Orphan Lung Diseases

Orphan (rare) lung disease is defined as a disease or condition affecting fewer than 200,000 persons in the United States (Office of Rare Diseases, NIH).[1] An estimated 25 million people in the United States have one of the more than 6000 orphan diseases.[2] [3] Thus orphan diseases pose a significant social burden not only in the United States but also worldwide. Orphan disease patients may experience difficulties in accessing high-quality health care for multiple reasons, including incorrect or delayed diagnosis, scarcity of relevant scientific knowledge and expertise, and lack of effective treatment.[4] The failure to diagnose an orphan disease is generally due to a failure to consider the diagnosis in the initial evaluation. Thus the diagnosis of orphan diseases is facilitated by considering a broad differential diagnosis at the outset and the ability to recognize characteristic features associated with these disorders.

The current issue of Seminars in Respiratory and Critical Care Medicine is devoted to orphan lung diseases. Although idiopathic pulmonary fibrosis (IPF) is one of the most common interstitial lung diseases (ILD), it belongs in the spectrum of orphan diseases. In the first article, Adkins and Collard provide a state of the art review on this disorder for which effective pharmacological therapy has yet to be identified. Acute exacerbation can unexpectedly complicate the course of patients with IPF and result in death.[5] The pathogenesis of this phenomenon needs to be better understood. In the second article, Poletti and colleagues discuss the current status of nonspecific interstitial pneumonia (NSIP). NSIP can occur as a form of idiopathic interstitial pneumonia (IIP) and needs to be distinguished from IPF. It can also be seen as a pulmonary manifestation of connective tissue diseases, drug-induced lung disease, and in other clinical contexts.[6] [7] Thus the optimal management of patients with NSIP requires thoughtful integration with clinicoradiological context as discussed by these authors.

There are multiple entities that are classified as benign lymphoid disorder of the lung. Lymphocytic interstitial pneumonia (LIP) is perhaps the best known of these and also belongs under the rubric of idiopathic interstitial pneumonias. As with NSIP, LIP can also be seen as pulmonary involvement in systemic diseases such as immunodeficiencies, autoimmune diseases, and drug reactions.[6] In the article by Tian and colleagues, LIP and several other benign lymphoid disorders are discussed, including an emerging entity designated IgG4-related disease (IgG4-RD), a fibroinflammatory multisystem disease. It is becoming apparent that IgG4-RD can involve any compartment of the respiratory system, including the airways, mediastinum, and pleura, as well as the lung parenchyma.[8] The relevance of IgG4-RD in various fibroinflammatory disorders previously considered “idiopathic” needs to be explored.

Cryptogenic organizing pneumonia (COP) and acute interstitial pneumonia (AIP) are two other forms of idiopathic interstitial pneumonias.[6] Cottin and Cordier provide an update on the diagnosis and management of COP with an emphasis on the need to exclude known causes of OP and other disorders that can mimic features of COP which are relatively nonspecific. A similar principle applies to the diagnosis of AIP. As detailed in the article by Mukhopadhyay and Parambil, identifiable causes of acute lung injury as well as preexisting chronic fibrotic lung disease (e.g., acute exacerbation of IPF), need to be excluded before diagnosing AIP. Appropriate management of patients in this context critically depends on this step.

Incredible progress has been achieved in recent years in our understanding of pulmonary lymphangioleiomyomatosis (LAM). Meraj and colleagues describe the evolution of this knowledge that has led to identification of an effective targeted therapy with sirolimus.[9] Collaboration between patient and scientific communities has played a major role in advancing the science and translating these advances into improved care of patients with this rare lung disease.

Similarly, important insights have been gained in recent years regarding the pathogenesis of pulmonary alveolar proteinosis (PAP), as discussed by Wang and colleagues. In the majority of patients, PAP is an autoimmune disease mediated by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). GMCSF therapy, delivered by subcutaneous or inhalational route, has emerged as a treatment option in the management of PAP.

Obliterative (constrictive) bronchiolitis is a rare form of obstructive lung disease and is discussed by Lynch and colleagues. This bronchiolar disorder is all too familiar to those who care for transplant recipients (ie, bronchiolitis obliterans syndrome), but it can also result from multiple other causes as outlined in their article. Vassallo reviews the concept of diffuse lung disease in cigarette smokers, including respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, pulmonary Langerhans cell histiocytosis, and acute eosinophilic pneumonia, as well as several other disorders for which cigarette smoking appears to be a risk factor. The spectrum of lung diseases associated with cigarette smoking, the leading cause of preventable deaths in the United States, continues to broaden.

Selman and Buendía-Roldán provide an update on hypersensitivity pneumonitis (HP), including the current diagnostic and therapeutic approach. Early diagnosis is crucial in preventing irreversible fibrosis. As noted by these authors, the offending antigen may not be identifiable in some patients with HP, making diagnosis and management more difficult.

Bhatt and Allen review the broad spectrum of eosinophilic lung disease, including idiopathic forms such as chronic eosinophilic pneumonia, and those associated with identifiable causes such as infections and drugs. These authors illustrate how to negotiate diagnostic challenges posed by patients with eosinophilic lung diseases.

In the last article, Shino and colleagues provide a case report describing neurofibromatosis-associated diffuse parenchymal lung disease. Questions are raised regarding potential interaction between neurofibromatosis and smoking in the genesis of cystic and fibrotic lung lesions.

In closing, I wish to express my thanks to the distinguished authors for their contributions. They are recognized experts on their respective topics and have been leading the way to improve our understanding of these orphan diseases. I hope the readers come away with a sense of optimism that the rarity of these diseases has not prevented meaningful advances that have improved the care of patients with these disorders.

• References

• 1 Office of Rare Diseases. http://rarediseases.info.nih.gov/ . Accessed: June 18, 2012
• 2 Brewer GJ. Drug development for orphan diseases in the context of personalized medicine. Transl Res 2009; 154 (6) 314-322
• 3 Groft SC, de la Paz MP. Rare diseases—avoiding misperceptions and establishing realities: the need for reliable epidemiological data. Adv Exp Med Biol 2010; 686: 3-14
• 4 Kole A, Faurisson F. Rare diseases social epidemiology: analysis of inequalities. Adv Exp Med Biol 2010; 686: 223-250
• 5 Collard HR, Moore BB, Flaherty KR , et al; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007; 176 (7) 636-643
• 6 American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165 (2) 277-304
• 7 Romagnoli M, Nannini C, Piciucchi S , et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders?. Eur Respir J 2011; 38 (2) 384-391
• 8 Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012; 39 (1) 180-186
• 9 McCormack FX, Inoue Y, Moss J , et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364 (17) 1595-1606