Recurrence of Desquamative Interstitial Pneumonia after Lung Transplantation

MELISSA B. KING, JOSE JESSURUN, and MARSHALL I. HERTZ

Departments of Internal Medicine, Division of Pulmonary and Critical Care, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota

	INTRODUCTION

TOP INTRODUCTION DISCUSSION REFERENCES

Desquamative interstitial pneumonia (DIP) is an uncommon form of interstitial lung disease of unknown etiology. This entity, first described by Liebow in 1965, is characterized by diffuse interstitial infiltrates on chest roentgenogram, restrictive pulmonary function tests, and histology that demonstrates intraalveolar accumulation of macrophages (1). These patients are thought to have a more favorable prognosis than other forms of idiopathic pulmonary fibrosis, and often respond well to corticosteroid therapy (2, 3). However, patients can progress to end stage disease, and may require lung transplantation as definitive treatment. In this report, we describe a woman with severe respiratory insufficiency secondary to DIP who underwent uncomplicated single lung transplantation. One month following transplantation, she developed symptoms of cough and dyspnea, and an open biopsy demonstrated DIP recurrence in the allograft. This is the first reported case of recurrent DIP following lung transplantation. The relapse of this disease in the transplanted lung suggests a systemic pathogenesis for DIP.

	CASE REPORT

The patient was a 50-yr-old woman, previously in good health, who presented with the onset of dyspnea and nonproductive cough following an episode of prolonged bronchitis. Her past medical history was remarkable for a history of depression, parathyroidectomy for a parathyroid adenoma and cigarette smoking, up to three packs per day at the time of presentation. Medications included conjugated estrogens and fluoxetine hydrochloride. She had been employed as a waitress and a minister, with no known toxic exposures. Physical examination revealed bilateral lower lobe inspiratory crackles and subtle digital clubbing. Pulmonary function testing demonstrated a restrictive abnormality, with FEV₁ 1.45 (52% predicted), FVC 1.74 L (47% predicted), FEV₁/FVC ratio 83%, total lung capacity 48% of predicted, and diffusing capacity of the lung for carbon monoxide (DL_CO) 23% of predicted. Arterial blood gas on room air was pH 7.43, PCO₂ 39, PO₂ 63. Resting oxygen saturation was 93%, which dropped to 82% with minimal exertion. Chest roentgenogram demonstrated bilateral lower lobe interstitial infiltrates. Bronchoscopy with transbronchial biopsy proved nondiagnostic; therefore, an open lung biopsy was performed, which was read at an outside hospital as severe interstitial fibrosis. The patient discontinued all cigarette use and was treated with prednisone and cyclophosphamide with some initial response, followed by a gradual worsening in pulmonary function.

Because of her deteriorating condition, she was referred to our medical center for lung transplantation 8 mo after the original diagnosis. Transplant evaluation again revealed a severe restrictive pulmonary defect. Cardiac evaluation, including echocardiogram, radionuclide gated blood pool scan and cardiac catheterization demonstrated only a mild decrease in right ventricular systolic function. Routine laboratory studies were unremarkable.

Twenty-four months later, she received an uncomplicated left single-lung transplant. Histopathologic analysis of the excised native lung showed diffuse filling of the alveoli and alveolar ducts by vacuolated or eosinophilic histiocytes some of which contained brown granules within their cytoplasm. Occasional multinucleated cells were also present. The respiratory bronchioles showed mild peribronchiolar mononuclear infiltrates with occasional intraepithelial neutrophils. No fibrous obliteration of their lumina was observed. Mild thickening by lymphocytes and fibrous tissue was present in approximately 30% of the parenchyma (Figure 1). These findings confirmed a diagnosis of desquamative interstitial pneumonitis. Approximately one month following transplantation, she developed symptoms of cough and dyspnea without any change in her chest radiograph. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy did not demonstrate any evidence of rejection. All cultures for bacterial, fungal and viral pathogens were negative. Pulmonary function tests demonstrated a progressive decline. The patient was treated empirically with high dose steroids as therapy for presumed rejection, without significant improvement in her symptoms or pulmonary function tests. A repeat bronchoscopy was again nondiagnostic. High resolution chest computerized axial tomography scan showed no significant infiltrates in the transplanted lung. Because of her worsening symptoms, she underwent thoracoscopic lung biopsy of the transplanted lung. Light microscopic examination of hematoxylin and eosin stained sections revealed findings consistent with recurrence of her underlying DIP. Immunohistochemical studies performed on this tissue highlighted the massive accumulation of CD68 (KP1) positive histiocytes within the alveoli and alveolar ducts. (Figures 2 and 3). Although she received further therapy with high dose steroids, her condition continued to deteriorate, with increasing oxygen requirements and falling DL_CO. Her chest radiograph worsened, and demonstrated diffuse interstitial infiltrates in the transplanted lung consistent with DIP. She developed complications of cytomegalovirus and Nocardia infections, and progressive respiratory insufficiency requiring mechanical ventilation. Despite aggressive treatment of her infections, she died of respiratory failure 8 months following her transplant. Autopsy findings confirmed diffuse distribution of the desquamative changes (Figure 4).

View larger version (147K): [in this window] [in a new window]   Figure 1.   Native lung, pneumonectomy specimen. Histiocytes filling the alveoli and alveolar ducts. Mild interstitial fibrosis is present. (Hematoxylin and eosin stain, ×180.)

View larger version (150K): [in this window] [in a new window]   Figure 2.   Open lung biopsy specimen of the transplanted lung. Massive intra-alveolar accumulation of histiocytes is apparent. (Hematoxylin and eosin stain, ×250.)

View larger version (118K): [in this window] [in a new window]   Figure 3.   Open lung biopsy specimen of the transplanted lung. (A) Pneumocytes lining the alveoli are highlighted by cytokeratin staining. (B) Immunohistochemical stain for CD-68 (KP1), a histiocytic marker, accentuates the distention of the alveoli by histiocytes. The intra-alveolar cells do not react with the cytokeratin antibody confirming their histiocytic lineage and disproving their derivation from desquamated pneumocytes. (Avidin-biotin technique with 3-3 diaminobenzadine chromogen, original magnification: ×200.)

View larger version (143K): [in this window] [in a new window]   Figure 4.   Section of the transplanted lung obtained at autopsy. Macrophages diffusely fill the alveoli. (Hematoxylin and eosin stain, original magnification: ×150.)

	DISCUSSION

TOP INTRODUCTION DISCUSSION REFERENCES

DIP was first described in 1965 by Liebow as a unique form of interstitial lung disease with a distinctive histology and characteristic clinical course which was generally felt to be more favorable than most forms of interstitial fibrosis. Pulmonary fibrotic processes were often described as either DIP or usual interstitial pneumonitis (UIP) based on the relative amounts of alveolitis and fibrosis seen on biopsy. Since these early descriptions, many authors have endorsed the concept that DIP represents one component within a spectrum of disease which is generally termed idiopathic pulmonary fibrosis. However, others suggest that DIP may represent a distinct entity which can also cause end stage lung fibrosis (4).

Clinically, patients present most commonly in middle age with symptoms of dyspnea and nonproductive cough. Physical examination demonstrates inspiratory crackles and sometimes clubbing. Pulmonary function testing reveals a predominantly restrictive defect, with symmetrical reduction in lung volumes. Gas exchange is impaired in this disease, often severely, with reductions in the DL_CO and an increased A-a gradient (3).

The radiographic appearance of DIP has been classically described as one of triangular shaped regions of ground glass density radiating from the hilus to the periphery; however, this is seen in only a minority of cases. Other roentgenographic patterns seen include diffuse, hazy ground glass densities, lower lobe interstitial infiltrates, small lung volumes and occasionally honeycombing. In some patients, the chest radiograph may have a completely normal appearance despite biopsy proven DIP (3, 7, 8). Computerized axial tomography scans most frequently demonstrate areas of ground glass density in the lower lobes (9).

