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Interstitial lung disease (ILD) comprises a group of respiratory diseases affecting the interstitium of the lungs, which occur when a lung injury triggers an abnormal healing response, and an inflammatory process leads to altered diffusion and restrictive respiratory dysfunction. The term "interstitial" may be misleading, as other components of the lungs are usually also involved (epithelium, airways, endothelium, and so on). Pediatric conditions (childhood interstitial lung disease, chILD) are different from adult forms, as growing and developing lungs are affected and more diverse and less prevalent diseases are seen in childhood. Diffuse parenchymal lung disease (DPLD) and diffuse lung disease (DLD) can be used interchangeably with ILD. Known etiologies of chILD include chronic infections, bronchopulmonary dysplasia, aspiration, genetic mutations leading to surfactant dysfunction, and hypersensitivity pneumonitis due to drugs or environmental exposures. Many forms are seen in disorders with pulmonary involvement (connective tissue disorders, storage diseases, malignancies, and so on), but several conditions have unknown origins (desquamative pneumonitis, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia in infancy, and so on). Currently, there is no consensus on pediatric classification; however, age grouping is proposed as some specific forms are more prevalent in infancy (developmental and growth abnormalities, surfactant dysfunction mutations, etc.) and others are usually seen in older cohorts (disorders in normal or immunocompromised hosts, systemic diseases, etc.). Clinical manifestations vary from mild nonspecific symptoms (recurrent respiratory infections, exercise intolerance, failure to thrive, dry cough, etc.) to a severe clinical picture (respiratory distress) and presentation related to the child's age. The diagnostic approach relies on imaging techniques (CT), but further investigations including genetic tests, BAL, and lung biopsy (VATS) are needed in uncertain cases. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs. Lung transplantation for selected cases in a pediatric transplantation center could be an option; however, limited data and evidence are available regarding long-term survival. International collaboration is warranted to understand chILD entities better and improve the outcomes of these patients. [ABSTRACT FROM AUTHOR]

Background: In uncommon diseases, the field of health-related quality of life (HR-QoL) has received little attention. Childhood interstitial lung diseases (chILD) are a diverse group of illnesses with a high rate of morbidity and mortality. These children's HR-QoL may be impacted by their reduced lung function, the effects of their nutrition, and the stressful nature of their medical regimens. Aim of the work: to compare the HR-QoL in chILD to an aged-matched healthy population and to determine the parameters linked to a changed quality of life. Patients and methods: This is a cross section controlled study conducted on 26 children aged from 2-16 years with chILD as well as 26 age and gender-matched healthy controls, they were selected by simple random method, during the period from October, 2022 to june, 2023. Clinical examination, imaging studies were done for the patients group to determine the severity grade of the disease. All participants were asked to complete the PedsQLTM 4.0 Generic Core Scale (0 to 100 points). Results: The chILD group had significantly lower total mean score of PedsQL (P= 0.000) in comparison to control group. The most significant predictors and influencing variables in the chILD group are prolonged oxygen therapy (p=0.001), radiological changes, higher Fan staging (Clinical severity score) (P=0.041), recurrent hospitalization (p=0.021), intensive care admission (P=0.006), Spo2 saturation and social class (0.040). Conclusion: Since chILD is an incurable illness that progresses slowly and does not significantly improve lung function, we should concentrate more on possibly treatable factors affecting quality of life (QOL). Doing so could result in better care for individuals with chILD. Similar to how pulmonary function tests are evaluated, QOL assessment must be given proper weight when assessing chILD patients. [ABSTRACT FROM AUTHOR]

Rationale: Neuroendocrine cell hyperplasia of infancy (NEHI) is an important form of children's interstitial and diffuse lung disease for which the diagnostic strategy has evolved. The prevalence of comorbidities in NEHI that may influence treatment has not been previously assessed.Objectives: To evaluate a previously unpublished NEHI clinical score for assistance in diagnosis of NEHI and to assess comorbidities in NEHI.Methods: We performed a retrospective chart review of 199 deidentified patients with NEHI from 11 centers. Data were collected in a centralized Research Electronic Data Capture registry and we performed descriptive statistics.Results: The majority of patients with NEHI were male (66%). The sensitivity of the NEHI Clinical Score was 87% (95% confidence interval [CI], 0.82-0.91) for all patients from included centers and 93% (95% CI, 0.86-0.97) for those with complete scores (e.g., no missing data). Findings were similar when we limited the population to the 75 patients diagnosed by lung biopsy (87%; 95% CI, 0.77-0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35% had aspiration or were at risk for aspiration, and 17% had evidence of immune system abnormalities.Conclusions: The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however, its specificity has not yet been addressed. Clinicians should consider evaluating patients with NEHI for comorbidities, including gastroesophageal reflux, aspiration, and immune system abnormalities, because these can contribute to the child's clinical picture and may influence clinical course and treatment. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD.Methods and Design: The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks' duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ.Discussion: This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases.Trial Registration: This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013-003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938. Registered on 8 November 2015. IZKS trial code: 2013-006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is a rare hematologic disorder that results from the clonal multiplication and accumulation of immature dendritic Langerhans cells. Its reported incidence rate varies, but is considered to be 2.6-8.9 per million children who are <15 years of age each year. It may affect any system or organ. The present study reported 4 pediatric LCH cases in order to highlight the heterogeneity of the initial presentation, and the pitfalls that may mislead clinicians and delay diagnosis. The clinical features, as well as the pathognomonic imaging, pathology findings and treatment options were presented. LCH may be rare, but it should always be included in the differential diagnosis of persistent eczema, unexplained skin lesions, diabetes insipidus and persistent bone pain, among others. While the debate on pathogenesis and treatment is ongoing, high index of suspicion among pediatricians, pediatric oncologists and other specialists (pathologists, dermatologists, orthopaedic surgeons, general practitioners or family physicians) is essential for early diagnosis, and optimal outcome. [ABSTRACT FROM AUTHOR]

