Eosinophilic Granuloma (Histiocytosis X)

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]

See also Imaging in Eosinophilic Granuloma of the Skeleton and Langerhans Cell Histiocytosis Imaging.

• References

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.

• References

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.

• References

Epidemiology

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.

• References

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.

• References

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.

• References

History

Presentations of pulmonary Langerhans cell histiocytosis X (PLCH) are variable.^[9] Approximately 25% of patients are asymptomatic, and their disease is diagnosed after an evaluation of incidental findings on chest radiographs. Others present with respiratory or constitutional symptoms. In order of decreasing frequency, common presenting symptoms are as follows:

• Nonproductive cough (56-70%)
• Dyspnea (40%)
• Fatigue (30%)
• Weight loss (20-30%)
• Chest pain (21%)
• Spontaneous pneumothorax, which may be recurrent, is a classic presentation found in 10-20% of patients.
• Fever (15%)
• Cystic bone lesions (4-20%): These may be painful and may predispose the patient to pathologic fracture.

• References

Physical Examination

Patients with pulmonary Langerhans cell histiocytosis X (PLCH) present with nonspecific physical findings. Neither inspiratory rales (crackles) nor clubbing is common. Cor pulmonale may develop; therefore, the following related findings may be present:

• Loud second heart sound with accentuated pulmonic component
• Tricuspid regurgitation murmur
• Right ventricular lift
• Peripheral edema

• References

Complications

Spontaneous pneumothorax is a common complication (10-20%) in pulmonary Langerhans cell histiocytosis X (PLCH).

PLCH is associated with an increased risk of malignancy, including Hodgkin and non-Hodgkin lymphoma, myeloproliferative disorders, and bronchogenic carcinoma.^[10]

Pathologic fracture may occur at the site of bone lesions.

Diabetes insipidus occurs in 10-15% of patients and indicates disease in the central nervous system.

Pulmonary arterial hypertension and, rarely, cor pulmonale, may develop as a result of hypoxemia and/or vascular occlusion due to PLCH lesions.

• References

Laboratory Studies

Results from routine laboratory testing in patients with pulmonary Langerhans cell histiocytosis X (PLCH) are nonspecific.

Peripheral eosinophilia is not observed.

• References

Imaging Studies

Chest radiographs in patients with pulmonary Langerhans cell histiocytosis X (PLCH) characteristically reveal bilateral, symmetric, ill-defined nodules and reticulonodular infiltrates. As the disease progresses, cystic lesions appear. An upper-zone predominance of radiographic findings with sparing of the costophrenic angles is typically observed, as follows:

• Cystic lesions can be of various sizes and thin or thick walled.
• Lung volume is normal or increased.
• Honeycombing indicates advanced disease.
• Bony lesions may occur on the ribs or any other site.
• Hilar or mediastinal adenopathy is rare and should prompt the consideration of sarcoidosis or malignancy.
• Pleural effusion is uncommon.

HRCT of the chest may be virtually diagnostic in the appropriate clinical setting. Pathognomonic findings include nodules and cysts, predominantly in the mid and upper lung zones, with sparing of the costophrenic regions. The nodules may be cavitary and variable in size. Likewise, the cysts may be of various diameters and wall thicknesses. A broad differential diagnosis must be considered in the following situations:

• If only nodules are present on HRCT, the findings are nonspecific, and a number of other granulomatous disorders cannot be excluded radiographically.
• When cysts are an isolated finding, LAM must be considered as well. Unlike PLCH, LAM is usually uniformly distributed throughout the lungs. Sparing of the costophrenic angles supports a diagnosis of PLCH.
• Emphysema is usually distinguishable, as walls do not surround the cystic spaces found in emphysema. However, extensive emphysema is sometimes difficult to differentiate from PLCH.

• References

Other Tests

Pulmonary function testing in pulmonary Langerhans cell histiocytosis X (PLCH) patients can demonstrate all patterns of abnormality: Normal, restrictive, obstructive, or mixed. Most patients have normal or near-normal total lung capacity with near-normal spirometry findings. Gas exchange, as measured by the diffusing capacity for carbon monoxide, is generally reduced. In rare cases, patients have reversible airflow limitation.

