Relapsing Pulmonary Langerhans Cell Histiocytosis after Lung Transplantation

BÉNÉDICTE ETIENNE, MICHÈLE BERTOCCHI, JEAN-PAUL GAMONDES, FABRICE THÉVENET, CHRISTOPHE BOUDARD, THÉRÈSE WIESENDANGER, ROBERT LOIRE, JEAN BRUNE, and JEAN-FRANÇOIS MORNEX

Hôpital Louis Pradel, Lyon, France

	INTRODUCTION

TOP INTRODUCTION DISCUSSION REFERENCES

In adults, pulmonary Langerhans cell histiocytosis (LCH) is an uncommon granulomatous disorder occurring almost exclusively in cigarette smokers. Its etiology is not clearly defined, but immune system interactions between Langerhans cells, pulmonary epithelial cells, and lymphocytes appear to be involved (1, 2). Spontaneous remissions sometimes occur, and corticosteroids alone or in combination with cytostatics are usually helpful (3, 4). In a few cases where the clinical status progressively worsens and conventional treatment is ineffective (4), recourse to lung transplantation may be proposed. As in any disease of unknown etiology, recurrence after transplantation may theoretically be a problem. We here report two cases of pulmonary LCH, which recurred after lung transplantation.

	CASE REPORT

Patient 1

A 19-yr-old man with a 5-pack-year history of smoking was first referred for lung transplantation in 1992. He had a stage II New York Heart Association (NYHA) dyspnea, a nonproductive cough, weight loss, fatigue, a mild obstructive syndrome, and oxygen desaturation on exercise (Table 1). The diagnosis of LCH had already been confirmed by transbronchial lung biopsy and a bone biopsy of the lower maxilla. Transplantation was denied, and his disease progressed despite corticosteroid therapy, leading to repeated bilateral pneumothorax treated by surgery in 1992, 1993, and 1994. He was readmitted in 1994 with right ventricular failure (stage IV), severe hypoxemia at rest (7 kPa), pulmonary hypertension (28 mmHg at rest, 40 mmHg on exercise), and underwent successful right lung transplantation in March 1995. Subsequent recovery was almost uneventful except for cytomegalovirus (CMV) pneumonia treated by ganciclovir and immunoglobulins. He received our routine immunosuppression regimen comprising ciclosporin (adjusted to a blood level of 150-250 ng/ml), azathioprin (1-2.5 mg/kg), and prednisone (0.1-0.5 mg/kg). A second CMV pneumonitis in August 1995 caused acute renal failure and leukopenia, but on recovery he showed no clinical spirometric, radiologic or pathologic evidence of acute or chronic rejection (Figure 1A, Table 1). He resumed smoking 15 cigarettes a day 6 mo after transplantation, as documented by history and by blood carboxyhemoglobin (HbCO) levels. Twelve months after transplantation, chest X-ray and thoracic CT scan revealed diffuse nodular opacities with thin-walled cysts in the transplant (Figure 1B). An open lung biopsy was performed and pathology showed early stage Langerhans cell granulomatosis, and bronchoalveolar samples revealed more than 6% CD1-positive cells. Corticotherapy was raised to 1 mg/kg/d then tapered to 0.5 mg/kg/d. Despite reinforced counseling to stop smoking, he continues. Six months later the patient is still asymptomatic but now presents mild obstructive disease (Figure 1C, Table 1).

View larger version (122K): [in this window] [in a new window]   View larger version (124K): [in this window] [in a new window]   View larger version (132K): [in this window] [in a new window]   Figure 1.   Patient 1, chest CT scan (1-mm slices) 8 mo after transplantation (A); 12 mo after transplantation showing a nodular infiltrate in the transplanted lung (B); 18 mo after transplantation showing diffuse destructive disease in the transplanted lung (C ).

