Interstitial Lung Disease In Children Research Articles

Contemporary and emerging technologies for research in children's rare and interstitial lung disease.

Although recent decades have seen the identification, classification and discovery of the genetic basis of many children's interstitial and rare lung disease (chILD) disorders, detailed understanding of pathogenesis and specific therapies are still lacking for most of them. Fortunately, a revolution of technological advancements has created new opportunities to address these critical knowledge gaps. High-throughput sequencing has facilitated analysis of transcription of thousands of genes in thousands of single cells, creating tremendous breakthroughs in understanding normal and diseased cellular biology. Spatial techniques allow analysis of transcriptomes and proteomes at the subcellular level in the context of tissue architecture, in many cases even in formalin-fixed, paraffin-embedded specimens. Gene editing techniques allow creation of "humanized" animal models in a shorter time frame, for improved knowledge and preclinical therapeutic testing. Regenerative medicine approaches and bioengineering advancements facilitate the creation of patient-derived induced pluripotent stem cells and their differentiation into tissue-specific cell types which can be studied in multicellular "organoids" or "organ-on-a-chip" approaches. These technologies, singly and in combination, are already being applied to gain new biological insights into chILD disorders. The time is ripe to systematically apply these technologies to chILD, together with sophisticated data science approaches, to improve both biological understanding and disease-specific therapy.

ABCA3 Deficiency-Variant-Specific Response to Hydroxychloroquine.

Biallelic variants in ABCA3, the gene encoding the lipid transporter ATP-binding cassette subfamily A member 3 (ABCA3) that is predominantly expressed in alveolar type II cells, may cause interstitial lung diseases in children (chILD) and adults. Currently, there is no proven therapy, but, frequently, hydroxychloroquine (HCQ) is used empirically. We hypothesized that the in vitro responsiveness to HCQ might correlate to patients' clinical outcomes from receiving HCQ therapy. The clinical data of the subjects with chILD due to ABCA3 deficiency and treated with HCQ were retrieved from the literature and the Kids Lung Register data base. The in vitro experiments were conducted on wild type (WT) and 16 mutant ABCA3-HA-transfected A549 cells. The responses of the functional read out were assessed as the extent of deviation from the untreated WT. With HCQ treatment, 19 patients had improved or unchanged respiratory conditions, and 20 had respiratory deteriorations, 5 of whom transiently improved then deteriorated. The in vitro ABCA3 functional assays identified two variants with complete response, five with partial response, and nine with no response to HCQ. The variant-specific HCQ effects in vivo closely correlated to the in vitro data. An ABCA3+ vesicle volume above 60% of the WT volume was linked to responsiveness to HCQ; the HCQ treatment response was concentration dependent and differed for variants in vitro. We generated evidence for an ABCA3 variant-dependent impact of the HCQ in vitro. This may also apply for HCQ treatment in vivo, as supported by the retrospective and uncontrolled data from the treatment of chILD due to ABCA3 deficiency.

Is it time to end race and ethnicity adjustment for pediatric pulmonary function tests?

The continued inclusion of race in spirometry reference equations is a topic of intense debate for adult lung function, but less discussion has focused on implications for children. Obtaining accurate estimates of children's lung function is an important component of the diagnosis of childhood respiratory illnesses, including asthma, cystic fibrosis, and interstitial lung disease. Given the higher burden among racial/ethnic minorities for many respiratory illnesses, it is critical to avoid racial bias in interpreting lung function. We recommend against the continued use of race-specific reference equations for a number of reasons. The original reference populations used to develop the equations were comprised of children with restricted racial diversity, relatively small sample sizes, and likely included some unhealthy children. Moreover, there is no scientific justification for innate racial differences in lung function, as there is no clear physiological or genetic explanation for the disparities. Alternatively, many environmental factors harm lung development, including allergens from pests, asbestos, lead, prenatal smoking, and air pollution, as well as preterm birth and childhood respiratory illnesses, which are all more common among minority racial groups. Race-neutral equations may provide a temporary solution, but still rely on the racial diversity of the reference populations used to build them. Ultimately researchers must uncover the underlying factors truly driving racial differences in lung function.

Lung biopsy in infants with severe bronchopulmonary dysplasia.