Gas exchange abnormalities may be present at rest. Although such abnormalities are most pronounced with exercise, most patients have a normal gradient of alveolar-arterial partial pressures.

Pulmonary exercise testing may demonstrate decreased exercise capacity with reduced oxygen utilization. Gas exchange, ventilatory, and pulmonary vascular abnormalities may also be present. Therefore, exercise limitation is generally multifactorial.

• References

Procedures

Analysis of bronchioalveolar lavage (BAL) fluid is sometimes diagnostic in pulmonary Langerhans cell histiocytosis X (PLCH). A greater than 5% increase in the number of Langerhans cells in BAL specimens is almost pathognomonic for PLCH. Although this finding is highly specific, it is not particularly sensitive. Langerhans cells can be recognized by their characteristic staining for S-100 protein or peanut agglutination antigen. These cells are CD1a-positive, and may also be identified by a specific monoclonal antibody (MT-1).

Although the disease is present in a patchy distribution, sometimes transbronchial biopsy may be diagnostic if sampling is done in a number of areas and sufficient tissue is obtained. Immunostaining for Langerhans cells (CD1a) improves the sensitivity and specificity of the biopsy sample. The diagnostic yield is approximately 10-40%.

Open or thoracoscopic lung biopsy is the most sensitive and specific diagnostic modality, and is generally recognized as the criterion standard. In addition to immunostaining, electron microscopy of tissue samples may be performed. Langerhans cells demonstrate the characteristic intracytoplasmic Birbeck granules. These are found in all Langerhans cells, but they are present in increased numbers in the pathologic Langerhans cells found in the lesions of PLCH.

• References

Histologic Findings

The earliest lesions of pulmonary Langerhans cell histiocytosis X (PLCH) consist of Langerhans cells grouped around the small airways. These inflammatory lesions expand to form granulomatous nodules composed of Langerhans cells as well as eosinophils, macrophages, lymphocytes, plasma cells, and fibroblasts.

In addition to looking for the typical morphologic features of Langerhans cells, immunostaining for S-100 and CD1a may also be useful. Electron microscopy helps in identifying Langerhans cells by demonstrating the presence of diagnostic pentilaminar cytoplasmic inclusion bodies, or Birbeck granules (x-bodies).

Of note, eosinophils may not always be present. Therefore, the name eosinophilic granuloma, despite being a commonly accepted term, is a misnomer.

Granulomas are centered on distal bronchioles. Evidence of pulmonary vascular involvement and respiratory bronchiolitis are often present, as well as infiltration and destruction of airway walls. As the disease progresses, cavitation occurs as a result of this destruction. The nodule fibroses, eventually forming a stellate scar.

Hematoxylin-eosin staining is demonstrated in the image below:

View Image

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

• References

Approach Considerations

Inpatient admission is indicated in pulmonary Langerhans cell histiocytosis X (PLCH) patients only to manage complications related to the disease as listed below.

Patients with superimposed respiratory infections, such as pneumonia, may require inpatient treatment.

Patients with spontaneous pneumothorax may require chest-tube placement and subsequent in-patient care. The recurrence rate of secondary spontaneous pneumothorax in PLCH is high. Therefore, some experts recommend surgical intervention, such as mechanical pleurodesis, parietal pleurectomy, or talc insufflation, to prevent further occurrences after the initial episode.

Acute respiratory failure necessitating in-patient management may occur as the result of a superimposed respiratory infection or spontaneous pneumothorax. Respiratory failure may also occur as a manifestation of end-stage disease.

• References

Medical Care

Smoking cessation is the most important medical intervention for pulmonary Langerhans cell histiocytosis X (PLCH). Smoking cessation often stabilizes the disease and sometimes leads to regression. It is also helpful in preventing bronchogenic carcinoma. Largely because of the rarity of PLCH, well-designed, prospective, randomized data regarding therapy are lacking.