Background: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases.Methods: A web-based chILD management platform with a registry and biobank was successfully designed and implemented.Results: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation.Conclusions: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD.Trial Registration Number: Results, NCT02852928. [ABSTRACT FROM AUTHOR]

The BRAF V600E mutation is reported in half of patients with Langerhans cell histiocytosis ( LCH). This study investigated the detection of the BRAF V600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E-mutated LCH were investigated to detect ccf BRAF V600E at diagnosis ( n = 48) and during follow-up ( n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem ( RO+ MS) LCH, 5/12 (42%) of patients with RO− MS LCH and 3/21 (14%) patients with single-system ( SS) LCH ( P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO− patients (mean, 0·16%; range, 0·01-0·39) ( P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders ( P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO− LCH resistant to first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Childhood interstitial lung disease (chILD) represents a rare heterogeneous group of respiratory disorders. In the absence of randomized controlled clinical trials, global collaborations have utilized case series with an aim to standardising approaches to diagnosis and management. Australasian data are lacking. The aim of this study was to calculate prevalence and report the experience of chILD in Australasia over a decade.Methods: Paediatric pulmonologists in Australia and New Zealand involved in the care of patients aged 0-18 years with chILD completed a questionnaire on demographics, clinical features and outcomes, over a 10 year period. These data, together with data from the 2 reference genetics laboratories, were used to calculate prevalence.Results: One hundred fifteen cases were identified equating to a period prevalence (range) of 1.5 (0.8-2.1) cases/million for children aged 0-18years. Clinical data were provided on 106 patients: the <2 year group comprised 66 children, median age (range) 0.50 years (0.01-1.92); the ≥2 year group comprised 40 children, median age 8.2 years (2.0-18.0). Management approach was heterogeneous. Overall, 79% of patients had a good clinical outcome. Mortality rate was 7% in the study population.Conclusion: chILD is rare in Australasia. This study demonstrates variation in the investigations and management of chILD cases across Australasia, however the general outcome is favorable. Further international collaboration will help finesse the understanding of these disorders. [ABSTRACT FROM AUTHOR]

Key Clinical Message Patients with personal or family history of congenital hypothyroidism, and/or neurological findings that also have chronic respiratory symptoms may have a mutation in the NKX2.1 gene as the unifying cause of their disease. Brain-lung-thyroid disease is the ensuing condition, which although rare, needs to be part of the differential diagnosis . [ABSTRACT FROM AUTHOR]

The objective of this study is to determine autoantibody profile in children with juvenile dermatomyositis (JDM). Children who were diagnosed with JDM (either recently diagnosed during the study period or follow-up patients) were included in the study. Autoantibodies were detected with commercially available Immunodot kit. Thirty patients were included in the study. Nine out of thirty patients (30%) were positive for one of the 12 autoantibodies tested. Anti-SRP antibody was most common antibody detected in 3 patients followed by anti-MDA-5 antibody in 2 patients; while anti-Jo1 antibody, anti-TIF1-γ antibody, anti-Mi-2 antibody, and anti-PM-Scl antibody were positive in 1 patient each. A different disease phenotype was observed with each autoantibody. The patient with anti-Jo1 antibody had a severe systemic disease in the form of interstitial lung disease; patients with anti-MDA-5 antibody and anti-Mi2 antibody had more severe skin disease with mild muscle disease and patients with anti-SRP antibody had significant skin and muscle disease. Anti-TIF1-γ and anti-PM-Scl antibodies were seen in patients with features of overlap syndrome (myositis-scleroderma). Estimation of autoantibodies may serve as an adjunct tool in delineating and defining distinct clinical phenotypes in children diagnosed with juvenile dermatomyositis. They may also help in prognostication. [ABSTRACT FROM AUTHOR]

Granulomatosis with polyangiitis is an ANCA-associated systemic vasculitis with a low incidence in the pediatric population. Lung involvement is a common manifestation in children affected by granulomatosis with polyangiitis, both at disease's onset and during flares. Its severity is variable, ranging from asymptomatic pulmonary lesions to dramatic life-threatening clinical presentations such as diffuse alveolar haemorrhage. Several radiologic findings have been described, but the most frequent abnormalities detected are nodular lesions and fixed infiltrates. Interstitial involvement, pleural disease and pulmonary embolism are less common. Histology may show necrotizing or granulomatous vasculitis of small arteries and veins of the lung, but since typical features may be patchy, the site for lung biopsy should be carefully chosen with the help of imaging techniques such as computed tomography. Bronchoalveolar lavage is helpful to confirm the diagnosis of alveolar haemorrhage. Pulmonary function tests are frequently altered, showing a reduction in the diffusion capacity for carbon monoxide, which can be associated with obstructive abnormalities related to airway stenosis. Nodular lung lesions tend to regress with immunosuppressive therapy, but lung disease may also require second line treatments such as plasmapheresis. In cases of massive diffuse alveolar haemorrhage, ventilator support is crucial in the management of the patient. [ABSTRACT FROM AUTHOR]

Key Clinical Message Patients with antisynthetase-positive interstitial lung disease ( ILD) alone sometimes develop myositis during follow-up, but myasthenia gravis ( MG) overlapping on antisynthetase syndrome is unusual. A 56-year-old woman with ILD and anti- EJ antibody treated for 8 years developed MG. Physicians should consider myositis and MG when patients develop muscle symptoms during follow-up. [ABSTRACT FROM AUTHOR]

Background: Childhood interstitial lung disease (chILD) is a heterogeneous group of rare disorders characterized by abnormal imaging findings, impaired gas exchange; and is associated with substantial morbidity and mortality. Neuroendocrine cell hyperplasia (NEHI) is a unique sub-group, which is more prevalent in infants and children younger than 2 years of age, and typically manifests with chronic tachypnea, retractions, hypoxemia and failure to thrive. NEHI insidiously appears in the first year of life, subtly masquerading as one of the more common lung diseases of childhood. Therefore, the diagnosis of NEHI is challenging and requires a systematic approach. Case presentation: We report a case of an infant, with a history of recurrent respiratory infections and wheezing, who presented with persistent hypoxemia (PaO2 88 mmHg) and chronic respiratory symptoms, that prompted an extensive diagnostic work up for chILD; eventually a diagnosis of NEHI was made. Conclusion: NEHI is a rare chILD disorder presenting in the first 2 years of life with common but challenging key clinical features. Increased awareness among pediatricians and prompt recognition of the clinical presentation may enable timely diagnosis and improve disease management and prognosis. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis ( LCH) is a rare disease, affecting subjects of any age, with extremely variable clinical manifestations. Although most patients with LCH have localized disease, requiring local or even no therapy, those patients with disseminated, 'multi-system' disease require specific therapy because they may be at risk for morbidity or even mortality. The current standard of care has developed empirically, based mainly on the experience of treating children with leukaemia and other haemo-proliferative disorders. At the time of writing, the combined use of vinblastine and prednisone remains the standard of care for children with multi-system LCH. The combination of cytarabine and cladribine is the current standard for second-line therapy of refractory cases with vital organ dysfunction. Recent advances in the knowledge of the pathogenesis of LCH may support a change in treatment strategy. Evidence of mutations that aberrantly activate RAF/ MEK/ ERK signalling in over two thirds of patients with LCH may direct a target therapy strategy. Vemurafenib, a small molecule widely used in the treatment of melanoma, is the main candidate for testing in prospective trials for patients with evidence of BRAFV600E mutation on lesional tissue. Additional molecules, including the recently approved trametinib, could follow. Identification of mutations in other genes in the remaining multisystem LCH cases could contribute to define a scenario in which target therapy becomes the main therapeutic choice in this intriguing disorder. However, because the long-term risks and benefits of these agents in children are unknown, and other effective treatments exist for many LCH patients, the optimal indications for administering a tyrosine kinase inhibitor to children is an open question. [ABSTRACT FROM AUTHOR]

Childhood Interstitial lung disease (chILD) is an umbrella term used to define a broad range of rare, diffuse pulmonary disorders with altered interstitial structure that leads to abnormal gas exchange. Presentation of chILD in infancy can be difficult to differentiate from other common causes of diffuse lung disease. This article aimed at paediatricians provides an overview of interstitial lung disease presenting in infancy and includes key clinical features, a suggested approach to investigation and a summary of management. An overview of three clinical cases has been included to demonstrate the diagnostic approach, characteristic investigation findings and varied clinical outcomes. [ABSTRACT FROM AUTHOR]

The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children's interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume. [ABSTRACT FROM AUTHOR]

Objectives: To report radiologic findings with histopathologic correlations of humidifier disinfectant-associated children's interstitial lung disease (HD-chILD) and to compare computed tomography (CT) findings between survivors and non-survivors.Methods: Forty-seven children with HD-chILD (27.4 ± 12.4 months old) were categorized as survivors (n = 25) and non-survivors (n = 22). The patterns, distributions, and chronological changes in lung lesions at follow-up CT were investigated. Histopathologic correlations were performed in 23 patients.Results: CT features were characterized by chronological changes, from consolidation to centrilobular opacities, and lesions eventually became faint centrilobular nodules. Histopathologic features were bronchocentric-distributed fibro-inflammatory lesions, which were more profound in the advanced stage than the early stage. Consolidation ≥ 30 % [hazard ratio (HR), 2.932], centrilobular opacities ≥ 60 % of the total lung volume (TLV; HR, 0.206) and spontaneous air leaks (HR, 3.457) were significant factors associated with patient survival, as per univariate analysis. Consolidation ≥ 30 % (HR, 3.519), centrilobular opacities ≥ 60 % (HR, 0.205) and diffuse ground glass opacity (GGO) ≥ 70 % of the TLV (HR, 3.521) were significant factors associated with patient survival, as determined via multivariate analysis.Conclusion: Distinctive chronological CT features were observed in the HD-chILD images. Spontaneous air leaks, consolidation, GGO, and centrilobular opacities were prognostic factors.Key Points: Chemical disinfectants can induce severe inhalation lung injury. Lung injury caused by inhaled disinfectants demonstrates chronologic changes in radiologic findings. Understanding of radiological characteristics is important to predict outcomes in chemical pneumonitis. Physicians should be aware of the potential risk of environmental chemicals. [ABSTRACT FROM AUTHOR]

Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children. [ABSTRACT FROM AUTHOR]

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Background: Lipids account for the majority of pulmonary surfactant, which is essential for normal breathing. We asked if interstitial lung diseases (ILD) in children may disrupt alveolar surfactant and give clues for disease categorization. Methods: Comprehensive lipidomics profiles of broncho-alveolar lavage fluid were generated in 115 children by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Two reference populations were compared to a broad range of children with ILD. Results: Class and species composition in healthy children did not differ from that in children with ILD related to diffuse developmental disorders, chronic tachypnoe of infancy, ILD related to lung vessels and the heart, and ILD related to reactive lymphoid lesions. As groups, ILDs related to the alveolar surfactant region, ILD related to unclear respiratory distress syndrome in the mature neonate, or in part ILD related to growth abnormalities reflecting deficient alveolarisation, had significant alterations of some surfactant specific phospholipids. Additionally, lipids derived from inflammatory processes were identified and differentiated. In children with ABCA3-deficiency from two ILD causing mutations saturated and monounsaturated phosphatidylcholine species with 30 and 32 carbons and almost all phosphatidylglycerol species were severely reduced. In other alveolar disorders lipidomic profiles may be of less diagnostic value, but nevertheless may substantiate lack of significant involvement of mechanisms related to surfactant lipid metabolism. Conclusions: Lipidomic profiling may identify specific forms of ILD in children with surfactant alterations and characterized the molecular species pattern likely to be transported by ABCA3 in vivo. [ABSTRACT FROM AUTHOR]

Background Rare chronic diseases of childhood are often complex and associated with multiple health issues. Such conditions present significant demands on health services, but the degree of these demands is seldom reported. This study details the utilisation of hospital services and associated costs in a single case of surfactant protein C deficiency, an example of childhood interstitial lung disease. Methods Hospital records and case notes for a single patient were reviewed. Costs associated with inpatient services were extracted from a paediatric hospital database. Actual costs were compared to cost estimates based on both disease/procedure-related cost averages for inpatient hospital episodes and a recently implemented Australian hospital funding algorithm (activity-based funding). Results To age 8 years and 10 months the child was a hospital inpatient for 443 days over 32 admissions. A total of 298 days were spent in paediatric intensive care. Investigations included 58 chest x-rays, 9 bronchoscopies, 10 lung function tests and 11 sleep studies. Comprehensive disease management failed to prevent respiratory decline and a lung transplant was required. Costs of inpatient care at three tertiary hospitals totalled $966,531 (Australian dollars). Disease- and procedure-related cost averages underestimated costs of paediatric inpatient services for this patient by 68%. An activity-based funding algorithm that is currently being adopted in Australia estimated the cost of hospital health service provision with more accuracy. Conclusions Health service usage and inpatient costs for this case of rare chronic childhood respiratory disease were substantial. This case study demonstrates that disease- and procedure-related cost averages are insufficient to estimate costs associated with rare chronic diseases that require complex management. This indicates that the health service use for similar episodes of hospital care is greater for children with rare diseases than other children. The impacts of rare chronic childhood diseases should be considered when planning resources for paediatric health services. [ABSTRACT FROM AUTHOR]

Aims Diffuse parenchymal lung diseases ( DPLD) in children comprise a wide spectrum of rare disorders. In 2007 the Children's Interstitial Lung Disease (ch ILD) Research Cooperative proposed a classification system for DPLD in children <2 years of age. The aims of our study were to determine the utility and reproducibility of this system in children <2 years of age, and test its extension to 18 years of age. Methods and results Of 211 cases, 93 were <2 years of age at presentation and 58% were included in the ch ILD classification. In 118 cases aged between 2 and 18 years there was a wider distribution of disorders, overlapping with those seen in adults, necessitating expansion of the ch ILD classification types to encompass all reviewed cases, in particular patients with 'adult' diffuse lung diseases. Many cases showed mixed histological patterns, overlap often being between groups of disorders more prevalent in infancy. Concordance between reporting pathologists was 90%. Conclusions The ch ILD scheme allows classification of conditions more common in children <2 years of age. It can be applied to children of any age, although additional entities need to be included. We propose a more histologically based system for use when assessing biopsies in this context. [ABSTRACT FROM AUTHOR]

Acquired lobar interstitial emphysema (ALIE), initially described in infants with bronchopulmonary dysplasia is now known to occur in other conditions such as a secondary post-traumatic or inflammatory injury as in patients requiring ventilatory support with chronic lung disease. The ALIE leads to progressive deterioration of lung function with massive distension and compression of lung parenchyma with consequent mediastinal shift in the course of chronic interstitial lung disease. This situation requires adequate clinical and radiological interpretation in order to make the proper patient selection i.e., between a candidate for lung biopsy for the benefit of a definitive diagnosis or one who in the course of a superimposed ALIE requires a diagnostic and therapeutic lobectomy. Two cases of this entity and descriptive decision-making diagnostic and surgical about pre-and intraoperative findings are presented. [ABSTRACT FROM AUTHOR]

A 13-year old girl presented with a decade long anemia, diffuse alveolar hemorrhage and interstistial lung disease; was eventually diagnosed as ANCA associated vasculitis. High index of suspicion is thus warranted for alternative diagnosis in chronic anemia, despite increased prevalence of infectious diseases and nutritional anemia. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical spectrum and factors associated with poor short-term outcomes in children with interstitial lung disease (ILD). Design: Retrospective chart review Setting: Pediatric Chest Clinic of a tertiary care hospital Methodology: We retrieved information regarding clinical course and laboratory features of all children diagnosed as ILD between January 1999 and February 2010. Disease severity was assessed using ILD score based on clinical features and SpO2 at the time of initial evaluation. Outcome was assessed after 3 months of initial diagnosis as improved or death/no improvement in symptoms. Results: 90 children (median age, 6.8 years; 62% boys) were diagnosed to have ILD during this period. 46 children were classified as having 'definite ILD' while 44 had 'possible ILD'. The commonest clinical features at presentation were cough (82.2%), dyspnea (80%), pallor (50%), and crackles (45.6%). 3 children (3.3%) died while 21 (23%) showed no improvement in clinical status on follow-up at 3 months. A higher ILD score (RR 3.72, 95% CI 1.4, 9.9) and lower alkaline phosphatase levels (median [IQR]: 205 [175.2] vs. 360 [245.7]; P=0.006) were found to be significantly associated with worse outcomes. Conclusion: The common clinical features of ILD in our study included breathlessness, cough and hypoxemia. A working diagnosis of ILD can be made with the help of imaging, bronchoscopy, or lung biopsy. A simple score based on clinical findings and pulse-oximetry might predict those children with poor short-term outcome. [ABSTRACT FROM AUTHOR]

Background. Diagnosis of interstitial lung disease (ILD) in children is challenging. Open lung biopsy was long considered to be the best procedure to obtain lung tissue in children. Thoracoscopic biopsy may be equally effective and less aggressive. In this report we analyze the results of the use of ultrasonic scalpel with the placement of three 5-mm trocars (one for thoracoscope and two working ports) for lung biopsy through thoracoscopy. Methods. We present a retrospective case series of children undergoing lung biopsy through thoracoscopy using three working ports and ultrasonic scalpel. The study was carried out from January 2011 to January 2012 in a third-level pediatric hospital. Results. A total of five patients aged 1 to 13 years were included. There were no complications in the five cases analyzed. The sample obtained was sufficient in all cases for histopathological study. During surgery, bleeding was reported on average of 4.3 ml (range: 0.5-10 ml). Operative time ranged from 2 to 3 h. Two cases required chest tube placement. These were removed 2 to 3 days after the surgical event, and patients were discharged without complications. Conclusions. Feasibility is confirmed of a technique for lung biopsy using an ultrasonic scalpel, which is easily reproducible in any hospital with the necessary resources to perform thoracoscopy. In this series there were no complications, bleeding was low and there was opportune placement of transpleural chest tube. [ABSTRACT FROM AUTHOR]

Summary: Interstitial lung diseases (ILDs) in children represent a heterogeneous group of respiratory disorders characterized by derangements of the alveolar walls. The key pathologic feature of ILDs is the altered repair of the alveolar surface after injury with a marked disruption in the integrity of the epithelium and, consequently, a dysregulated communication between epithelial and mesenchymal pulmonary components. Concomitant to the loss of cell-cell contact, epithelial cells undergo a process called epithelial to mesenchymal transition and acquire a mesenchymal identity. Among the factors involved in disease progression, transforming growth factor-β has been identified as a master switch in the induction of fibrosis. This article reviews recent advances in the understanding of the mechanisms involved in the pathogenesis of ILDs, and provides information on their adaptation in the context of lung growth. [Copyright &y& Elsevier]

During the past 10 years, descriptions of large registries of children with juvenile systemic sclerosis (jSSc) have improved our knowledge of this disease. jSSc differs from the adult disease in presentation as well as disease course. Two courses of disease have been described: a rapidly progressive and fatal illness with cardiac involvement; and, more commonly, a chronic course with less overall mortality. Subclinical disease, especially cardiac and pulmonary disease, should be specifically sought and appropriately monitored, particularly in the first years of disease. Use of screening pulmonary function tests and high-resolution CT increases the chance of detecting interstitial lung disease. Close attention needs to be paid to cardiac health, with improved understanding of the specific causes of death to aid in the development of preventive measures. Therapies that best balance risks and benefits are likely to differ between children and adults. Given the relative rarity of jSSc, pediatric trials will require multinational collaborative efforts. [ABSTRACT FROM AUTHOR]

The article presents the authors' insights on the histopathological processes and the effects of pulmonary interstitial glycogenesis (PIG), an infant lung disorder on concurrent disease processes. It discusses the ChILD Research Network study which revealed that PIG is not the driver of prognosis in infants with lung diseases. The author adds that a cooperative multidisciplinary effort among clinicians, radiologists, and pathologists can lead to better understanding the natural history of PIG.

STUDY OBJECTIVES: To present diagnosis and treatment modalities of children with interstitial lung disease associated with frequent or rare surfactant protein C gene (SFTPC) mutation. PATIENTS: Twenty-two children with chronic lung disease associated with SFTPC mutation in a heterozygous form. RESULTS: Mutations located in the BRICHOS domain (‘BRICHOS domain’ group) were identified in six children, whereas 16 children carried mutations located outside the BRICHOS domain (‘non-BRICHOS domain’ group). The median age of onset was 3 (0–24) months. Four patients had neonatal respiratory distress, and symptom onset was associated with acute bronchiolitis in nine patients. Cough, tachypnoea and failure to thrive were initially noticed in all the children. Physical examination at presentation revealed tachypnoea (n=22), clubbing (n=1) and crackles (n=5). Low oxygen saturation (<95%) was observed in 18 patients. The predominant findings on initial high-resolution CT (HRCT) scans were basal-predominant ground-glass opacity (n=21) and cystic spaces (n=3). Bronchoalveolar lavage fluid (BALF) cell counts showed 379±56x103cells/ml with increased neutrophil percentage (18±4%) independent of the mutation status. The median follow-up was 3.2 (1–18.3) years. Eighteen patients were treated by monthly methylprednisolone pulses associated with oral prednisolone (n=16), hydroxychloroquine (n=11) and/or azithromycin (n=4). Fifteen patients benefited from enteral nutrition. CONCLUSION: Initial diagnosis is based on clinical presentation, radiological features and BALF analysis, but the definitive diagnosis requires genetic analysis. Although progressive improvement was seen in most patients, the development of new therapeutic strategies with minimal side effects is needed. [ABSTRACT FROM AUTHOR]

Juvenile-onset amyopathic dermatomyositis is an uncommon variant of juvenile-onset dermatomyositis (JDM), characterized by the hallmark cutaneous features of dermatomyositis for at least 6 months without clinical or laboratory evidence of muscle disease. Cutaneous calcinosis, vasculopathy, and interstitial lung disease frequently complicate the course of classic JDM (typical JDM with myositis) but are infrequent in amyopathic JDM. Recent literature suggests that approximately 75% of amyopathic JDM patients will remain free from muscle disease after years of follow-up, while approximately 25% of patients will evolve to having classic JDM.Noclinical, laboratory, or ancillary parameters have been found to be predictive for this transition to muscle disease. Treatment of the cutaneous disease of amyopathicJDMcenters on photoprotection and topical therapies directed against inflammation. Oral antimalarials are effective for cutaneous disease not adequately controlled with topical care. Systemic corticosteroids, while central to the treatment of classic JDM, are controversial in the treatment of amyopathic JDM. Randomized controlled trials are not available to guide the management of this disease. Proponents for early aggressive systemic corticosteroid therapy for amyopathic JDM advocate that this intervention may decrease the likelihood of progression to classic JDM, and/or prevent disease-specific complications of JDM such as calcinosis. Opponents of early intervention with systemic corticosteroids favor expectant management directed toward controlling skin disease, citing the predictable adverse effects of systemic corticosteroids in the face of uncertain benefit. Other therapeutic options for severe and recalcitrant cutaneous disease, including methotrexate, intravenous immunoglobulin, and rituximab, are reviewed, as are treatment options for calcinosis cutis. Inweighing the available evidence, the authors conclude that early aggressive treatment of amyopathic JDMwith systemic immunosuppressant agents should be avoided in most cases as the risk of these medications will outweigh the measurable benefit. The reported literature suggests a good prognosis for amyopathic JDM. Ongoing clinical follow-up is recommended in all cases to allow early detection of subtle signs of muscle disease. [ABSTRACT FROM AUTHOR]

The article describes the case of a five-year-old child diagnosed with Langerhans' cell histiocytosis (LCH) with pulmonary involvement. Topics covered include miliary mottling of the patient as revealed by a chest radiograph, chemotherapy administered to the patient following the LCH diagnosis and the importance for clinicians to search for an alternative diagnosis if there is no response to tuberculosis treatment in patients with miliary shadowing in the lungs.

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The article discusses the use of high-resolution computer tomography (HRCT) in assessing pediatric diffuse interstitial lung disease (DILD). It is stated that HRCT is a non-invasive tool used to gain information on the pattern and anatomical distribution of lung pathology and is useful in targeting sites for lung biopsy. It cites that the HRCT findings, which include septal thickening, nodules and air cysts, are generally not pathognomonic. It also mentions the HRCT findings of pediatric DILG.

The ATP-binding cassette transporter ABCA3 mediates uptake of choline-phospholipids into intracellular vesicles and is essential for surfactant metabolism in lung alveolar type II cells. We have shown previously that ABCA3 mutations in fatal surfactant deficiency impair intracellular localization or ATP hydrolysis of ABCA3 protein. However, the mechanisms underlying the less severe phenotype of patients with ABCA3 mutation are unclear. In this study, we characterized ABCA3 mutant proteins identified in pediatric interstitial lung disease (pILD). E292V (intracellular loop 1), E690K (adjacent to Walker B motif in nucleotide binding domain 1), and T1114M (8th putative transmembrane segment) mutant proteins are localized mainly in intracellular vesicle membranes as wild-type protein. Lipid analysis and sucrose gradient fractionation revealed that the transport function of E292V mutant protein is moderately preserved, whereas those of E690K and T1114M mutant proteins are severely impaired. Vanadate-induced nucleotide trapping and photoaffinity labeling of wild-type and mutant proteins using 8-azido[32P]ATP revealed an aberrant catalytic cycle in these mutant proteins. These results demonstrate the importance of a functional catalytic cycle in lipid transport of ABCA3 and suggest a pathophysiological mechanism of pILD due to ABCA3 mutation. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILD) is a heterogenous group of disorders defined by histological alterations in alveolar structures. ILD is a rare group of conditions in children, with a prevalence estimated at 0,36/100.000. ILD in children can be divided into three groups: ILD with known cause, ILD from systemic disorders and ILD with unknown causes. Some formes are encountered unique in children, many of them with hereditary forms and familial clustering. The classic concept regarding the development of ILD combines an individual/genetic predisposition with an initiating agent. Recently the paradigm has shifted away from inflammation to one of tissue injury with aberrant wound healing resulting in collagenous fibrosis. The median age at onset is 8 month. Physical examination may reveal tachypnea, cyanosis, dry cough, retractions, clubbing, fever, wheezing, chest pain, weight loss, signs of pulmonary hypertension and so on. Auscultation may be normal or reveal dry crackles. ILD should be suspected when respiratory symptoms, diffuse infiltrates on the chest radiograph and/or restrictive ventilatory abnormalities with impaired gas exchange persist for more than three month. Chest radiography may be normal in active disease, but typically there are five possible abnormal patterns: ground glass, reticular, nodular, reticulonodular and honeycomb. HRCT has become an integral part of the evaluation of the patient with ILD. Pulmonary function testing are consistent with restrictive physiology. Lung biopsy may become necessary in some cases, but when the HRCT and clinical picture are typical, biopsy is not recommended. The diagnostic begins with history, physical examination, chest radiograph, and lung function tests. On the basis of this information, the patients may be divided into two groups: cases with known causes, and cases that do represent idiopathic ILD. For the "chronic pneumonitis" of unknown cause prednisolone and an antifibrogenic drug like is hidroxycloroquine (Plaquenil) are the treatment of choice. In children, mortality for all types of chronic ILD is 11% and for ILD of unknown origin is 43%. [ABSTRACT FROM AUTHOR]

The article discusses the medical case of a 3-year-old girl with juvenile dermatomyositis (JDM) related interstitial lung disease(ILD). Details related to her diagnosis and the medications she has undergone are mentioned. It was found that extracorporeal membrane oxygenation is effective in treating severe JDM-related ILD.

The article reports on the prevalence of interstitial lung disease (ILD) among children. It is noted that ILD is a spectrum of diseases including various rare lung conditions. In this study, eight children with a common father were assessed for evidence of lung disease in relation with rheumatologic findings. It was found out that ILD and autoimmunity in a kindred of children suggest a novel genetic disorder of autosomal dominant pattern and variable penetrance.

This review summarizes important original articles in the field of pediatric lung transplantation that were published in 2005. The review is intended to be comprehensive, but not exhaustive. [ABSTRACT FROM AUTHOR]

Pulmonary interstitial emphysema (PIE) contributes to worsening respiratory status in already compromised premature infants. Various treatments for PIE include high-frequency ventilation, postural therapy, pneumonectomy or lobectomy and selective bronchial intubation. While right main stem bronchus intubation is easy to perform at the bedside for treatment of PIE in the left lung, left main stem bronchus intubation for the treatment of right-sided PIE remains challenging and the technique was rarely reported and poorly described. In this case report, we revisit this procedure and describe successful treatment of right lung PIE with hyperinflation by selective left main stem intubation at 2 weeks of life in a 24-week-old premature infant who had respiratory distress syndrome and pulmonary hemorrhage. A detailed description is given to allow clinical bedside replication following specific anatomic landmarks. [ABSTRACT FROM AUTHOR]

Here we report two patients with severe juvenile dermatomyositis (JDM) complicated with extra musculocutaneous involvement. The first case (a 10-year-old boy) had unusual initial presentation of JDM complicated with interstitial lung disease documented with high-resolution computed tomography. He had a rapidly progressive course and died in 7 weeks after the onset of the disease despite steroid and immunosuppressive treatment. The second case (a 14-year-old boy) was presented with myositis complicated with hepatitis. He also had a chronic course of JDM with unfavorable outcome. It appears that the prognosis of patients with severe JDM is related with the degree of autoimmune vasculitis on extra musculocutaneous involvement. [ABSTRACT FROM AUTHOR]

Background: Children with chronic infectious interstitial lung disease often have to undergo open lung biopsy to establish a final diagnosis. Open lung biopsy is an invasive procedure with major potential complications. Transthoracic lung biopsy (TLB) guided by computed tomography (CT) is a less-invasive well-established procedure in adults.Objective: Detailing the role of low-dose CT-guided TLB in the enhanced diagnosis of chronic lung diseases related to infection in children.Materials and Methods: A group of 11 children (age 8 months to 16 years) underwent CT-guided TLB with a 20-gauge biopsy device. All investigations were done under general anaesthesia on a multidetector CT scanner (SOMATOM Volume Zoom, Siemens, Erlangen, Germany) using a low-dose protocol (single slices, 120 kV, 20 mAs). Specimens were processed by histopathological, bacteriological, and virological techniques.Results: All biopsies were performed without major complications; one child developed a small pneumothorax that resolved spontaneously. A diagnosis could be obtained in 10 of the 11 patients. Biopsy specimens revealed chronic interstitial alveolitis in ten patients. In five patients Chlamydia pneumoniae PCR was positive, in three Mycoplasma pneumoniae PCR was positive, and in two Cytomegalovirus PCR was positive. The average effective dose was 0.83 mSv.Conclusion: Low-dose CT-guided TLB can be a helpful tool in investigating chronic infectious inflammatory processes in children with minimal radiation exposure. It should be considered prior to any open surgical procedure performed for biopsy alone. In our patient group no significant complication occurred. A disadvantage of the method is that it does not allow smaller airways and vessels to be assessed. [ABSTRACT FROM AUTHOR]

Aims: Interstitial pneumonitis in children is very rare and most cases have been classified according to their counterparts in adults, although the term ‘chronic pneumonitis of infancy’ has recently been proposed for a particular pattern of interstitial lung disease in infants. We reviewed our paediatric cases of interstitial pneumonitis, first, to look at the spectrum of histological patterns found in this age group and, second, to determine whether the classification of such cases in childhood is both appropriate and worthwhile. Methods and results Twenty-five of 38 open lung biopsies showed an overlapping spectrum of interstitial pneumonitis, including three cases that fulfilled the histological criteria for chronic pneumonitis of infancy. There were 11 cases of reactive pulmonary lymphoid hyperplasia (either lymphoid interstitial pneumonitis or follicular bronchiolitis), five of which were associated with abnormalities of the immune system. Four cases were classified as desquamative interstitial pneumonitis and the remaining seven cases were classified as non-specific interstitial pneumonitis. There were no cases with the histological features of usual interstitial pneumonitis. Most patients responded to steroids but tended to have a residual deficit in lung function. Mortality appeared to be associated with presentation at a young age. Conclusion Classification of interstitial pneumonitis according to their adult counterparts is appropriate for this younger age group and can provide valuable information for the clinician. The term ‘chronic pneumonitis of infancy’ refers to a specific histological pattern, but whether it represents a separate disease or a reflection of pulmonary immaturity remains to be proven. [ABSTRACT FROM AUTHOR]

Evaluates the value of a systematic approach to the diagnosis of pediatric interstitial lung disease (ILD). Median age of onset of symptoms; Adequacy of non-invasive tests (NITs) for specific diagnosis; Suggestive diagnosis with invasive testing.

Paediatric interstitial lung disease (ILD) is rare and diverse, meaning no single centre will see sufficient children to perform the studies needed to make progress. This EU FP-7 grant will standardise the evaluation of these rare conditions by establishing pan- European multidisciplinary expert panels and establish consensus on treatment protocols and standard operating procedures across Europe. We will work with patient groups to determine optimal treatment endpoints and biomarkers. A biobank will be established as a Europe-wide resource for mechanistic studies. Ultimately we aim to do the first randomised controlled trial of a pharmacological treatment in paediatric ILD. [ABSTRACT FROM AUTHOR]

A retrospective review of 529 fiberoptic bronchoscopies was done with an aim to identify conditions where it will be most useful. The common indications were persistent/ recurrent pneumonia, persistent collapse, stridor and pulmonary hemorrhage. The diagnostic yield was maximum when it was performed to identify structural abnormalities and the yield was relatively poor in suspected drug resistant tuberculosis, and interstitial lung diseases. Serious complications were seen in children with pulmonary arterial hypertension. Fiberoptic bronchoscopy is an important tool for management of respiratory problems but should be performed with caution in children with pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

The article discusses developments in imaging childhood interstitial lung disease (chILD). The identification of surfactant protein abnormalities is a good example of knowledge changing the evaluation of chILD. Understanding of chILD has been limited due to reluctance to obtain lung biopsies in children. The primary imaging modality for chILD is computed tomography (CT) scanning. The article also discusses the classification scheme of chILD and the roles of imaging in chILD.