Genetic Causes and Clinical Features of Childhood Interstitial Lung Diseases in China

Study Overview
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Brief Summary
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Recruitment of a carefully characterized cohort of chILD patients, to generate a database and biobank via collecting data on chILD in China. Importantly, compatibility with ongoing United States and Europe chILD data base developments will be factored in.

Detailed Description
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Children Interstitial lung disease (chILD) is a heterogeneous group of rare respiratory disorders of known and unknown etiologies that are mostly chronic and associated with high morbidity and mortality. ILD are characterized by inflammatory and fibrotic changes of the lung parenchyma structure that typically result in the presence of diffuse infiltrates on lung imaging, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect and/or impaired gas exchange. Genetic factors are important contributors to chILD. Genetic variations have been mainly described in genes encoding (or interacting with) the surfactant proteins (SP): SP-C (SFTPC) and the ATP-binding cassette-family A-member 3 (ABCA3) (ABCA3), and less frequently in the genes encoding NKX homeobox 2 (NKX2)-1 (NKX2-1), SP-B (SFTPB), SP-A (SFTPA) ,MARS and other genes. To investigate genetic defects and clinical features of chILD in China, wide recruitment and interdisciplinary critical peer review of all diagnoses from discharge diagnosis coding system of Children's Hospital of Fudan University will be included. Each case will be given a diagnosis independently; if no firm diagnosis is possible, the investigators will review the case periodically as new information becomes available. During the first year of the study, clinicians´ decisions according to clinical practice and outcomes will be independently monitored and assessed. The investigators will systematically optimize and clarify the relative weight of a large spectrum of single and composite clinical outcomes, sequential limited chest CT (to minimise radiation exposure), lung function testing, histopathological categorization of lung biopsies, serum markers and genetic tests. Variability, reproducibility and the effects of training on reading images will be investigated. This project will analyse in detail treatment and outcomes within and between subjects using data collected. Analysis of the collected data will support the definition of trial protocols planned in the future.

Official Title
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Genetic Causes and Clinical Features of Childhood Interstitial Lung Diseases in China

Conditions
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Interstitial Lung Diseases of Childhood, Genetic Testing

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The chILD syndrome exists when a child with DLD has had the common causes of DLD excluded as the primary diagnosis and has at least three of the following four criteria: (1) respiratory symptoms (e.g., cough, rapid and/or difficult breathing, or exercise intolerance);(2) respiratory signs (e.g., resting tachypnea, adventitious sounds, retractions, digital clubbing, failure to thrive, or respiratory fail- ure); (3) hypoxemia; and (4) diffuse abnormalities on CXR or a CT scan. Exclusion Criteria: These include cystic fibrosis, congenital or acquired immunodeficiency, congenital heart disease, bronchopulmonary dysplasia, pulmonary infection, primary ciliary dyskinesia presenting with newborn respiratory distress and recurrent aspiration.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| chILD<br>The chILD syndrome exists when a child with DLD has had the common causes of DLD excluded as the primary diagnosis and has at least three of the following four criteria: (1) respiratory symptoms (e.g., cough, rapid and/or difficult breathing, or exercise intolerance); (2) respiratory signs (e.g., resting tachypnea, adventitious sounds, retractions, digital clubbing, failure to thrive, or respiratory fail- ure); (3) hypoxemia; and (4) diffuse abnormalities on CXR or a CT scan. | Other: No intervention<br>* It's an observational study, so no intervention will be carried out.<br>|
| Control<br>Healthy subjects were recruited from participants of an ongoing prospective birth cohort study: 'The Pulmonary Function Assessment for Bronchopulmonary Dysplasia (BPD) and Recurrent Lower Respiratory Tract Infections (LRTI) in Chinese Children'. Exclusion criteria were major birth defects, upper airway pathology, cardiac or neurological diseases, failure to thrive, a history of severe respiratory disease with intensive care unit admission, previous physician-diagnosed LRTI, gestational age (GA) <37 weeks or birthweight (BW) <2.5 kg. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosed with specific cause for chILD | (yes/no) Specific causes for chILD based on the 2013 Official American Thoracic Society Clinical Practice Guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Having pathogenic gene mutations | (yes/no) Genetic variations have been mainly described in genes encoding (or interacting with) the surfactant proteins (SP): SP-C (SFTPC) and the ATP-binding cassette-family A-member 3 (ABCA3) (ABCA3), and less frequently in the genes encoding NKX homeobox 2 (NKX2)-1 (NKX2-1), SP-B (SFTPB), SP-A (SFTPA) ,MARS and other genes. | 6 years | 
| Hypoxemia | (yes/no) Change of PO2 in arterial blood gases from baseline when diagnosed with chILD | 6 years | 
| Deterioration of pulmonary imaging | (yes/no) Change of clinical judgment on pulmonary imaging from baseline if X-ray or CT were done | 6 years | 
| Change from baseline in lung function on the spirometry forced expiratory | Volume at one second (FEV1) in Liter | 6 years | 
| Abnormal autoantibody at baseline when diagnosed with chILD | (yes/ no) | 6 years | 
| Pathological change of lung biopsy | (yes/no) Clinical judgment on histopathological categorization of lung biopsy when diagnosed with chILD | 6 years | 
| Deterioration of pulmonary arterial hypertension | (yes/no) Change of pulmonary artery pressure from baseline in echocardiagraphy | 6 years | 
| Change of BALF(bronchoalveolar lavage fluid) | (yes/no) Cytology analysis on BALF at the baseline when diagnosed with chILD | 6 years | 
| Survival | (yes/no) | 1 years | 
| Survival | (yes/no) | 2 years | 
| Survival | Five-year | 5 years | 
| Abnormal thyroid hormone at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal myocardial zymogram at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal serum immunoglobulin at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal serum creatinine at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal blood urea nitrogen at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal alanine transferase at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Abnormal allergen at baseline when diagnosed with chILD | (yes/no) | 6 years | 
| Recurrent hospitalization | yes:Hospitalization more than twice per year after diagnosed with chILD; no:Hospitalization less than three times per year after diagnosed with chILD; | 1 year after diagnosis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chILD, clinic features, genetic backgrounds, outcomes