spirometry results had a clinical rather than technical reason. Family/patient feedback for both arms was very positive. CONCLUSION: These results suggest that home spirometry in children should ideally be remotely supervised by a physiologist, but acceptable results can be obtained if resources do not allow this, provided that training is delivered and results monitored according to our protocol.

Limitations of regional ventilation inhomogeneity indices in children with cystic fibrosis.

BACKGROUND: Scond is a multiple breath washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, Scond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (Sacin or Sacin *). METHODS: Scond , Sacin  and the alternative indices, Scond *, and Sacin * were retrospectively calculated in subjects with CF aged 3 to 18 years and age-matched controls, who underwent sulfur hexafluoride MBW between 2003 and 2015. The upper limit of normal was based on 95th percentile of the control population. RESULTS: One hundred and twenty-seven subjects with CF (44% male; mean age ± SD: 7.5 years ± 4.9) and 94 controls (53% male; 7.9 years ± 5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, Scond reached a maximum value at lung clearance index (LCI) values of approximately 9. In subjects with LCI ≥ 9 Scond * showed good correlation with LCI, whilst Scond had no relationship with LCI (Spearman rank correlation Scond */LCI, 0.49; P < .01; Scond /LCI, -0.068; P = .46). In subjects with mild disease (LCI < 9) Scond was more frequently abnormal than Scond * (37% vs 16%; P = .01). CONCLUSIONS: Scond and Sacin are sensitive indices of early regional inhomogeneity, but are of no value when LCI ≥ 9. In these subjects, Scond * & Sacin * are potential alternatives.

Outcome according to subspecies following lung transplantation in cystic fibrosis pediatric patients infected with Mycobacterium abscessus.

BACKGROUND: Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M abscessus comprises three subspecies (M abscessus subsp abscessus, M abscessus subsp massiliense, and M abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single center was related to the M abscessus subspecies and genetic cluster. METHODS: CF patients with chronic M abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M abscessus isolates were identified to subspecies level by polymerase chain reaction and sequencing. Genetic cluster was determined by variable number tandem repeat profiling and whole-genome sequencing (WGS), and sequence type inferred from WGS. RESULTS: Thirteen patients with chronic M abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n = 1 with M abscessus bolletii, n = 5 with M abscessus massiliense, and n = 7 with M abscessus abscessus infection. Eight (62%) patients (one with M abscessus massiliense and seven with M abscessus abscessus) died post-lung transplant. The patient with M abscessus bolletii and three patients with M abscessus massiliense did well post-transplant. One patient with M abscessus massiliense is receiving ongoing treatment. CONCLUSIONS: Dramatically worse outcomes are observed in patients infected with M abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M abcsessus strains can have acceptable outcomes.

One-year outcomes in a multicentre cohort study of incident rare diffuse parenchymal lung disease in children (ChILD).

We performed a prospective, observational, cohort study of children newly diagnosed with children's interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3-7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88-96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8-12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Evaluation of inter-observer variation for computed tomography identification of childhood interstitial lung disease.

Making chILD diagnoses on CT is poorly reproducible, even amongst sub-specialists. CT might best improve diagnostic confidence in a multidisciplinary team setting when augmented with clinical, functional and haematological results. http://bit.ly/327jRCw.

Diagnosing and managing bronchiolitis obliterans in children.

INTRODUCTION: Bronchiolitis obliterans (BO) is a chronic and irreversible obstructive lung disease leading to the obstruction and/or obliteration of the small airways. Three main BO entities are distinguished: post-infectious BO (PIBO); BO post lung transplantation; and BO after bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT). All three entities are separate, however, there are similarities in histopathological characteristics and possibly in aspects of the development pathway. Areas covered: We review current evidence of bronchiolitis obliterans diagnosis and management in children. The diagnosis of BO is usually based on a combination of history, clinical and radiological findings, although lung biopsy and histopathology remain the gold standard approaches to confirm BO. Expert opinion: At present, we do not have a clear understanding of the mechanisms of the development of BO and lack strong evidence for treatment. Although most BO in children is post-infectious, most of the current evidence for treatment originates from studies analyzing BO in adult lung transplant and HSCT patients. BO management requires multidisciplinary approach and care in specialized centers.

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Comparison of facemask and mouthpiece interfaces for multiple breath washout measurements.

BACKGROUND: Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children. METHODS: We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children. RESULTS: In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age. CONCLUSION: Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur.