Ten-year experience of whole lung lavage in pediatric Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary Alveolar Proteinosis (PAP) is extremely rare and can be caused by hereditary dysfunction of the granulocyte macrophage colony-stimulating factor receptor (GM-CSF) receptor, autoantibodies against GM-CSF, or other diseases leading to alveolar macrophage (AM) dysfunction. This leads to protein accumulation in the lung and severe dyspnea and hypoxemia. Whole lung lavage (WLL) is the first line treatment strategy. METHODS: Here, we present data from more than ten years of WLL practice in pediatric PAP. WLL performed by the use of a single lumen or double lumen tube (SLT vs. DLT) were compared for technical features, procedure time, and adverse events. RESULTS: A total of n=57 procedures in six PAP patients between 3.5 and 14.3 years of age were performed. SLT based WLL in smaller children was associated with comparable rates of adverse events but with longer intervention times and postprocedural intensive care treatment when compared to DLT based procedures. DISCUSSION: Our data shows that WLL is feasible even in small children. DLT based WLL seems to be more effective, and our data supports the notion that it should be considered as early as possible in pediatric PAP. CONCLUSION: WLL lavage is possible in small PAP patients but should performed in close interdisciplinary cooperation and with age appropriate protocols.

Bilateral lung transplantation for pediatric pulmonary arterial hypertension: perioperative management and one-year follow-up.

Background: Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes. Methods: Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020. Results: Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic (n = 4) or heritable PAH (n = 4), PAH associated with congenital heart disease (n = 2), pulmonary veno-occlusive disease (n = 1), and pulmonary capillary hemangiomatosis (n = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months). Conclusion: LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading.

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.

Diagnostic workup of childhood interstitial lung disease.

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed.

ABCA3-related interstitial lung disease beyond infancy.

BACKGROUND: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. METHOD: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. RESULTS: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. CONCLUSION: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Diffuse alveolar hemorrhage in children with interstitial lung disease: Determine etiologies!

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children's interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician's awareness of diagnostic shortcomings. PATIENTS AND METHODS: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the "Phenomizer." RESULTS: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible. CONCLUSION: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy.

COVID-19 in pediatric lung transplant recipients: Clinical course and outcome.

BACKGROUND: COVID-19 causes high morbidity and mortality in adult lung transplant (LTX) recipients. Data on COVID-19 in children after LTX is limited. We report the clinical presentation and outcome of SARS-CoV-2 infection in 19 pediatric LTX recipients. METHODS: Between March 2020 and June 2022, SARS-CoV-2 testing was performed on all pediatric LTX patients with COVID-19 symptoms or contact with a SARS-CoV-2 infected person. Positive patients were prospectively evaluated for symptoms, treatment and outcome. Vaccination status and immune response were recorded. RESULTS: Nineteen out of 51 pediatric LTX recipients had a SARS-CoV-2 infection. Mean age was 12.3 years (IQR 9-17), 68% were female, 84% had preexisting comorbidities. Mean time between LTX and SARS-CoV-2 infection was 4.8 years (IQR 2-6). No patients experienced severe COVID-19: 11% were asymptomatic, and 89% had mild symptoms, primarily rhinitis (74%), fever (47%), and cough (37%). One SARS-CoV-2 positive patient was hospitalized due to combined fungal and bacterial infection. Mean duration of symptoms was 10.5 days (IQR 3-16), whereas mean period of positivity by antigen test was 21 days (IQR 9-27, p = 0.013). Preventive antiviral therapy was initiated in 3 patients. After a mean follow-up of 2.5 months (IQR 1.1-2.4), no patient reported persistent complaints related to COVID-19. Lung function tests remained stable. CONCLUSIONS: Unlike adult LTX recipients, children and adolescents are at low risk for severe COVID-19, even with risk factors beyond immunosuppression. Our findings cast doubt on the necessity of excessive isolation for these patients and should reassure clinicians and caregivers of LTX patients.

Minimal important difference in childhood interstitial lung diseases.