Patient 2

A 30-yr-old man with an 8-pack-year history of smoking presented in 1994 with the diagnosis of LCH made by an open lung biopsy in 1991. He had a diabetes insidipus, treated by intranasal desmopressine, indicative of hypothalamic involvement. Since 1991, he has repeatedly suffered bilateral pneumothorax treated by surgery. On admission, he had a stage II-III dyspnea, a mild obstructive syndrome and significant oxygen desaturation on exercise (Table 1). He underwent left single lung transplantation in July 1995. He received our routine immunosuppression regimen (as above), and his clinical status rapidly improved, although he developed septicemia due to Staphylococcus aureus and severe hyponatremia due to desmopressine abuse. Moreover, despite strong counseling, he resumed smoking at least 1 pack a day 3 mo after transplantation. Resumption of smoking was confirmed by history and by blood HbCO levels. Six months after transplantation, he developed a grade 2 lung rejection, which responded to high doses of corticosteroids. Respiratory status and radiologic surveillance tests were satisfactory (Figure 2A, Table 1), but 1 yr after transplantation, routine thoracic CT scan and transbronchial biopsy revealed a recurrence of LCH. A thoracic CT scan showed diffuse thin-walled cysts in the left (transplanted) lung (Figure 2B) and histopathology confirmed granulomatous and cystic lesions with positive tissue immunostaining for S100 protein. Bronchoalveolar lavage samples revealed an alveolitis with 61% alveolar macrophages and less than 6% CD1-positive cells. Despite advice, he still has not stopped smoking, and is now symptomatic with stage II dyspnea requiring corticotherapy (1 mg/kg/d). His pulmonary function test values (Table 1, Figure 2C) show a small but real loss of function.

View larger version (125K): [in this window] [in a new window]   View larger version (147K): [in this window] [in a new window]   View larger version (141K): [in this window] [in a new window]   Figure 2.   Patient 2, chest CT scan (1-mm slices) 6 mo after transplantation (A); 12 mo after transplantation showing diffuse cysts (B); 16 mo after transplantation showing diffuse destructive disease in the transplanted lung (C ).

	DISCUSSION

TOP INTRODUCTION DISCUSSION REFERENCES

Pulmonary LCH results from the local accumulation of Langerhans cells leading to the formation of destructive granulomas (3, 5). It usually resolves or stabilizes under corticosteroid therapy, though a few patients progress to end-stage pulmonary disease. We have transplanted lungs into seven adult patients with LCH (six single lung and 1 heart-lung). Five patients remain well, as judged by routine CT scans, at 15, 30, 70, 80, and 90 mo after intervention. Two patients have suffered recurrence of LCH in the grafted lung. To our knowledge, these are the first reports of recurrence of LCH, although other diseases of unknown etiology, such as giant cell pneumonitis (6), sarcoidosis (7, 9), diffuse panbronchiolitis (9), and lymphangioleiomyomatosis (10, 11), may recur after lung transplantation. It is noteworthy that both our patients resumed smoking shortly after transplantation. Our current institutional policy for lung grafts in tobacco smokers requires full cessation of smoking for 6 mo before grafting. After transplantation, compliance and continuation of smoking cessation are evaluated by interview (10% relapse rate, in agreement with many other centers) and by monitoring of blood HbCO levels at 1- to 3-mo intervals. All patients are vigorously counseled to maintain complete smoking cessation. Bronchiolar abnormalities due to cigarette smoking play a major role in recruiting large numbers of Langerhans cells. These are weakly phagocytic, potent antigen-presenting cells that express MHC class II molecules constitutively (12). In addition, both patients, unlike the five successfully grafted subjects, had evidence of extra-pulmonary manifestations of LCH. These observations may provide insight into the pathogenesis of the disease. Current concepts involve an immune response in which Langerhans cells serve as accessory cells and interact with lymphocytes and epithelial cells (11, 12). In the transplanted lung, donor Langerhans cells, initially present in the grafted lung, are progressively replaced by Langerhans cells derived from the recipient's bone marrow (10). Our observations suggest that these Langerhans cells can modulate disease in the context of a different major histocompatibility complex expression, as the grafts were not MHC matched. We speculate that the pathogenesis in our two relapsing patients may involve both the repopulation of the transplanted lung by abnormally reactive Langerhans cells from the recipient, as suggested by their previous systemic LCH involvement, as well as exogenous stimulation by tobacco smoke.

Conclusion

Although lung transplantation may be proposed as an efficient treatment for end-stage LCH, the risk of recurrence of the disease must be discussed when systemic disease is present, and patients must be forcefully counseled to quit cigarette smoking.

	Footnotes

Correspondence and requests for reprints should be addressed to Pr. Jean-François Mornex, Hôpital Louis Pradel, BP Lyon Montchat, 69394 Lyon cedex 03, France. E-mail: mornex{at}clermont.inra.fr

(Received in original form December 23, 1996 and in revised form May 20, 1997).

Acknowledgments: The authors thank Timothy Greenland for critically reviewing their manuscript.

	References

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