Lung biopsy is infrequently performed in the population of infants with severe bronchopulmonary dysplasia (BPD). Yet, its presentation may overlap with other infant diffuse lung diseases, including those within the spectrum of childhood interstitial lung diseases (chILD). Lung biopsy might differentiate between these entities or identify those with an extremely poor prognosis. Both might alter the clinical management of some infants diagnosed with BPD. In this tertiary referral center, we drew on a retrospective cohort of 308 preterm infants with severe BPD. Of these, nine underwent lung biopsy between 2012 and 2017. We aimed to assess the indication for lung biopsy, the prior clinical history, safety of the procedure, and describe the biopsy findings. Finally, we considered management decisions in relation to the biopsy results in these patients. All nine infants undergoing biopsy survived the procedure. The mean gestational age and birth weight of the nine patients were 30 ± 3 (range 27-34) weeks and 1421 ± 571 (range 611-2140) grams. All infants received serial echocardiograms to assess pulmonary hypertension, genetic testing, and computed tomography angiography (CTA) before biopsy. In all nine patients moderate to severe alveolar simplification was present and eight had some degree of pulmonary interstitial glycogenosis (PIG) ranging from focal to diffuse. Following biopsy, two infants with PIG received high dose systemic steroids and two separate infants had care redirected. In our cohort, lung biopsy was safe and well tolerated. Findings from lung biopsy may aid decision making in selected patients as a part of a step-wise diagnostic algorithm.

Current situation and prospect of transbronchial cryobiopsy in the precise diagnosis of children's interstitial lung disease

儿童间质性肺疾病（ILD）病因复杂、种类繁多，其诊断包括完整的病史采集、症状、体征、无创和有创检查，其中肺活检是诊断儿童ILD的金标准，也是分类和分型的依据。病理学确诊需要获得足够量的组织标本，因此其诊断仍面临极大挑战。经支气管冷冻肺活检（TBCB）因具有取材量大、标本质量高、病理诊断效能高和创伤小等诸多优势，新近被应用于儿童ILD的精准诊断中，后者对于指导治疗决策和预后非常重要。本文就TBCB在儿童ILD中的临床应用现状作一综述，旨在提高儿科医师对儿童ILD的诊疗水平以及对TBCB临床价值的认识，并为推广TBCB在儿童呼吸系统疾病中的应用奠定基础。.

Learning to make a difference for chILD: Value creation through network collaboration and team science.

Addressing the recognized challenges and inequalities in providing high quality healthcare for rare diseases such as children's interstitial lung disease (chILD) requires collaboration across institutional, geographical, discipline, and system boundaries. The Children's Interstitial Lung Disease Respiratory Network of Australia and New Zealand (chILDRANZ) is an example of a clinical network that brings together multidisciplinary health professionals for collaboration, peer learning, and advocacy with the goal of improving the diagnosis and management of this group of rare and ultra-rare conditions. This narrative review explores the multifaceted benefits arising from social learning spaces within rare disease clinical networks by applying the value creation framework. The operation of the chILDRANZ network is used as an example across the framework to highlight how value is generated, realized, and transferred within such collaborative clinical and research networks. The community of practice formed in the chILDRANZ multidisciplinary meetings provides a strong example of social learning that engages with the uncertainty inherent in rare disease diagnosis and management and pays attention to generate new knowledge and best practice to make a difference for children and families living with chILD. This review underscores international calls for further investment in, and support of, collaborative clinical networks and virtual centers of excellence for rare disease.

Diffuse alveolar haemorrhage in children: an international multicentre study

Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome. 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. 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. 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

BackgroundThe 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...

РЕЗУЛЬТАТЫ КАТАМНЕСТИЧЕСКОГО НАБЛЮДЕНИЯ И ОСОБЕННОСТИ ТЕЧЕНИЯ COVID-19 У ПАЦИЕНТОВ С НЕЙРОЭНДОКРИННОЙ КЛЕТОЧНОЙ ГИПЕРПЛАЗИЕЙ МЛАДЕНЦЕВ

Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare interstitial lung disease in children. The clinical features of the disease are characterized by tachypnea, moist rales/crepitus, retraction of compliant chest areas and delayed weight gain. The disease is diagnosed using the NEHI clinical scale coupled with the computed tomography of the chest organs. The clinical manifestations of NEHI regress as the child grows, but may persist up to the age of 10 y/o. The purpose of the research was to characterize the course of NEHI including the features of COVID-19 and the impact of passive smoking in children below the age of 8 y/o. Materials and methods: a single-center longitudinal study with follow-up observation of 29 patients with NEHI in January 2012 - December 2022 aged 8 months to 8 years old, 21 of which had COVID-19. Results: 20 of 29 patients with a known follow-up have undergone the long-term oxygen therapy (LTOT) at home lasting from 2 weeks up to 5.5 years (Me 1 year and 2 months; IQR 6 months - 4.5 years). Bronchial asthma was diagnosed in 2. 8 (28%) were diagnosed with atopic dermatitis, 6 (21%) with mental retardation, 3 (10%) with acute urticaria, and 2 (7%) with allergic rhinitis. Gastroesophageal reflux disease (GERD) was diagnosed in 7, all requiring LTOT. The frequency of episodes of respiratory infection was maximum in the first 2 years of life, amounting to 16 episodes per 2 years (Me 7; IQR 4 to 10), and the maximum frequency of hospitalizations during this age period was 5 (Me 2; IQR 1 to 2). Children-passive smokers were diagnosed with malnutrition more often (75%, p=0.449) and required LTOT more often (75%, p=0.694), were more often hospitalized (42%, p=0.422). Despite the possible need for LTOT patients with NEHI had COVID-19 in the form of nasopharyngitis in the majority of cases (89%). Only 8 out of 14 patients had symptoms of NEHI after 5 years of age, and only 1 out of 5 after 7 years. Malnutrition (body mass index for the age<-2) in the first year of life was diagnosed in 13 (45%) children. Malnutrition persisted in 9 out of 24 (37%) by the second year of life, in 5 out of 19 (26%) by the third year, and in 2 out of 14 (14%) by the fourth year of life. Not a single child died. Conclusion: the course of NEHI is characterized by the absence of lethal outcomes, frequent respiratory infections that led to hospitalizations in the first 2 years of life, mild course of COVID-19, regression of clinical symptoms and malnutrition as the child grows, comorbidity with atopic diseases and GERD. The priority should be given to the prevention of passive smoking in children with NEHI.

A 10-month-old infant with respiratory distress and hypoxemia

A 10-month-old infant with Prader-Willi Syndrome presented with a 7 month history of increased work of breathing, wheeze, inspiratory crepitations, and mild hypoxemia. Subsequent investigations including chest CT suggested the diagnosis to be neuroendocrine cell hyperplasia of infancy (NEHI). NEHI is a rare cause of children’s interstitial lung disease. Childhood interstitial lung disease should be considered in an infant with persistent tachypnea, crepitations, and hypoxemia.

Childhood Interstitial Lung Disease.

Childhood interstitial lung disease (chILD) is a heterogeneous group of diseases with various clinical and imaging findings. The incidence and prevalence have increased in recent years, probably due to better comprehension of these rare diseases and increased awareness among physicians. chILDs present with nonspecific pulmonary symptoms, such as tachypnea, hypoxemia, cough, rales, and failure to thrive. Unnecessary invasive procedures can be avoided if specific mutations are detected through genetic examinations or if typical imaging patterns are recognized on computed tomography. Disease knowledge and targeted therapies are improving through international collaboration. Pulmonary involvement in systemic diseases is not uncommon. Pulmonary involvement may be the first finding in connective tissue diseases. This review aims to present a systematic patient-targeted approach to the diagnosis of chILD.

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

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. 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." 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. 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.

Minimal important difference in childhood interstitial lung diseases

BackgroundMonitoring 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...

Pediatric pulmonology 2021 year in review: Rare and diffuse lung disease.

The field of rare and diffuse pediatric lung disease is experiencing rapid progress as diagnostic and therapeutic options continue to expand. In this annual review, we discuss manuscripts published in Pediatric Pulmonology in 2021 in (1) children's interstitial and diffuse lung disease, (2) congenital airway and lung malformations, and (3) noncystic fibrosis bronchiectasis including primary ciliary dyskinesia. These include case reports, descriptive cohorts, trials of therapies, animal model studies, and review articles. The results are put into the context of other literature in the field. Each furthers the field in important ways, while also highlighting the continued need for further studies.

Interstitial Lung Disease in Children: "Specific Conditions of Undefined Etiology" Becoming Clearer.

