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(Chest. 2004;125:1028-1032.)
© 2004 American College of Chest Physicians

Pneumothorax in Pulmonary Langerhans Cell Histiocytosis*

Jose L. Mendez, MD; Hassan F. Nadrous, MD; Robert Vassallo, MD; Paul A. Decker, MS and Jay H. Ryu, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Mendez, Nadrous, Vassallo, and Ryu) and Division of Biostatistics (Mr. Decker), Mayo Clinic, Rochester, MN.

Correspondence to: Jay H. Ryu, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: ryu.jay{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Pulmonary Langerhans cell histiocytosis (PLCH) is a smoking-related interstitial lung disease characterized by development of cystic changes that predispose to occurrence of pneumothorax.

Study objectives: To determine the frequency, recurrence rate, and optimal management of pneumothorax associated with PLCH.

Design: Retrospective study.

Setting: Tertiary care, referral medical center.

Patients: One hundred two adults >= 18 years old with histologically confirmed PLCH seen at Mayo Clinic Rochester over a 23-year period from 1976 to 1998.

Interventions: None.

Measurements and results: Sixteen of 102 patients (16%) with PLCH had pneumothorax; mean age at the time of diagnosis was 29.4 years (range, 18 to 52 years), and all had smoked cigarettes. There were 37 episodes of pneumothoraces (1 to 5 episodes per patient); 10 patients (63%) had more than one episode. Median age at diagnosis of PLCH was significantly younger in patients with pneumothorax when compared to those without pneumothorax (27 years vs 41.5 years, p < 0.001), but pulmonary function parameters and survival after diagnosis were not significantly different. Rate of recurrent pneumothorax was 58% to the ipsilateral side when the episode was managed by observation or chest tube without pleurodesis, and 0% after surgical management with pleurodesis.

Conclusions: These data support the early use of surgical therapy with pleurodesis in managing patients with PLCH and spontaneous pneumothorax.

Key Words: histiocytosis X • Langerhans cell histiocytosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pulmonary Langerhans cell histiocytosis (PLCH) occurring in adults is an uncommon interstitial lung disease that results from the accumulation of specific histiocytic cells known as Langerhans cells in the lung, and is strongly associated with cigarette smoking.1 2 3 4 5 This disorder has also been previously referred to as primary pulmonary histiocytosis-X, pulmonary eosinophilic granuloma, and pulmonary Langerhans cell granulomatosis. The course of PLCH in adults is variable and unpredictable, ranging from asymptomatic stability to progressive relentless disease leading to respiratory failure and death over a period of months.1 2 6

Spontaneous pneumothorax is a recognized feature of PLCH and likely results from destruction of lung parenchyma with associated cystic changes.2 3 6 A history of pneumothorax is obtained in approximately 10% of patients with PLCH.2 3 6 7 8 9 10 11 Although the occurrence of recurrent pneumothorax in patients with PLCH is generally acknowledged, the rate of recurrent pneumothorax and optimal management strategy for this complication has not been clarified. We examined our cohort of 102 patients with PLCH to gain insight into these issues.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We identified 102 adults >= 18 years old with histologically confirmed PLCH seen at our institution over a 23-year period from January 1, 1976, to December 31, 1998.6 Histologic confirmation of PLCH in these patients had been obtained by surgical lung biopsy, transbronchoscopic lung biopsy, or biopsy of an organ other than the lung with findings on a high-resolution CT of the chest that were consistent with the diagnosis. From this cohort of 102 patients, a subset of patients who had pneumothorax during the course of their disease was identified for further study. Pneumothorax was defined as the presence of air in the pleural space as demonstrated by chest radiography and/or CT of the chest.

The following clinical data were abstracted: age, sex, smoking history, symptoms at presentation, physical examination and laboratory findings, episodes of pneumothorax and management, treatment for PLCH, comorbid medical conditions, and results of pulmonary function studies. The recurrence of a pneumothorax was defined as one that occurs on the ipsilateral side > 7 days after a pneumothorax has resolved.12 Follow-up information was obtained from patients by a self-administered survey sent to all living patients included in the study, review of medical records and correspondences, and phone interview. In addition, for the present report, institutional databases were used to gather current follow-up.

Spirometry and measurements of total lung capacity (TLC), residual volume, and diffusing capacity for carbon monoxide were performed in our laboratory using standard techniques.6 Pulmonary function data collected included plethysmographically determined TLC, FVC, FEV1, FEV1/FVC ratio, and carbon monoxide diffusing capacity.

