Rare Diffuse Interstitial Lung Diseases

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Chapter 54 Rare Diffuse Interstitial Lung Diseases

More than 7000 rare conditions exist, and although individually uncommon, together these diseases affect about 11% of all populations. Most rare diseases are chronic, often progressive, and can therefore form a significant portion of the workload for physicians. The term orphan disease is frequently applied to rare conditions and was originally used to suggest a lack of knowledge, research, or specific therapy. In many cases, however, significant progress in understanding the molecular basis of these diseases has resulted in biologically targeted treatments, making a definitive diagnosis especially important for these patients. This chapter describes select rare diffuse lung diseases, either primary or occurring in the context of systemic disease (secondary), likely to be encountered by most physicians, and particularly those for which a firm diagnosis can benefit patient management.

Rare Cystic Lung Diseases


Lymphangioleiomyomatosis (LAM) is a cystic lung disease that affects almost exclusively women and has a prevalence of approximately 5 women per 1 million of most populations. LAM may occur sporadically or as part of the autosomal dominant genetic disorder, tuberous sclerosis complex (TSC). In both forms the lungs and lymphatics are infiltrated by LAM cells, an abnormal cell clone harboring biallelic inactivating mutations in the genes associated with TSC, either TSC-1 or more often TSC-2. LAM cells accumulate and cause progressive cystic destruction of the lungs, probably by the elaboration of proteolytic enzymes (Figure 54-1). LAM cells form small nodular clumps associated with lymphatic endothelial cells, which in turn form lymphatic channels that allow LAM cells to disseminate throughout the body. LAM cells also infiltrate the axial lymphatics and form the smooth muscle elements of angiomyolipoma, a rare tumor of the perivascular epithelioid cell family, present in up to 40% of women with sporadic LAM and almost all patients with TSC-LAM.

Other, extrapulmonary manifestations are related to lymphatic obstruction and include lymphadenopathy in up to 30% of patients and lymphangioleiomyomas, cystic lymphatic swellings usually in the abdomen, pelvis, or retroperitoneum occurring in up to 20% of patients (Figure 54-2). Thoracic and abdominal chylous collections are present in up to 10% of patients. LAM is also associated with a higher prevalence of meningioma than the general population. Cystic lung destruction results in recurrent pneumothorax and progressive airflow obstruction, with an average decline in forced expiratory volume in 1 second (FEV1) of 120 mL per year (normal, ~27 mL/yr). However, the clinical course of patients with LAM varies, with some remaining stable for many years. At present, no features definitively predict which patients will develop progressive disease; however, onset at a younger age, presentation with breathlessness, and poor lung function at presentation suggest more aggressive disease.

Patients with LAM most frequently present with breathlessness or pneumothorax, although chylous pleural effusions, complications of angiomyolipoma, or weight loss can also be the presenting feature. Recurrent pneumothorax or airflow obstruction in younger women, particularly nonsmokers, should raise the possibility of LAM. In most cases the computed tomography (CT) findings of multiple round thin-walled cysts with no zonal predominance suggest the diagnosis. Increasingly, patients are being identified with LAM after investigations for other problems where cystic lung disease is observed on high-resolution CT (HRCT) scanning. In addition, screening for LAM at 18 years of age by CT is recommended for women with TSC; many of these patients have evidence of LAM on CT, but only a minority have respiratory symptoms.

With diagnostic criteria recently formulated by the European Respiratory Society (ERS), a definite diagnosis of LAM can be made based on a characteristic HRCT scan with a renal angiomyolipoma, histologic evidence of LAM cells at other sites (e.g., lymphangioleiomyomas, chylous collections in abdomen or thorax), or the presence of TSC. If TSC or extrapulmonary manifestations are not present, lung biopsy is required for a definitive diagnosis. Transbronchial biopsy can occasionally be helpful, although in most patients, video-assisted thorascopic surgery (VATS) is preferred. LAM cells characteristically stain with the monoclonal antibody HMB-45 and also express α–smooth muscle actin, estrogen, and progesterone receptors. The use of these immunohistochemical markers improves identification of LAM cells in lung tissue, including smaller transbronchial biopsies. The recent observation that vascular endothelial growth factor type D (VEGF-D) serum level is increased in about two thirds of patients with LAM has led to its use as a diagnostic marker for LAM. Importantly, a serum VEGF-D level greater than 800 ng/mL can differentiate LAM from other cystic lung diseases, including Langerhans cell histiocytosis, Birt-Hogg-Dube disease, and emphysema.

Patients with sporadic LAM should undergo clinical examination and where necessary, formal screening to exclude tuberous sclerosis complex. Only one third of patients with TSC have the classical triad of epilepsy, learning difficulties, and facial angiofibromas. Many patients with TSC-LAM have normal intelligence and mild skin changes that may be overlooked. Almost all patients with TSC-LAM have renal angiomyolipomas, which tend to be larger and more frequently multiple and bilateral than in those with sporadic LAM. Making the diagnosis of TSC is important for the management of other aspects of TSC and for the patient’s offspring.

To confirm LAM in the presence of cystic lung disease or to evaluate patients for renal angiomyolipoma, a CT scan of the abdomen and pelvis should be performed. Angiomyolipomas greater than 4 cm are prone to growth, rupture, and hemorrhage and should be treated prophylactically when large or in the presence of symptoms.

General management of LAM includes avoidance of estrogen supplementation, including oral contraceptives and hormone replacement therapy. Prophylactic vaccination, pulmonary rehabilitation, and oxygen should be given when appropriate. Bronchodilators are helpful for those with airflow obstruction. Patients with LAM are prone to pneumothorax, which occurs in more than 70% of patients and is recurrent in the majority, and early surgical intervention is recommended. Patients considering pregnancy should be warned that the disease may be more active in pregnancy, particularly an increase in pneumothorax. Those with TSC should receive genetic counseling. For patients with severe disease, including those with TSC, lung transplantation can be performed.

Previously, hormone treatment with progesterone or other antiestrogen therapies have been used for these patients, but no evidence indicates there is a benefit for most patients. Studies show that rapamycin, an inhibitor of mTOR pathway, is effective in reducing the rate of decline of FEV1 in patients with impaired lung function. In those with renal angiomyolipoma, including those with TSC, a reduction in tumor volume is seen in those treated with rapamycin. On cessation of therapy, decline in lung function resumes and angiomyolipoma volume increases, and these patients may need long-term therapy. ERS recommends that mTOR inhibitors for LAM not be used routinely but likely have a role in patients with progressive disease.

Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a bronchocentric disease categorized by a clonal proliferation of Langerhans cells in the lungs with focal granuloma and small airways destruction resulting in nodules and cystic change. LCH is part of a spectrum of diseases characterized by activated Langerhans cells, including Letterer-Siwe disease (acute disseminated LCH) and Hand-Schüller-Christian disease (chronic idiopathic xanthomatosis). The latter two entities are systemic cancerlike diseases of childhood and are not discussed further here. Adult LCH is generally restricted to the lung, although up to 30% of patients have extrapulmonary features; most often diabetes insipidus caused by pituitary involvement, skin lesions, or bone lesions causing pain and rarely, central nervous system lesions.

Langerhans cell histiocytosis typically affects individuals between 20 and 40 years of age, almost all of whom are current or recent smokers. The infiltrating Langerhans cell clone expresses the surface protein CD1a and has a characteristic appearance on electron microscopy with Birbeck inclusion granules (Figure 54-3). LCH may coexist with areas of desquamative interstitial pneumonitis, another smoking-related entity characterized by activation of macrophages. Similar to LAM, LCH is of variable severity, with approximately one quarter of LCH patients detected by imaging being asymptomatic. Pneumothorax is the presenting feature in about 20% of patients; the rest present with cough, dyspnea, or weight loss. The chest x-ray film is abnormal in most patients, showing reticular shadowing with midzone and upper-zone predominance (Figure 54-4). The CT scan shows a mixture of nodules, cavitating nodules, and cysts, often with thick, irregular walls forming bizarre shapes (Figure 54-5); characteristically, the bases of the lungs are relatively spared. As the disease progresses, the cysts tend to amalgamate, and nodules become less common. The diagnosis is usually suspected by the combination of these imaging appearances in younger smokers. Absolute confirmation often requires a surgical biopsy (Figure 54-6). However, bronchoalveolar lavage (BAL) fluid with greater than 5% Langerhans cells identified by CD1a positivity, often with increased macrophages and eosinophils, is supportive and can be diagnostic in the correct clinical context.

Lung function is normal in about 15% of LCH patients, although most have airflow obstruction with impaired gas transfer or a mixture of obstructive and restrictive changes. The course of LCH is variable, with spontaneous remission and even resolution in some patients; up to half of patients improve by CT criteria. However, some develop progressive respiratory failure, and a poor outcome is predicted by older age at onset, persistent constitutional symptoms, extrapulmonary involvement, and the presence of pulmonary hypertension. The overall survival for LCH patients is approximately 70% after 10 years, although some will require evaluation for pulmonary transplantation.

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