Respiratory Failure, Pulmonary Hypertension, and Critically Ill chILD – A Case for Early Lung Biopsy

Abstract INTRODUCTION: Children's interstitial and diffuse lung disease (chILD) is a group of rare lung disorders involving the lung parenchyma, interstitium, distal airways and/or vasculature, impairing the alveolar capillary gas exchange surface and lung function. DESCRIPTION: A term baby presented with persistent cyanosis, left pneumothorax and pneumomediastinum at birth, resulting in chest tube placement and invasive mechanical ventilation. Persistent hypoxemic respiratory failure and pulmonary hypertension (PH) resulted in HFOV, iNO, pressor support and VA-ECMO from day 2-13. She received surfactant, multiple courses of stress steroids and high ventilator settings (FiO2 80-100% and peak pressures mid 30s-early 40s). Bronchoscopy showed normal anatomy and copious mucoid secretions. She continued to have significant PH. Chest CT revealed diffuse ground-glass opacities, interlobular septal thickening, pneumatocele, normal pulmonary veins; rapid whole genome sequence (WGS) was negative. Given her critically ill condition there was debate about optimum timings for lung biopsy which was ultimately done at 10 weeks of age. Biopsy revealed developmental growth arrest, severe pulmonary arteriopathy, patchy extensive pulmonary alveolar proteinosis with abnormal pattern of surfactant protein expression, and nonspecific ultrastructural findings including abundant well-formed small lamellar bodies admixed with composite lamellar bodies. Research WGS to assess for other variants is pending. She was deemed not a candidate for lung transplantation and despite the initiation of alternative therapies like hydroxychloroquine and additional steroids, her family opted for withdrawal of care. DISCUSSION: Surfactant disorders account for ∼22% of chILD cases. NKX2-1 and TBX4 disorders are associated with PH but there is significant overlap of clinical phenotype. Lung biopsy and genetic testing help prognostication and counseling in children with rapidly progressive lung disease and infants on ECMO. NKX2-1 gene may have downstream effects on surfactant function and is associated with diffuse lung disease, hypothyroidism and neurologic findings. Pulmonary manifestations with TBX4 mutations include acinar dysplasia, lethal neonatal lung disorders and bronchial and parenchymal lung abnormalities. Immunosuppressive therapy like corticosteroids and hydroxychloroquine has been trialed in chILD. 50% of chILD disorders have a genetic basis or likely genetic mechanism and testing might avoid the need for initial lung biopsy. Research WGS may uncover more variants and subtle deletions/ insertions which could plausibly be associated with chILD, and may be otherwise undetected on WGS. Early lung biopsy may be helpful in directing clinical management when genetic testing is still ambiguous or non-diagnostic.