BACKGROUND: Monitoring disease progression in childhood interstitial lung diseases (chILD) is essential. No information for the minimal important difference (MID), which is defined as the smallest change in a parameter that is perceived as important prompting a clinician to change the treatment, is available. We calculated MIDs for vital signs (respiratory rate, peripheral oxygen saturation in room air, Fan severity score) and health-related quality of life (HrQoL) scores. METHODS: This study used data from the Kids Lung Register, which is a web-based management platform that collects data of rare paediatric lung disorders with a focus on chILD. Data of vital signs and HrQoL scores (Health Status Questionnaire, chILD-specific questionnaire and PedsQL V.4.0) were collected. MIDs were calculated according to distribution-based (one-third SD) and anchor-based methods (using forced expiratory volume in 1 s and forced vital capacity) as anchors. RESULTS: Baseline data of 774 children were used to calculate the following MIDs: respiratory rate 1.3 (z-score), O2 saturation in room air 3.0%, Fan severity score 0.2-0.4, Health Status Questionnaire 0.4-0.8, chILD-specific questionnaire 4.4%-8.2%, physical health summary score 7.8%-8.9%, psychosocial health summary score 3.4%-6.9% and total score 5.1%-7.4%. Results of the responsiveness analysis generally agreed with the MIDs calculated. CONCLUSIONS: For the first time, we provide estimates of MIDs for vital signs and HrQoL scores in a large cohort of chILD using different methods.

Unusual phenotypes in patients with a pathogenic germline variant in DICER1.

Pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms' tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

Acquired von Willebrand syndrome (AVWS) type 2, characterized by decreased high molecular weight multimers, is common in children with severe pulmonary hypertension (PH).

Background and objectives: Emerging evidence suggests that increased degradation of von Willebrand factor and decrease in high molecular weight multimers occurs in patients with pulmonary hypertension (PH). However, the link between acquired von Willebrand Syndrome (AVWS) type 2 and PH remains poorly understood. Material and methods: We retrospectively evaluated the charts of 20 children with PH who underwent bilateral lung transplantation (LuTx) between 2013 and 2022. Von Willebrand variables were determined in 14 of these patients; 11 patients had complete diagnostics including multimer analysis. Results: We confirmed AVWS in 82% of the children studied (9 of 11 patients by multimer analysis). The two remaining patients had suspected AVWS type 2 because of a VWF:Ac/VWF:Ag ratio of <0.7. Platelet dysfunction or suspicion of VWD type 1 were found in two separate patients. All but one of the 14 children with severe PH had a coagulation disorder. Most patients (9 proven, 2 suspected) had AVWS type 2. Notably, 3 of 5 patients (60%) with normal VWF:Ac/VWF:Ag ratio >0.7 had abnormal VWF multimers, indicating AVWS type 2. Hemostatic complications were observed in 4 of 12 (33%) patients with VWS and 3 of 6 (50%) patients without diagnostics and therapy. Conclusion: For children with moderate to severe PH, we recommend systematic analysis of von Willebrand variables, including multimer analysis, PFA-100 and platelet function testing. Awareness of the diagnosis "AVWS" and adequate therapy may help to prevent these patients from bleeding complications in case of surgical interventions or trauma.

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease.

BACKGROUND: No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. RESULTS: 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O2-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O2-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. CONCLUSIONS: Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).

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.

Healthcare resource utilisation and medical costs for children with interstitial lung diseases (chILD) in Europe.

BACKGROUND: No data on healthcare utilisation and associated costs for the many rare entities of children's interstitial lung diseases (chILD) exist. This paper portrays healthcare utilisation structures among individuals with chILD, provides a pan-European estimate of a 3-month interval per-capita costs and delineates crucial cost drivers. METHODS: Based on longitudinal healthcare resource utilisation pattern of 445 children included in the Kids Lung Register diagnosed with chILD across 10 European countries, we delineated direct medical and non-medical costs of care per 3-month interval. Country-specific utilisation patterns were assessed with a children-tailored modification of the validated FIMA questionnaire and valued by German unit costs. Costs of care and their drivers were subsequently identified via gamma-distributed generalised linear regression models. RESULTS: During the 3 months prior to inclusion into the registry (baseline), the rate of hospital admissions and inpatient days was high. Unadjusted direct medical per capita costs (€19 818) exceeded indirect (€1 907) and direct non-medical costs (€1 125) by far. Country-specific total costs ranged from €8 713 in Italy to €28 788 in Poland. Highest expenses were caused by the disease categories 'diffuse parenchymal lung disease (DPLD)-diffuse developmental disorders' (€45 536) and 'DPLD-unclear in the non-neonate' (€47 011). During a follow-up time of up to 5 years, direct medical costs dropped, whereas indirect costs and non-medical costs remained stable. CONCLUSIONS: This is the first prospective, longitudinal study analysing healthcare resource utilisation and costs for chILD across different European countries. Our results indicate that chILD is associated with high utilisation of healthcare services, placing a substantial economic burden on health systems.

