Background

Eosinophilic granuloma, also known as pulmonary histiocytosis X (PHX) or pulmonary Langerhans cell histiocytosis X (PLCH), is an uncommon interstitial lung disease that is epidemiologically related to tobacco smoking. It chiefly affects young adults, primarily occurring in the third or fourth decades of life.^[1]

Pathophysiology

Pulmonary Langerhans cell histiocytosis X (PLCH) is histologically characterized by parenchymal infiltration of the lungs by activated Langerhans cells. Langerhans cells are differentiated cells of the dendritic cell system and are closely related to the monocyte-macrophage line. These antigen-presenting cells are normally found in the skin, reticuloendothelial system, heart, pleura, and lungs. They may be identified by immunohistochemical staining or by the presence of Birbeck granules via electron microscopy.

PLCH is similar to pediatric histiocytic disorders (Letterer-Siwe disease and Hand-Sch ü ller-Christian disease). However, in contrast to pediatric histiocytoses, which involve multiple organs, PLCH usually manifests in a single organ—the lung. About 4-20% of patients with PLCH also have cystic lesions in the bones. Other organ systems are only rarely affected.^[2]

The accumulation of Langerhans cells in the lungs is hypothesized to occur in response to exposure to cigarette smoke. Supporting this hypothesis is the finding that the initial histologic and radiographic findings are peribronchiolar. In addition, the disease is most prominent in the upper and middle lung zones, as seen in other smoking-related lung diseases. The granulomatous infiltrates seen in PLCH are composed of Langerhans cells, eosinophils, lymphocytes, macrophages, plasma cells, and fibroblasts, which form nodules centered on the terminal and respiratory bronchioles, causing destruction of the airway walls. In late stages of the disease, fibrotic stellate scarring occurs, and end-stage PLCH is characterized by this scarring along with cystic spaces and honeycombing.

Etiology

No occupational causes or geographic predispositions are recognized for pulmonary Langerhans cell histiocytosis X (PLCH). People with PLCH, almost invariably, are cigarette smokers. Antigenic stimulation from 1 or more components of tobacco smoke is likely responsible for the disease. Because only a few tobacco smokers develop the disease, other susceptibility factors, such as host genetics and environmental exposures, most likely play an important role in pathogenesis. Some reports in the literature also describe PLCH developing following radiation and/or chemotherapy for lymphoma. Additional investigation is needed to further our understanding of this disease process.

Frequency

United States

Pulmonary Langerhans cell histiocytosis X (PLCH) is a rare disorder and the true prevalence is unknown. At 1 specialty referral center in the United States, PLCH was identified in less than 5% of patients who underwent lung biopsy for the diagnosis of interstitial lung disease.^[3]At another center, 15 cases of PLCH were found after lung biopsy, compared with 274 cases of sarcoidosis.^[4]

International

In Belgium, 3% of patients evaluated at 20 pulmonary referral centers were diagnosed with PLCH.^[5]A large Japanese study estimated the prevalence of pulmonary Langerhans cell histiocytosis X (PLCH) at 0.27 males and 0.07 females per 100,000 population based on hospital discharge diagnoses over a 1-year period.^[6]Scant epidemiologic data are available regarding this disease in the developing world.

Race

Because of the rarity of pulmonary Langerhans cell histiocytosis X (PLCH) , no definitive epidemiologic data related to racial background are available.

Sex

No sex predilection is recognized for pulmonary Langerhans cell histiocytosis X (PLCH).

Age

The peak incidence of pulmonary Langerhans cell histiocytosis X (PLCH) occurs in the 20- to 40-year age bracket.

Prognosis

The prognosis for pulmonary Langerhans cell histiocytosis X (PLCH) varies and is related to smoking cessation. Most patients who continue to smoke experience disease progression, but for those who successfully quit smoking, the disease often stabilizes or regresses.

Retrospective studies suggest that the following factors are associated with adverse outcomes in PLCH:

Extremes of age
Extensive cysts and honeycombing radiographically
Prolonged corticosteroid therapy
Multiorgan involvement
Abnormal pulmonary function, including reduced gas exchange, as measured by diffusing capacity for carbon monoxide; obstructive ventilatory defect (reduced ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity [FVC], or FEV₁/FVC); and/or evidence of airtrapping (high residual volume/total lung capacity)

Young men who have diabetes insipidus have the worst prognosis.

Favorable signs include the radiographic finding of sparing of the costophrenic angles and a cellular, nonfibrotic biopsy specimen.

Mortality/morbidity

Pulmonary Langerhans cell histiocytosis X (PLCH) has a highly variable course. Some patients have spontaneous remissions, especially when they stop cigarette smoking, whereas others progress to end-stage fibrotic lung disease.

In one retrospective study, median survival was 12.5 years after diagnosis.^[7]A European study showed similar findings, with a median survival of 13 years.^[8]

Factors associated with a poorer prognosis include multisystem involvement other than bone (including diabetes insipidus related to pituitary involvement), recurrent pneumothorax, severe pulmonary artery hypertension, older age at diagnosis, severe pulmonary function test abnormalities, and more widespread cystic changes on imaging studies.

Cigarette smoking is important to disease activity. Smoking worsens morbidity and mortality. Smoking cessation frequently stabilizes the disease and sometimes leads to its regression.

Patient Education

The public must be educated about the likely etiologic role of cigarette smoking. Pulmonary Langerhans cell histiocytosis X (PLCH)is thought to be largely preventable through smoking cessation.

Instruct patients to promptly report the development of hemoptysis. This symptom may indicate malignancy or superimposed bacterial/fungal infection, such as Aspergillus species infection.

Clinical Presentation

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Media Gallery

Low-power photomicrograph of a lung-tissue specimen that demonstrates the classic stellate nodule of pulmonary histiocytosis X (hematoxylin-eosin stain).

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Author

Eleanor M Summerhill, MD, FACP, FCCP Department of Pulmonary and Critical Care Medicine, Lahey Hospital and Medical Center, Winchester Hospital

Eleanor M Summerhill, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society, Association of Program Directors in Internal Medicine, Rhode Island Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Received research grant from: Sanofi Pharmaceutical.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Michael Peterson, MD Chief of Medicine, Vice-Chair of Medicine, University of California, San Francisco, School of Medicine; Endowed Professor of Medicine, University of California, San Francisco-Fresno, School of Medicine

Michael Peterson, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Robert S. Crausman, MD, MMS, to the development and writing of this article.