Children's interstitial lung disease (chILD) is a rare group of pediatric lung diseases affecting the lung interstitium diffusely. In this work, we focused our attention on a specific infant group of chILD, also known as "specific conditions of undefined aetiology", including pulmonary interstitial glycogenosis (PIG) and neuroendocrine cell hyperplasia of infancy (NEHI). PubMed was searched to conduct this narrative review. We searched for articles in English using the following keywords: (1) neuroendocrine cell hyperplasia of infancy; (2) NEHI; (3) pulmonary interstitial glycogenosis; (4) PIG; (5) chILD. An increasing interest and insight into these two conditions have been reported. The updated literature suggests that it is possible to look at these disorders as a continuum of diseases, rather than two different entities, since they share a pulmonary dysmaturity. NEHI and PIG are featured by dysmaturity of airway development and consequent respiratory distress. Understanding the underlying pathogenic mechanisms would lead to identifying new targeted therapies to ameliorate the mortality and morbidity of these rare conditions.

The Challenging Diagnosis of Interstitial Lung Disease in Children-One Case Report and Literature Review.

Childhood interstitial lung disease (chILD) includes a heterogeneous spectrum of rare respiratory disorders in children associated with substantial morbi-mortality. Interstitial tissue, and other pulmonary structures, epithelium, blood vessels, or pleura are involved, resulting in a restrictive lung disfunction. Respiratory symptoms set in progressively and are often subtle, making thorough clinical history and physical examination fundamental. The etiology often is obscure. The clinical presentation mimics pneumonia or asthma, leading to a diagnostic delay. Challenging diagnosis may require genetic tests, bronchoalveolar lavage, or lung biopsy. Alongside general supportive therapeutic measures, anti-inflammatory, immunosuppressive or antifibrotic agents may be used, based on data derived from adult studies. However, if accurate diagnosis and treatment are delayed, irreversible chronic respiratory failure may ensue, impacting prognosis. The most frequent chILD is hypersensitivity pneumonitis (HP), although it is rare in children. HP is associated with exposure to an environmental antigen, resulting in inflammation of the airways. Detailed antigen exposure history and identification of the inciting trigger are the cornerstones of diagnostic. This article provides the current state of chILD, revealing specific features of HP, based on a clinical case report of a patient admitted in our clinic, requiring extensive investigations for diagnosis, with a favorable long-term outcome.

Интерстициальные заболевания легких у детей в Астраханской области

Интерстициальные заболевания легких у детей в Астраханской области

Childhood interstitial lung disease: The end of a diagnostic odyssey

Dear Editor, Childhood interstitial lung disease is a heterogeneous group of rare disorders featuring pulmonary interstitial remodelling and diffuse parenchymal infiltrates on imaging.1 Incidence is estimated at 0.13–16.2 cases/100,000 children per year.1 ABCA3 (ATP-Binding Cassette, Subfamily A, Member 3) (OMIM #601615) is expressed in alveolar type II cells involved in pulmonary surfactant production,2 thus attributed

Characteristics of gastroesophageal reflux disease in children with interstitial lung disease.

Childhood interstitial lung disease (chILD) is a rare group of respiratory tract disorders. One of the factors suggested to be associated with its etiopathogenesis is microaspiration related to gastroesophageal reflux disease (GERD). The aim of the present study was to determine the frequency and characteristics of GERD in children with chILD, with a particular focus on proximal GER episodes. This was a prospective cross-sectional study. Consecutive patients with chILD underwent 24-h multichannel intraluminal pH-impedance monitoring. Different types of gastroesophageal reflux episodes (GER) were recorded and compared with regard to the GERD diagnosis. Sixty-two children (median age of 1.22 years) were included. GERD was diagnosed in 20 (32.3%) of them. The GERD (+) and GERD (-) subgroups differed mainly in their esophageal exposure to acid content (2.9 vs. 1.0%, p = 0.02) and bolus exposure (3.0 vs. 1.4%, p < 0.0001), as well as total number of GER (72.5 vs. 42.0 p = 0.0004), acid GER (35.5 vs. 15.0 p = 0.004), and acid proximal GER (21.0 vs. 12.0 p = 0.02). There were no differences in the number of proximal GER comparing GERD (+) and GERD (-) subgroups. The frequency of GERD seems to be relatively high in the population of children with chILD used in this study. However, it has not demonstrated an association between proximal GER and GERD diagnosis in chILD, which casts uncertainty over the microaspiration theory proposed to link the two diseases. The latter conclusion, however, needs to be confirmed using more accurate aspiration assessment methods.