Acute exacerbations in children's interstitial lung disease.

INTRODUCTION: Acute exacerbations (AEs) increase morbidity and mortality of patients with chronic pulmonary diseases. Little is known about the characteristics and impact of AEs on children's interstitial lung disease (chILD). METHODS: The Kids Lung Register collected data on AEs, the clinical course and quality of life (patient-reported outcomes - PRO) of rare paediatric lung diseases. Characteristics of AEs were obtained. RESULTS: Data of 2822 AEs and 2887 register visits of 719 patients with chILD were recorded. AEs were characterised by increased levels of dyspnoea (74.1%), increased respiratory rate (58.6%) and increased oxygen demand (57.4%). Mostly, infections (94.4%) were suspected causing an AE. AEs between two register visits revealed a decline in predicted FEV1 (median -1.6%, IQR -8.0 to 3.9; p=0.001), predicted FVC (median -1.8%, IQR -7.5 to 3.9; p=0.004), chILD-specific questionnaire (median -1.3%, IQR -3.6 to 4.5; p=0.034) and the physical health summary score (median -3.1%, IQR -15.6 to 4.3; p=0.005) compared with no AEs in between visits. During the median observational period of 2.5 years (IQR 1.2-4.6), 81 patients died. For 49 of these patients (60.5%), mortality was associated with an AE. CONCLUSION: This is the first comprehensive study analysing the characteristics and impact on the clinical course of AEs in chILD. AEs have a significant and deleterious effect on the clinical course and health-related quality of life in chILD.

Interventional Bronchus Occlusion Using Amplatzer Devices - A Promising Treatment Option for Children with Persistent Air Leak.

BACKGROUND: Persistent air leak (PAL) is a severe complication of secondary spontaneous pneumothorax (SSP). Surgical interventions are usually successful when medical treatment fails, but can be associated with significant complications and loss of potentially recoverable lung parenchyma. METHODS: Retrospective analysis of efficacy and safety of interventional bronchus occlusions (IBO) using Amplatzer devices (ADs) in children with PAL secondary to SSP. RESULTS: Six patients (four males, 4-15 years of age) underwent IBO using ADs as treatment for PAL. Necrotizing pneumonia (NP) was the most common cause (n=4) of PAL. Three patients were previously healthy and three suffered from chronic lung disease. All patients required at least two chest tubes prior to the intervention for a duration of 15-43 days and all required oxygen or higher level of ventilatory support. In three cases, previous surgical interventions had been performed without success. All children improved after endobronchial intervention and we observed no associated complications. All chest tubes were removed within 5-25 days post IBO. In patients with PAL related to NP (n=4), occluders were removed bronchoscopically without re-occurrence of pneumothorax after a mean of 70 days (IQR: 46.5-94). CONCLUSION: IBO using ADs is a safe and valuable treatment option in children with PAL independent of disease severity and underlying cause. A major advantage of this procedure is its less invasiveness compared to surgery and the parenchyma- preserving approach.

Cardiovascular Burden Is High in Pediatric Lung Transplant Recipients.

BACKGROUND: Cardiovascular morbidity is common in adults after lung transplantation (LTx) but has not been described for pediatric LTx recipients. Early subclinical cardiovascular damage is reflected by increases in pulse wave velocity (PWV; indicating arteriosclerosis), intima-media thickness (IMT; indicating atherosclerosis), and left ventricular mass index (LVMI; indicating left ventricular hypertrophy). METHODS: We annually assessed 47 pediatric LTx recipients in a prospective longitudinal study (144 observations, mean 3.1 visits/patient, range of 1-4 visits, mean follow-up 2.2 y). RESULTS: At inclusion, increased PWV and IMT were detected in 13% and 30%, respectively, and elevated LVMI was detected in 33%. Higher PWV was associated with male sex, longer time since LTx, higher diastolic blood pressure, and lower glomerular filtration rate. Male sex and lower hemoglobin levels were associated with higher IMT, and the presence of diabetes was associated with higher LVMI. CONCLUSIONS: Pediatric LTx recipients suffer from a high and sustained burden of subclinical cardiovascular damage. In light of improving long-term outcomes, cardiovascular morbidity needs to be addressed. Our analysis identified classical and nonclassical risk factors to be associated with the measures for cardiovascular damage, which could serve as targets for intervention.

