Rare or Orphan Lung Diseases

It is an honor for me to edit this issue of the Seminars in Respiratory and Critical Care Medicine on unusual and rare respiratory disorders. At the very outset, it is important to recognize that there are many more unusual or rare lung diseases than discussed in this issue of the Seminars. The disorders selected for discussion here are indeed unusual and rare, but they are important enough to warrant the cognizance of practicing pulmonologists and interested physicians. Some of the disorders, such as tracheopathia osteoplastica and pulmonary alveolar microlithiasis, are perhaps more common than we recognize. They remain undetected, given the lack of symptoms.

Lymphangioleiomyomatosis (LAM) is a perplexing disorder; Johnson and Tattersfield provide detailed information on the clinical aspects of this disease. Their discussion also includes the current information on the biology of the LAM cells and the role of the receptors for estrogen and progesterone in their nuclei. Because LAM possesses histologic features identical to those in tuberous sclerosis, the relationship of LAM to tuberous sclerosis is also discussed.

Pulmonary Langerhans' cell histiocytosis (PLCH) is, as noted by the authors Vassallo and Limper, an uncommonly important cause of interstitial lung disease. PLCH is an important diagnostic consideration in the differential diagnosis of diffuse infiltrative lung disease, particularly amongst smokers. The authors describe the clinical details as well as review the recent progress in our understanding of the etiology, clinical presentation, and diagnostic and therapeutic approaches to PLCH. The authors also summarize a rational diagnostic algorithm and current management strategies.

Pulmonary alveolar microlithiasis is included in this issue of the Seminars because of its rarity. It is an extremely uncommon lung disease described in approximately 400 patients worldwide. Of all the rare and uncommon disorders covered in this issue of the Seminars, microlithiasis has shown a strong tendency to occur among family members. Beyond this documented fact, the etiology remains unknown. The disorder possesses enough clinical and diagnostic characteristics that it should be relatively easy to establish the diagnosis.

In their manuscript on pulmonary alveolar proteinosis, Mazzone, Thomassen, and Kavuru pay special attention to the newer developments in the understanding of this uncommon pulmonary disease. The encouraging aspect of dealing with this disorder is that many investigators are currently actively carrying out animal as well as clinical research to learn the pathogenetic mechanism of this disease. Mazzone and colleagues discuss the relatively newly gathered information on the role played by granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in the development of pulmonary alveolar proteinosis. The idea that the disorder is the result of relative GM-CSF deficiency has led to therapeutic trials in which GM-CSF has been administered subcutaneously and by aerosolization.

Allen, Magro, and King provide an excellent outline of the confusing entities frequently lumped together under the broad category of eosinophilic pneumonias, or ``PIE'' syndromes or pulmonary infiltrates with peripheral blood eosinophilia. The discussion encompasses the differences between acute and chronic eosinophilic pneumonia, differential diagnoses of these two major types of eosinophilic pneumonias, and diagnostic features and tests, as well as therapy.

The article by Parish and Rosenow includes a comprehensive discussion of mediastinal granuloma. This disorder is distinctly more common in the United States than in other regions of the world. Many terms have been used synonymously to describe mediastinal granuloma, including mediastinal fibrosis, sclerosing mediastinitis, mediastinal adenitis, mediastinal collagenosis, and fibrosing mediastinitis. This entity leads to chronic, nonmalignant, but often progressive, inflammatory disease of the mediastinum. Currently, the cause of this unusual disorder is thought to stem from the antigenic stimulation of fibroblasts by histoplasma infection, even though tuberculosis can lead to similar problems.

The systemic as well as respiratory aspects of relapsing polychondritis are well outlined by Staats, Utz, and Michet Jr. Relapsing polychondritis is an unusual clinical entity that is frequently discussed with other collagen and rheumatologic disorders because of its systemic manifestations and clinical features. Although it is well known that relapsing polychondritis is primarily a disease of cartilage, it is one of the more difficult diseases in terms of our ability to clearly document the diagnosis. According to the authors, there have been over 600 cases reported in the literature. Respiratory complications are important because they can lead to life-threatening situations.

The difficult clinical problem of pulmonary and tracheobronchial amyloidosis is well outlined by Berk, O'Regan, and Skinner. Whereas pulmonary amyloidosis may present with symptoms caused by parenchymal involvement, the tracheobronchial variety usually presents with symptoms similar to those caused by a variety of airway disorders. It is not typically associated with systemic amyloidosis or pulmonary parenchymal involvement. It is a rare manifestation of amyloidosis, usually presenting with common symptoms that mimic many respiratory processes. Tracheobronchial amyloidosis is often recurrent, and requires repeated attempts at resection to minimize patient symptoms and potential complications from further airway destruction.

Another rare disorder discussed here is tracheobronchopathia osteochondroplastica. In my opinion, this uncommon disorder of the major airways with a lengthy descriptive designation may not be as uncommon as is reported. Many patients with this disorder are asymptomatic, and it is not uncommon to detect minor degrees of tracheobronchopathia osteochondroplastica during bronchoscopy performed for unrelated indications. Of all the disorders discussed in this issue of the Seminars, tracheobronchopathia osteochondroplastica is the only one in which the diagnosis is definitely documented by bronchoscopic visualization.

Wurfel and Raghu discuss the role of genetics in interstitial lung disorders, with special emphasis on the unusual pulmonary disorders discussed in this issue of the Seminars. Not all of the rare and unusual respiratory disorders discussed here have known genetic predisposition. Some cases of pulmonary alveolar proteinosis and several cases of pulmonary alveolar microlithiasis are known to be familial in origin. Nevertheless, the discussion by Wurfel and Raghu provides an appraisal of what is known regarding the role of genetics in various interstitial lung diseases.

For many of the unusual respiratory disorders discussed, there are no satisfactory therapies. Indeed, palliative therapy is the only measure that can be offered to these patients. However, as discussed above, investigators are looking into the possibility of newer therapies, such as the role of GM-CSF in reversing the pulmonary process in pulmonary alveolar proteinosis.

The authors of the papers in this issue and I hope that the readers of the Seminars will benefit from the excellent discussions of these unusual and rare respiratory disorders.