Rare Interstitial Lung Diseases

1. Pulmonary Langerhans cell histiocytosis (PLCH) is most commonly encountered in young adult smokers. Approximately 90% of PLCH patients smoke cigarettes or have a history of substantial second-hand smoke exposure. Langerhans cells are dendritic cells of the monocyte-macrophage lineage, which regulate mucosal airway immunity. The identification of mutations in the genes BRAF and MAP2K1 in up to 50% of patients suggests that at least a proportion of PLCH cases represents a smoking-induced dendritic cell neoplasm with a prominent inflammatory component. The earliest lesion in PLCH is the peribronchial accumulation of Langerhans cells and other immune cells that lead to the typical radiographic and histologic patterns.

Symptoms: Cough and dyspnea on exertion, sometimes fever, weight loss, sweating, chest pain. Pneumothorax may be the first symptom. Pulmonary function tests usually reveal decreased carbon monoxide diffusing capacity of the lungs (DLCO). Patients often have airflow obstruction (sometimes partially reversible) with hyperinflation, although a mixed pattern can be observed. Chest radiographs may initially be normal or show nodular opacities and/or a reticular pattern sparing supradiaphragmatic areas. High-resolution computed tomography (HRCT) reveals centrilobular nodules and multiform, irregular thin-walled cysts in the upper and middle lobes. A small proportion of patients may have symptoms due to a disease that is extrathoracic. Establishing a definite diagnosis requires ­­­the presence of clinical features and demonstration of Langerhans cells in tissue specimens (transbronchial or surgical lung biopsy). A probable diagnosis is based on clinical features and HRCT.

Differential diagnosis: Lymphangioleiomyomatosis (in young women), desquamative interstitial pneumonia, emphysema, lymphocytic interstitial pneumonia, Birt-Hogg-Dubé syndrome.

Treatment includes mandatory smoking cessation and follow-up with pulmonary function tests (repeated initially every 3-6 months, later every 6-12 months). Smoking cessation may promote disease stabilization/regression and sometimes complete resolution. Other patients experience a progressive decline despite smoking cessation. In patients with persistent symptoms or worsening pulmonary function test results despite successful smoking cessation, use oral prednisone (1 mg/kg/d for 1 month with the dose tapered over 5 months). If disease progression ensues consider the use of cladribine.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the case-report nature of evidence. Lorillon G, Bergeron A, Detourmignies L, et al. Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med. 2012 Nov 1;186(9):930-2. PubMed PMID: 23118088. Diffuse lesions limited to the lungs and causing respiratory insufficiency may be an indication for lung transplant.

2. Lymphangioleiomyomatosis (LAM): The disease can be sporadic or seen in the setting of tuberous sclerosis complex. Sporadic LAM is a rare disease that almost exclusively affects young women. Dysfunction of either the TSC1 or TSC2 gene leads to the proliferation of atypical smooth muscle cells around the bronchi, blood vessels, and lymphatic vessels, resulting in bronchial obstruction and the formation of parenchymal cysts.

Manifestations: Pneumothorax, chylothorax, progressive dyspnea on exertion, cough, sometimes hemoptysis, angiomyolipomas of the kidneys and other organs. Chest radiographs reveal lung hyperinflation and a reticular pattern (sometimes with nodular opacities and small cysts).

HRCT findings:

1) Characteristic features: Multiple (>10) bilateral thin-walled and well-defined cysts, normal or increased lung volume, absent signs of other interstitial diseases.

2) Features compatible with LAM: From 2 to 9 thin-walled and well-defined cysts <30 mm in diameter, other features as listed above.

Diagnostic criteria: A definite diagnosis of LAM can be established if a patient with a compatible history and characteristic chest image on HRCT has ≥1 of the following features: Histopathologic confirmation of LAM by surgical lung biopsy or biopsy of retroperitoneal or pelvic masses, presence of lymphangioleiomyomas, renal angiomyolipomas, tuberous sclerosis complex, or chylous pleural and ascitic effusion. It is also established in the presence of LAM cells or LAM clusters in cytologic examination of effusions or lymph nodes and by elevated serum vascular endothelial growth factor D (VEGF-D) >800 pg/mL.

Treatment: Bronchodilators are used for patients with reversible airflow obstruction. Pleurodesis can be performed following initial pneumothorax because of the high rate of ipsilateral recurrence. Estrogen-containing birth control pills and estrogen replacement therapy should be avoided. Counselling around pregnancy is required, given that pregnancy has been associated with an increased risk of spontaneous pneumothorax, chylothorax, and bleeding from renal angiomyolipomas. Counselling regarding air travel is also advised. The mammalian target of rapamycin (mTOR) inhibitor sirolimus 1 to 2 mg/d may be considered in patients with a forced expiratory volume in 1 second (FEV1) <70%,Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to sparse data and indirectness. McCormack FX, Inoue Y, Moss J, et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16. PubMed PMID: 21410393; PubMed Central PMCID: PMC3118601. especially in the presence of rapid progression, renal angiomyolipoma >3 cm, large lymphangioleiomyoma, and thoracic or abdominal chylous effusion. Lung transplant should be considered in patients with respiratory insufficiency (resting hypoxemia and VO2max <50% predicted).

3. Pulmonary alveolar proteinosis (PAP) is characterized by the progressive accumulation of an abnormal surfactant in the alveoli, which leads to impaired gas exchange and respiratory failure. Three forms are recognized: congenital, acquired, and secondary (associated with many secondary etiologies). Acquired disease is the most common and associated with a high prevalence of antibodies to granulocyte and macrophage colony-stimulating factor (GM-CSF) that are thought to be pathogenic.

Symptoms: Slowly progressive dyspnea and nonproductive cough; sometimes fatigue, weight loss, low-grade fever. Untreated patients are more susceptible to respiratory infections (nocardia, mycobacteria, and opportunistic fungi). The clinical course of acquired autoimmune disease follows 3 distinct patterns: progressive deterioration, stable disease, or spontaneous resolution. Chest radiographs reveal ground-glass opacities and consolidations with air bronchogram. HRCT shows areas of ground-glass opacities that are well demarcated from the normal lung parenchyma as well as thickening of the interlobular septa, which produces a “crazy paving” pattern. Positive serum and/or bronchoalveolar lavage (BAL) autoantibodies to GM-CSF (titers >1/400 or concentrations >5 microg/mL) are characteristic of acquired PAP.

Diagnosis is based on clinical features, radiologic features, and BAL fluid examination (a characteristic “milky” appearance; cytologic examination reveals a granular periodic acid–Schiff [PAS]-positive lipoproteinaceous material that is both extracellular and fills alveolar macrophages). Positive serum and/or BAL autoantibodies against GM-CSF (titers >1/400 or concentrations >5 microg/mL) are characteristic of acquired PAP. Surgical lung biopsy is required for diagnosis in a minority of patients. Secondary causes of PAP need to be excluded.

Treatment: Whole-lung lavage under general anesthesia for patients with severe dyspnea and hypoxemia. Subcutaneous or inhaled administration of GM-CSF may be an option for adults who cannot undergo or who have not responded to whole-lung lavage. Rituximab can be considered in severe autoimmune cases not responsive to conventional therapy.