Full recovery of right ventricular systolic function in children undergoing bilateral lung transplantation for severe PAH.

BACKGROUND: We investigated whether RV function recovers in children with pulmonary arterial hypertension (PAH) and RV failure undergoing lung transplantation (LuTx). METHODS: Prospective observational study of 15 consecutive children, 1.9 to 17.6 years old, with PAH undergoing bilateral LuTx. We performed advanced echocardiography (Echo) and cardiac magnetic resonance imaging (MRI), followed by conventional and strain analysis, pre- and ∼6 weeks post-LuTx. RESULTS: After LuTx, RV/LV end-systolic diameter ratio (Echo), RV volumes and systolic RV function (RVEF 63 vs 30 %; p < 0.05) by MRI completely normalized, even in children with severe RV failure (RVEF < 40%). The echocardiographic end-systolic LV eccentricity index nearly normalized post-LuTx (1.0 vs 2.0, p < 0.0001) while RV hypertrophy regressed more slowly and was still evident. We found especially the end-systolic RV/LV ratios by Echo (diameter: 0.6 vs 2.6) or MRI (volumes: 0.8 vs 3.4) excellent diagnostic tools (p < 0.05): Together with RVEF by MRI, these ratios were superior to tricuspid annular plane systolic excursion (TAPSE; p = 0.4551) in assessing global systolic RV dysfunction. Moreover, children with severe PAH had reduced RV 2D longitudinal strain (Echo, MRI; p = 0.0450) and decreased RV 2D radial and circumferential strain (MRI; p = 0.0026 and p = 0.0036 respectively), all of which greatly improved following LuTx. CONCLUSION: We demonstrate full recovery of RV systolic function in children within two months after LuTx for severe PAH, independently of the patients' age, weight, and hemodynamic compromise preceding the LuTx. Even in end-stage pediatric PAH with poor RV function and low cardiac output, LuTx should be preferred over heart-lung transplantation.

Indications and outcome after lung transplantation in children under 12 years of age: A 16-year single center experience.

OBJECTIVE: Paediatric lung transplantation poses unique management challenges. Experience regarding indications and outcome is scarce, especially in younger children. The primary aim of this study was to investigate outcome after first lung transplantation in children <12 years of age in comparison to adolescents (12-17 years old). METHODS: Records of patients <18 years who underwent first lung transplantation between 01/2005 and 01/2021 were retrospectively reviewed, and compared between children <12 years old and adolescents. Median (IQR) follow-up was 51 (23-91) months. RESULTS: Of the 117 patients underwent first lung transplantation at our institution, of whom 42 (35.8%) patients were <12 years and 75 (64.2%) ≥12 years old. Compared to adolescents, children were more often transplanted for interstitial lung disease (33.3% vs 12%, p = 0.005) and precapillary pulmonary hypertension (28.6% vs 12%, p = 0.025), and required more often intraoperative cardiopulmonary bypass (31% vs 14.7%, p = 0.036) and postoperative ECMO support (47.6% vs 13.3%, p < 0.001). Postoperatively, children required longer ventilation times (78 vs 18 hours, p = 0.009) and longer ICU stay (9.5 vs 3 days, p < 0.001) compared to their older counterparts. Primary graft dysfunction grade 3 at 72 hours (9.5% vs 9.3%, p = 0.999), in-hospital mortality (2.4% vs 6.7%, p = 0.418), graft survival (80% vs 62%, p = 0.479) and freedom from chronic lung allograft dysfunction (76% vs 59%, p = 0.41) at 8-year follow-up did not differ between groups. CONCLUSIONS: Lung transplantation in children under 12 years is challenging due to underlying medical conditions and operative complexity. Nevertheless, outcomes are comparable to those in older children.

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers' approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012-2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

Multiple breath washout quality control in the clinical setting.

BACKGROUND: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting. METHODS: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland, in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 96 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland. RESULTS: Before the implementation of real-time QC in Bern, only 58% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After the implementation of real-time QC, MBW test acceptability improved to 75% in Bern. In Zurich, after the implementation of real-time QC, test acceptability improved from 38% to 70%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 84% in Bern and 93% in Zurich. CONCLUSION: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability.