Most patients with this disorder are smokers, but few smokers have it.



Mrs. C, age 43, became my patient about five years ago. Since then, I have seen her for a number of minor complaints—aches and pains from a motor vehicle accident, upper respiratory infections (URIs), occasional anxiety. But her main problem was that she smoked cigarettes.

In June 2003, a cough and a mild expiratory wheeze responded to in-office bronchodilation. Mild hyperaeration and a slightly flattened diaphragm on chest x-ray raised suspicion for early chronic obstructive pulmonary disease (COPD). Pulmonary function tests revealed a forced expiratory volume in one second (FEV1) of 75%. Diffusing capacity was normal.

We counseled Mrs. C once again to quit smoking. She readily agreed. In time, bupropion, nicotine-replacement products, and behavioral techniques would help her intermittently to “cut down,” but she was never able to quit completely.

WORSENING SYMPTOMS

In March 2007, Mrs. C came with symptoms of another URI and what was likely an exacerbation of COPD, possibly worsened by posterior rhinorrhea. She was treated with oseltamivir (Tamiflu), azithromycin, and cough syrup with codeine. At follow-up one week later, she reported feeling “80%” better. However, in view of the cigarette smoking and the young age at which she was already showing signs of COPD, I ordered a noncontrast CT of her chest.


The CT report noted the total number of nodules in the upper, middle, and lower lobes of both lungs to be more than 30 and described them as “too many to count. Some appear to be cavitating, particularly the ones in the right upper lobe, unless they are dilated bronchi” (see CT above). The largest one (1.5 cm) was located in the peripheral right lung. The differential diagnoses included inflammatory conditions, e.g., rheumatoid nodules, vasculitis, and Wegener's granulomatosis; infection with Mycobacterium avium intracellulare or Mycobac-terium tuberculosis; septic embolisms; multiple metastases; and lymphoma. We referred Mrs. C to pulmonology.

TEST RESULTS

In the meantime, except for a mild nonspecific elevation of noncardiac C-reactive protein, Mrs. C's laboratory studies were unremarkable. However, her purified protein derivative (PPD) test resulted in a 30-mm area of induration. Mrs. C did not recall having been tested before for TB. She did not work in health care and denied any known exposure at work or at home; her husband, who was her chief household contact, was PPD-negative. Mrs. C had never traveled to any exotic places and had not traveled recently at all. She was not complaining of cough (at this time), fevers, night sweats, or weight loss. Her appetite was good. By the time we had collected all these results, her symptoms had resolved.

Nevertheless, the pulmonologist agreed with the radiologist that the differential diagnosis was “extensive.” A thoracic surgeon concurred that a lung biopsy was indicated.

In May, Mrs. C underwent thoracic surgical exploration with biopsy of a sample from the lateral segment of the left upper lobe. The report noted “multiple focally fibrotic nodular infiltrates which extend into the adjacent alveolar septal interstitium.…The cellular lesions consist of varying numbers of Langerhans cells admixed with macrophages, lymphocytes, and eosinophils.” The Langerhans cells were immunoreactive for CD1, CD68, S100, and lysozyme. Stains (and later cultures) were negative for acid-fast organisms and fungi. Mrs. C had pulmonary Langerhans cell histiocytosis (PLCH).

IN THE NAME OF SPECIFICITY

Formerly known as pulmonary eosinophilic granuloma and pulmonary histiocytosis, the current designation of PLCH is meant to differentiate this disorder of primary pulmonary involvement from other Langerhans cell diseases that affect multiple organs, such as Letterer-Siwe and Hand-Schuller-Christian disease.1, The Langerhans cell is a migratory antigen-presenting cell found in such organs and tissues as the skin, heart, lung, and lymphoid system. Langerhans cells are important in immune activation and tolerance.

More than 90% of PLCH patients smoke.

Most of them are white and present in the third or fourth decade of life; women seem to present later. One hypothesis proposes that cigarette smoke triggers the accumulation of Langerhans cells in the lung. However, the fact that few smokers actually get PLCH suggests other factors, perhaps a coexisting viral illness, are involved.

The incidence of PLCH is sporadic, making an inherited genetic predisposition less likely.2 However, an acquired genetic component may play a role in PLCH as well as in the increased incidence of malignancy associated with it. Sorting the role of PLCH in the generation of malignancy from the increased incidence generally seen in smokers is less clear.

PICTURE OF PLCH

The clinical presentation of PLCH varies. Roughly 25% of patients are asymptomatic at diagnosis. Dry cough and dyspnea are common. About one third of patients have constitutional symptoms. Other presentations include pneumothorax, pleuritic chest pain, and, uncommonly, hemoptysis. Pulmonary function tests may be normal, but mildly reduced carbon monoxide diffusing capacity, obstructive flow rates, or a combination of both are also possible.

The presence of cystic and nodular lesions in the upper and middle lung fields is almost pathognomonic for PLCH, but in one retrospective analysis, most patients presented with either nodules or cystic lesions.3 Because lung-tissue involvement is patchy, endobronchial or transbronchial lung biopsies tend to have a low yield. Open or thorascopic lung biopsy remains the best way to confirm the diagnosis.

PLCH begins as a proliferation of Langerhans cells along the small airways. These cellular lesions expand to nodules as large as 1.5 cm, although most are smaller.

TREATMENT

First, help patients stop smoking. Those who stop tend to improve or stabilize over the short to medium term. However, longer-term studies have suggested that perhaps 25%-33% will progress to advanced interstitial and vascular pulmonary disease leading to cor pulmonale, respiratory failure, and death.

Some reports document objective improvement in symptoms and signs of the disease. Patients with advanced disease tend to show pulmonary hypertension out of proportion to their imaging and pulmonary function abnormalities, making prognostic predictions even more difficult.1

Steroid use is supported more by anecdotal reports than controlled clinical trials. Chemotherapeutic agents have also been used in severe and refractory cases, but their effectiveness is unclear. Patients with advanced PLCH have undergone lung transplantation, but recurrence in the grafted lung has been seen even after cigarette smoking has long ceased.

Mrs. C was able to stop smoking with the help of varenicline (Chantix) and is now feeling well. She has had no recurrences of bronchitis or bronchospasm, and she needs no medication. A CT scan five months after the first shows “fewer nodules.… The lower lobe…is clear.” In view of her positive PPD test, an infectious disease specialist put Mrs. C on prophylactic isoniazid for nine months. She will need long-term follow-up.

 

Dr. Price is an internist in South Amboy, N.J.

 

References

1. Sundar KM, Gosselin MV, Chung HL, Cahill BC. Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest. 2003;123:1673-1683.

2. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans'-cell histiocytosis. N Engl J Med. 2000;342: 1969-1978.

3. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med. 2002;346:484-490.