The most striking histologic feature of DIP is intra-alveolar accumulation of clumps of cells. The term "desquamative" was coined because these cells were originally thought to be alveolar type II cells, which had sloughed from the epithelial surface. Electron microscopy studies have revealed that the majority of these cells are histiocytes. Early descriptions emphasized uniformity of the histologic changes, and minimal interstitial fibrosis. Subsequent studies suggest that this disease can be heterogeneous and that fibrosis of the alveolar septae with eventual honeycombing is common and may represent an end stage result of persistent inflammation. Areas of DIP can coexist with lesions of either normal lung or frank honeycombing, suggesting that the heterogeneity of this disorder is due to different stages of the same disease process (10).

The pathogenesis of DIP is unknown. It is likely that this disorder occurs in susceptible individuals following an initial injury to the alveolar epithelium. Such injury may be caused by viral infections (11), or environmental exposures to dusts or toxins. An association between idiopathic pulmonary fibrosis and agents such as cigarette smoke or dusts has been demonstrated (12, 13). In addition, the familial occurrence of idiopathic pulmonary fibrosis suggests that genetic factors modulate the response to injurious agents. Once alveolar injury has occurred, this may trigger formation of immune complexes, which recruit and activate alveolar macrophages, generating an inflammatory response that causes proliferation of type 2 pneumocytes as a reparative phenomenon (6, 14, 15). With uncontrolled inflammation, there may be eventual fibrotic destruction of the functioning alveolar unit.

This patient presented with characteristic findings of DIP, underwent lung transplantation, and had a rapid recurrence of this disease in the graft. Her initial lung biopsy, described as severe interstitial fibrosis with intraalveolar accumulations of histiocytes, was consistent with DIP, and this diagnosis was confirmed by examination of her excised native lung. Both open lung biopsy and autopsy specimens revealed histologic findings identical to her underlying disease. Although environmental exposures, toxins, medications and connective tissue diseases can all cause a clinical and histologic picture consistent with DIP, she had no history to suggest this. Serologic evaluation for rheumatologic etiologies was negative. Although she was briefly exposed to a medication reported to cause a pulmonary fibrotic picture, fluoxetine hydrochloride, this drug was discontinued and was not in use when her disease recurred.

It is generally accepted that pulmonary fibrotic disorders are ideally suited to unilateral lung transplantation, as their physiology promotes preferential ventilation and perfusion of the lung graft. Recent registry data from the International Society for Heart and Lung Transplantation demonstrates that interstitial pulmonary fibrosis is the second most common indication for single lung transplantation, exceeded only by emphysema (16). This case is the first report of recurrence of DIP in a transplanted lung. A small number of other diseases are known to recur in lung grafts, including sarcoidosis, lymphangioleiomyomatosis, and diffuse panbronchiolitis (17). Two cases of a recurrent pulmonary fibrotic disorder have been previously reported. Both of these cases demonstrated interstitial fibrosis associated with intraalveolar multinucleated giant cells, consistent with the diagnosis of giant cell interstitial pneumonitis (20, 21).

The relapse of this disease in our patient suggests that in certain individuals, DIP represents a pulmonary manifestation of a systemic disease. Alternatively, the presence of the native lung may trigger disease in the lung graft, perhaps mediated by surface characteristics of the remaining lung. As this patient demonstrates, recurrence of DIP in the graft may be devastating to the eventual outcome. Further studies may help define this category of patients so that we can design more effective treatment strategies for this disease.

	Footnotes

Correspondence and requests for reprints should be addressed to Melissa B. King, M.D., Box 276 UMHC, 420 Delaware Street SE, Minneapolis, MN 55455.

(Received in original form March 3, 1997 and in revised form May 30, 1997).

	References

TOP INTRODUCTION DISCUSSION REFERENCES

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