Controversies and Evolving Concepts in Orphan Lung Diseases

Nishant Gupta, MD

Jay H. Ryu, MD

Orphan (rare) lung diseases encompass a wide variety of disorders that, in combination, affect approximately 1 out of every 2,000 individuals. According to the United States National Institutes of Health Office of Rare Diseases, a disease qualifies as an orphan (rare) disease if the estimated prevalence is less than 200,000 patients in the United States. Based on this definition, there are approximately 7,000 orphan diseases affecting an estimated 25 to 30 million people in the United States, with similar corresponding estimates in Europe. About 5 to 10% of the orphan diseases involve the lungs, either as the primary organ or as a part of multisystem involvement, amounting to approximately 1.5 to 3 million individuals living with a rare lung disease in the United States and a similar number in Europe. Thus, although uncommon on an individual basis, as a whole, orphan lung diseases represent a significant public health burden.

Orphan lung diseases have seen remarkable progress in the past few years. Perhaps the biggest driver of this progress has been the identification of underlying disease-causing mutations and better elucidation of the molecular mechanisms that drive the disease pathogenesis. In addition, close-knit collaborations between patients, clinicians, and scientists, often driven by patient advocacy organizations, have provided much-needed momentum to sustain meaningful progress and ensure the fruits of scientific advancements are reaped by patients across the world. Moreover, lessons learned from orphan lung diseases also provide valuable insights into the pathophysiology of more common lung diseases. In this issue of Seminars in Respiratory and Critical Care Medicine, we aim to provide a comprehensive overview of select orphan lung diseases, with key emphasis on highlighting the recent advances that have transformed patient care in these disorders.

The issue begins with a review of selected idiopathic interstitial pneumonias (IIPs), which in turn represent a major component of the broader field of interstitial lung diseases (ILDs). Bolaki and Antoniou provide an update on the entity of combined pulmonary fibrosis and emphysema which occurs in individuals with a smoking history and is associated with characteristic physiologic and imaging features. Nonspecific interstitial pneumonia (NSIP) is an incompletely understood IIP, which is commonly seen in conjunction with autoimmune connective tissue diseases (CTDs) but may be seen as a standalone feature in the absence of a well-defined CTD (idiopathic NSIP). Teoh and Corte describe the current understanding of NSIP and provide a framework to guide optimal evaluation and management of patients with NSIP. Immunoglobulin G4–related disease is a recently described multisystem fibroinflammatory disorder that can exhibit a wide array of intrathoracic manifestations. Casal Moura and colleagues update the readers on evolving concepts regarding this disorder with a focus on pleuropulmonary features. Hypersensitivity pneumonitis (HP) is a form of ILD triggered by the inhalational exposure of certain antigens by susceptible individuals that initiates a cascade of abnormal immunological responses leading to lung damage. The identification of HP and differentiating HP from other forms of ILDs can be quite challenging, owing to the myriad forms of disease presentation and the lack of identifiable antigen exposure history in a significant proportion of the patients. Fernández Pérez et al present an excellent overview of the current understanding of HP and provide a useful guide to approach the diagnosis and management of HP in clinical practice. Kropski provides a summary of the spectrum of mutations that can lead to the development of familial ILD. Familial interstitial pneumonia is now estimated to account for approximately 20% of all ILD cases. This is a rapidly evolving field and, in the near future, promises not only an improved understanding of the pathophysiology of development of ILD but also personalized prognostic and treatment strategies for patients guided by specific disease-causing mutations. Hermansky–Pudlak syndrome (HPS) is one of the causes of familial ILD with a well-defined genetic basis. HPS is an autosomal recessive disorder that can affect multiple organ systems with characteristic features being oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis. Although seen worldwide, HPS is much more prevalent in patients with Puerto-Rican heritage due to a founder effect. Rojas and Young provide a comprehensive overview of HPS, including the genetics, various systemic manifestations, and an approach to the optimal diagnosis and management of patients with HPS.

The next three articles focus on the three major diffuse cystic lung diseases encountered in the pulmonary clinics: Birt–Hogg–Dubé syndrome (BHD), lymphangioleiomyomatosis (LAM), and pulmonary Langerhans cell histiocytosis (PLCH). Diffuse cystic lung diseases represent a heterogenous group of disorders with varied underlying pathophysiological mechanisms that share a common clinicoradiological phenotype of air-filled cyst formation in the pulmonary parenchyma. While all three of the diffuse cystic lung diseases highlighted in this issue are ultra-rare, they exemplify the tremendous progress that can be made in individual disease states with improved understanding of the underlying molecular pathogenesis. Also, there is hope and optimism that improved understanding of the pathophysiology behind cyst formation in orphan lung diseases may help shed light on more common causes of lung destruction such as emphysema. Kennedy et al provide a state-of-the-art review on the current understanding of mechanisms of cyst formation in patients with BHD, including seminal work by the authors that links cyst formation in BHD to a defect in lung morphogenesis. Xu and colleagues provide an overview of the current advances in the field of LAM, which is perhaps the orphan lung disease with the most significant scientific advancements including the recent approval of a targeted treatment in the form of sirolimus by regulatory agencies in the United States and the European Union. The subtopic of diffuse cystic lung diseases culminates in an article from Shaw et al discussing the current status of PLCH, where the recent discovery of mutations in the mitogen-activated protein kinase pathway has transformed our understanding of the disease pathogenesis and firmly entrenched PLCH to be an inflammatory myeloid neoplasm as opposed to a purely cigarette-smoke–driven lung disease.

The subsequent two articles in this issue focus on two rare lung diseases that are characterized by abnormal alveolar airspace accumulation of calcium phosphate stones (pulmonary alveolar microlithiasis [PAM] and surfactant protein (pulmonary alveolar proteinosis [PAP]). Our understanding of both of these diseases has grown significantly in the past few years. The genetic mutation underlying the pathogenesis of PAM has been identified which has led to the formation of an animal model of the disease that faithfully recapitulates the human manifestations, and has suggested novel biomarkers and treatment strategies for patients in the near future. Shaw and colleagues discuss these advancements in their article on PAM. PAP is a syndrome that encompasses various distinct entities rather than being a single disease, with vastly improved understanding of the molecular pathogenesis, as well as recent development of highly sensitive and specific noninvasive diagnostic biomarkers and novel treatment approaches beyond whole lung lavage. This topic is covered by Kelly and McCarthy.

The issue is rounded off by a discussion of amyloidosis and various disorders that can affect the bronchioles. Amyloidosis refers to the extracellular deposition of fibrils formed from a variety of serum proteins, most commonly fragments of monoclonal light chains (AL amyloidosis). Baqir and Moua review various types of amyloidosis and the spectrum of intrathoracic manifestations related to these disorders which are likely underrecognized. Bronchiolar injury is a component in many forms of lung diseases including those related to systemic disorders. Ravaglia and Poletti provide an update on the classification and concepts regarding bronchiolar disorders as well as diagnostic approach.

We would like to express our sincere gratitude to all the authors who spent their valuable time and effort in providing state-of-the-art reviews on the earlier-mentioned topics. Our hope is that this issue of the journal provides the readers with a readily accessible source of up-to-date information on a wide variety of orphan lung diseases, helps raise awareness about these disorders, aid in early and improved diagnosis, and assist in evidence-based management of patients suffering from these disorders. This is truly an exciting time for orphan lung diseases, where tremendous scientific advancements are being made at a rapid pace leading to a significant positive impact in the lives of patients with these rare disorders.