Childhood interstitial lung disease associated with connective tissue disease and immune mediated is the second most common chILD diagnostic category. As knowledge of the molecular and genetic underpinnings of these rare disorders advances, the recognized clinical spectrum of pulmonary manifestations that can be associated with them continues to broaden. This review will focus on chILD and other pulmonary complications associated with primary immune disorders, namely monogenic inborn errors of immunity as well as acquired systemic autoimmune and autoinflammatory diseases. Pulmonary complications, including ILD in these diseases can confer increased risk for morbidity and mortality and can be complex to manage due to the multiple organ systems that can be impacted in these systemic disorders. Thankfully, pulmonologists do not have to work alone. These diseases often have stereotypical patterns of extra-pulmonary features which aid in their recognition. In collaboration with a multidisciplinary team of subspecialists, the pulmonary and other systemic manifestations can be managed effectively together. The goal of this review is to familiarize the reader with the distinct patterns of ILD and associated systemic/immunologic features that are characteristic of monogenic inborn errors of immunity and systemic autoimmune and autoinflammatory diseases. In addition, this review will highlight current, emergent and innovative therapeutic strategies and will underscore the important role of multidisciplinary management to improving outcomes for these patients.

In recent years, a number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these ‘primary immune regulatory disorders’ can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverese pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic mutations in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.