Objective: Report the clinical presentation, pathogenesis, natural history, and diagnosis of a novel pediatric lung disease.

Methods: We studied 8 patients with cystic lung disease presenting in childhood. Routine history, physical, laboratory, immunologic, pulmonary function, radiographic, and whole exome sequence (WES) data were collected; extensive CC-motif chemokine receptor 2 (CCR2)-related genetic and other studies were done.

Results: Clinical presentation included dyspnea in 5 patients and cough in 4 patients. The physical examination was unremarkable except for digital clubbing in 4 patients. Serial chest CT scans revealed cysts along pleura and septa that increased in both number and size over time; quantitative CT analysis suggested cysts were continuous with distal airways. Serial pulmonary function tests showed progressive airflow obstruction. Lung histology identified reduced numbers of alveolar macrophages, pulmonary alveolar proteinosis (PAP), marked T/B cell lymphoid hyperplasia, peribronchiolar mononuclear cell infiltration and fibrosis, and areas of normal lung. All patients had biallelic CCR2 variants that blocked CCR2 expression and CCL-2-mediated signaling, impaired monocyte migration (but not phagocytosis or ROS production), and increased CCL-2  levels in blood. Hematologic indices, adaptive immunity, interferon-? signaling, and GM-CSF signaling were undisturbed. The natural history included abnormal BCG vaccination responses and recurrent inflammation/infections.

Conclusion: Complete CCR2 deficiency causes an unrecognized progressive polycystic lung disease in children. Serum CCL-2 testing may be helpful in identifying this disease among patients with unexplained polycystic lung disease.