Statistical Analysis
Select patient demographics were compared between those patients who had a pneumothorax vs those who did not have a pneumothorax using the two-sample rank-sum test for continuous variables and {chi}2 for categorical variables. Survival probabilities were estimated using the Kaplan-Meier method.13 The log-rank test14 was used to compare survival between the pneumothorax and nonpneumothorax groups. In all cases, p <= 0.05 was considered statistically significant. The institutional review board for medical research approved the study; consent was obtained for patient participation in the follow-up survey.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of 102 adults with histologically confirmed PLCH, 16 patients (16%) had one or more episodes of pneumothorax. There were 12 men and 4 women; median age at the time of PLCH diagnosis was 27 years (range, 18 to 52 years). The age at diagnosis was significantly younger in these patients when compared to the group (86 patients) not having pneumothorax (median age, 27 vs 41.5 years; p < 0.001). Pneumothorax was the initial manifestation of PLCH in 11 of these patients (69%). All initial episodes of pneumothorax were spontaneous and unilateral except for two patients (18-year-old and 20-year-old smokers, respectively) presenting with bilateral spontaneous pneumothoraces. Of the remaining 14 patients, 10 patients had their initial pneumothorax on the right side. All 16 patients had a history of cigarette smoking, with an average (mean ± SD) exposure of 9.8 ± 6.1 pack-years (range, 1 to 20 pack-years); 13 patients (81%) were active smokers at the time of their initial pneumothorax (Table 1 ). The amount of smoking exposure at the time of PLCH diagnosis was significantly lower in the group of patients having pneumothorax compared to those who did not (9.8 ± 6.1 pack-years vs 29.5 ± 22.1 pack-years, p < 0.001), likely due to their younger age.


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  		Table 1.. Epidemiologic and Clinical Features for 16 Patients With PLCH and Spontaneous Pneumothorax

 
These 16 patients had 37 episodes of pneumothoraces (mean, 2.3 episodes; range, 1 to 5 episodes). Ten patients (63%) had more than one episode of pneumothorax. None of these episodes, including two episodes of bilateral spontaneous pneumothoraces, were fatal. Pulmonary function testing maneuvers and exercise may have contributed to the development of pneumothorax in one patient each, but no episodes were associated with flying, underwater, or other exertional activities.

Pulmonary function data obtained within 1 year of the initial episode of pneumothorax were available in 12 patients; mean FVC was 68 ± 18% of predicted normal, FEV1 was 61 ± 18% of predicted normal, and carbon monoxide diffusing capacity was 49 ± 24% of predicted normal. The mean FEV1/FVC ratio was 76 ± 13%, and the mean residual volume/TLC ratio was 133 ± 55% of predicted normal. Compared to PLCH patients without pneumothorax, FVC, FEV1, and diffusing capacity at the time of PLCH diagnosis in these patients were not significantly different (p > 0.1).

Sixteen recurrent pneumothoraces occurred to the hemithorax involved in the initial episode (including two patients presenting with bilateral pneumothoraces) among nine patients (56%). Pneumothorax occurred on the side contralateral to the initial episode in 4 of 14 patients (29%) who presented with a unilateral pneumothorax. One of these patients had a recurrent pneumothorax. Thus, there were 17 recurrences of pneumothorax in total.

Details regarding management of pneumothorax were available in 34 of 37 episodes (92%) [Table 2 ]. Among 22 episodes (involving 24 hemithoraces) of pneumothorax managed by observation or chest tube drainage without pleurodesis, the rate of recurrence was 58% (14 recurrences), 17% when managed by observation only, and 72% when treated by chest tube drainage only. The remaining 12 episodes were managed surgically by thoracotomy with mechanical pleurodesis (10 episodes), pleurectomy (1 episode), or chemical pleurodesis (1 episode). Sites of air leak were oversewn or stapled when identified (three episodes). The rate of recurrent pneumothorax after surgical management among these 12 episodes was 0%.


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  		Table 2.. Mode of Pneumothorax Management and Recurrence Rates in 16 Patients With PLCH

 
Thirteen patients were smoking at the time of their first pneumothorax. Five of these patients quit smoking soon after their first pneumothorax, seven patients continued to smoke, and the smoking history was unclear in the remaining patient. In the group that continued to smoke (seven patients) there were eight recurrences, compared to five recurrences in the group that quit smoking (five patients). Eight patients (50%) received corticosteroid therapy for the treatment of PLCH.

Five of the pneumothorax patients (31%) died, and 29 of the nonpneumothorax patients (34%) died during the follow-up period. Causes of death included respiratory failure and/or cor pulmonale in three patients (complicated by pulmonary embolism in one patient), one premature death unrelated to the pulmonary diagnosis, and unknown in the remaining patient. Among the 11 survivors, 2 patients were on the waiting list for lung transplantation and 1 additional patient was undergoing evaluation for assessment of lung transplantation candidacy. Median survival after diagnosis of PLCH was 13. 8 years in patients with pneumothorax (n = 16) and 18.3 years for those without pneumothorax (n = 86) [p = 0.715]. The duration of follow-up after the first pneumothorax was 127 ± 81 months (mean ± SD; range, 5 to 336 months).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A relatively high recurrence rate (58%) was observed in our patients with PLCH when pneumothorax was managed without pleurodesis. Episodes of pneumothorax that were managed with observation only represented cases of small pneumothorax, which likely explains the relatively low rate of recurrence (17%) when compared to the group managed by chest tube drainage (72%). In contrast, there was no recurrent pneumothorax after surgical management that included pleurodesis.

PLCH commonly afflicts relatively young adults and is associated with significant morbidity and mortality as illustrated in our group of patients.1 2 3 6 7 8 9 10 11 15 16 Overall, the sex distribution is approximately equal, but in our subgroup of patients having pneumothorax, the majority were young men.1 2 3 6 7 8 9 10 11 15 16 Although cigarette smoking is strongly associated with PLCH, there was no apparent difference in the rate of recurrent pneumothorax when our patients who quit smoking after their initial episode were compared to those who did not.

Patients with PLCH are likely predisposed to the development of pneumothorax based on destructive changes in the lung parenchyma resulting from their disease.1 2 Thin-walled cysts, nodules (with or without cavitation), or a combination of these are present in the lungs of patients with PLCH.1 2 Central cavitation in nodules can sometimes be traced to ectatic destroyed small airways.17 In addition, traction emphysema of alveoli adjacent to the stellate scars and peribronchiolar fibrosis is commonly observed.15 17 As the disease advances, cystic spaces coalesce and bullae appear accompanied by increasing hyperinflation.

Although dyspnea and cough are common presenting features, spontaneous pneumothorax can be the initial manifestation of PLCH, as occurred in 11% of our 102 patients.1 2 3 6 7 8 9 16 Pneumothorax has been reported to occur in 4 to 17% of patients with PLCH during the course of their disease.6 7 8 9 10 11 15 16 None of our patients died from pneumothorax. However, a 16% mortality rate has been associated with secondary spontaneous pneumothorax occurring in patients with other lung diseases.18

The most common conditions underlying secondary spontaneous pneumothorax are reported to be COPD and Pneumocystis carinii infection associated with HIV infection.19 Cystic fibrosis, tuberculosis, and pulmonary lymphangioleiomyomatosis are other lung diseases well recognized to be associated with spontaneous pneumothorax.18 20 The recurrence rates for spontaneous pneumothorax in these clinical settings have ranged from 11 to 79% (Table 3 ).6 7 8 9 10 11 12 15 16 18 19 20 21 22 23 24 25 26 27 28 29 30


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  		Table 3.. Frequency of Spontaneous Pneumothorax and Recurrence Rates

 
The rate of recurrence for patients with secondary spontaneous pneumothorax are appreciably higher when compared to the average rate of recurrence of 30% in patients with primary spontaneous pneumothorax.20 Thus, some authors have recommended interventions to prevent recurrence of pneumothorax after the first episode of secondary spontaneous pneumothorax.31 In general, surgical management with mechanical pleurodesis, parietal pleurectomy, or talc insufflation appears to be more effective than instillation of a sclerosing agent through a chest tube.31 Surgical management in our cases was performed through a thoracotomy because most of these patients were treated before thorascopic methods became popularized. We currently perform many of these procedures thoracoscopically.

Lung transplantation is an option for some of these patients with PLCH who have progressive lung disease and respiratory insufficiency. Although prior pleurodesis and thoracic surgical procedures will cause adhesions and make transplantation surgery more difficult, they are not considered contraindications to lung transplantation.32

In conclusion, our data regarding spontaneous pneumothorax occurring in patients with PLCH suggest a high rate of recurrence in the absence of interventions to prevent additional episodes. Surgical management that includes measures to produce pleural symphysis appears to be effective in preventing recurrence of pneumothorax in patients with PLCH. Such surgical management may be justified in these patients after the first episode of pneumothorax, particularly those that are large enough to require chest tube drainage, if the surgical risk is not excessive. This is our current preferred approach for these patients to prevent recurrence of pneumothorax. These findings support the recommendations for the management of secondary spontaneous pneumothorax outlined in the recent American College of Chest Physicians Delphi Consensus Statement.31


   Footnotes
 
Abbreviations: PLCH = pulmonary Langerhans cell histiocytosis; TLC = total lung capacity

Received for publication May 16, 2003. Accepted for publication August 13, 2003.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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