The use of corticosteroids is controversial. Corticosteroids may be considered in patients with a persistence of clinically significant pulmonary or constitutional symptoms or those with documented progression of disease. Corticosteroid therapy is not indicated in patients with normal lung function. Recommendations for the use of corticosteroids are based largely on retrospective data and expert opinion.

Investigational therapies include interleukin-2 (IL-2) and anti–tumor necrosis factor-alpha (anti–TNF-alpha). Both agents have been reported to improve outcomes in pediatric disseminated histiocytosis. This finding may lead to the investigation of their use in adult PLCH.

Useful adjunctive therapies include the following:

• Supplemental oxygen therapy for those with clinically significant hypoxemia (SaO₂< 89% or PaO₂< 55 mmHg) at rest or with exertion
• Aggressive treatment for pulmonary infections with prompt initiation of antibiotic therapy
• Bronchodilator therapy in the presence of an obstructive ventilatory defect

• References

Surgical Care

Lung transplantation is an option for select patients with advanced disease. Recurrence of pulmonary Langerhans cell histiocytosis X (PLCH) has been reported in the transplanted lung.^[12]

• References

Consultations

Refer patients with suspected pulmonary Langerhans cell histiocytosis X (PLCH) to a pulmonary disease specialist.

• References

Activity

Exercise and pulmonary rehabilitation are encouraged in pulmonary Langerhans cell histiocytosis X (PLCH). These activities may improve the patient's functional status, even if they have no effect on disease progression.

• References

Prevention

Effective antismoking measures can prevent pulmonary Langerhans cell histiocytosis X (PLCH). See Medscape's Smoking Resource Center.

• References

Long-Term Monitoring

In the care of patients with pulmonary Langerhans cell histiocytosis X (PLCH) , important considerations include the patients' smoking history and current smoking status, the presence or absence of extrapulmonary disease and constitutional symptoms, and close monitoring for progression of pulmonary disease.

Pulmonary artery hypertension is a known complication of infiltrative lung diseases, and in PLCH the magnitude of pulmonary artery hypertension may be greater than expected for given the degree of hypoxemia or level of impairment on pulmonary function testing.

The increased risk of pulmonary malignancies must be considered.

Smoking cessation counseling and adjunctive pharmacologic therapy with bupropion and nicotine replacement are key components of long-term management.

Perform pulmonary function testing and radiographic studies every 3-6 months, as the patient's clinical condition warrants.

Assess arterial oxygen saturation both at rest and with activity.

Echocardiography should be considered in all patients with clinically significant dyspnea in order to screen for pulmonary artery hypertension. If echocardiographic results suggest moderate-to-severe pulmonary artery hypertension, these findings should be further evaluated and confirmed with right-heart catheterization. At the time of catheterization, the response to vasodilators may also be assessed.

Patients should be vaccinated annually for influenza and should also receive the pneumococcal vaccine.

• References

Medication Summary

The mainstays of treatment for pulmonary Langerhans cell histiocytosis X (PLCH) are smoking cessation and supportive therapy. The use of corticosteroids in the treatment of PLCH is controversial. Their efficacy has not been proven in well-designed, prospective, randomized, controlled trials. Some experts recommend a trial of corticosteroids for those patients with persistent symptomatic disease or evidence of progression.

Patients with an obstructive ventilatory defect on pulmonary function testing may benefit from bronchodilator therapy.

Supplemental oxygen therapy is indicated for all patients with either resting or exertional hypoxemia. Oxygen therapy may help to prevent or slow progression of pulmonary hypertension and cor pulmonale, and it provides a mortality benefit in chronic obstructive pulmonary disease.

• References

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is used as an immunosuppressant to treat autoimmune disorders. By reversing increased capillary permeability and suppressing the activity of polymorphonuclear cells, it may decrease inflammation. Prednisone is an oral corticosteroid with relatively limited mineralocorticoid activity. It is best prescribed in consultation with a pulmonary disease specialist.

• References

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

• References