The Multicenter International LAM Ef cacy of Sirolimus (MILES) Trial was a double blind, randomized, parallel group trial of 1 year of treatment with sirolimus or placebo followed by 1 year of observation [63]. Patients who were treated with placebo lost about 10% of their lung function over the course of the treatment year, while patients who received sirolimus had stable lung function, improved functional performance, and improved quality of life. Patients with increased VEGF-D levels responded better to treatment with sirolimus and declined faster without treatment [24]. During the observation year, lung function decline resumed in the sirolimus group and paralleled that of the placebo group. The ATS/JRS LAM Clinical Practice Guidelines recommendations are that sirolimus be used for LAM patients who have an FEV1 that is less than or equal to 70% predicted, problematic chylous effusions, rapidly progressive disease, or a substantial disease burden based on other lung function parameters, such as DLCO [64].

The median survival after transplant in LAM is 12 years [65], which is greater than most lung disorders, most likely because LAM patients with end-stage lung disease typically have few prior co-morbidities. Although several cases of recurrence of LAM in the allograft have been reported [20, 22, 66–68], graft failure due to recurrence is unusual and is not considered a contraindication in most centers [69]. Lung transplantation can be safely performed in most patients despite prior pleurodesis [66, 67, 70]. Sirolimus has been associated with bronchial dehiscence post-transplantation, so discontinuation is recommended on the date that transplant is performed [71, 72].

Pulmonary Langerhans Cell Histiocytosis (PLCH)

PLCH is a DCLD that is characterized by centrilobular lesions composed of CD1a positive dendritic cells (DCs) and other infammatory cells with surrounding brosis. Approximately 90% of adult PLCH patients smoke cigarettes or marijuana or have a history of substantial second-­ hand smoke exposure [73–75]. Dyspnea and/or cough are present in many PLCH patients, but some patients have minimal or no symptoms [74]. Constitutional symptoms, such as weight loss and fever, occur in up to 20% of patients [74]. Pneumothorax is the presenting symptom in about 15% of patients [76] and a similar proportion of patients have extrapulmonary involvement, such as lytic bone lesions, diabetes insipidus, or skin lesions [74, 77–80]. Disease course is variable and unpredictable, ranging from spontaneous resolution, to complete remission with smoking cessation, to rapid progression despite abstinence from tobacco.

Pathogenesis

Through advances in research, driven largely by discoveries in the form of LCH that occurs primarily in pediatric patients

and has no association with smoking [81–83], PLCH is understood to be an infammatory myeloid neoplasm. In PLCH, abnormal dendritic cells (DCs) with activating MAPK mutations accumulate within the pulmonary parenchyma in response to cigarette (or marijuana) smoke exposure [75] and recruit infammatory and stromal cells. Data from human studies and mouse models indicate that the mutant DCs and accumulated infammatory cells release cytokines, cytotoxic mediators, and matrix-degrading enzymes, which leads to nodule formation and cystic destruction [84].

Mutations in BRAF, ARAF, and MAP2K1 genes have been found in myeloid lineages in children and adults with LCH, and in patients with PLCH [85–87]. The most commonly identi ed BRAF mutation in PLCH is V600E. The MAPK mutations found in the PLCH lesions are similar to mutations found in melanoma [88], hairy cell leukemia [89], papillary thyroid cancer [90], as well as other histiocytic disorders, such as Erdheim-Chester disease (ECD) [91].

Pathological and Radiographic Characteristics

Histologically, PLCH lesions are nodular, patchy, peribronchiolar in ltrates that are composed of dendritic cells, lymphocytes, macrophages, and eosinophils. DCs can be identi ed within the lesions by their unique morphological and immunohistochemical features, including staining for S-100 and CD1a.

The underlying mechanisms responsible for lung destruction in PLCH are not well understood. The CD1a positive cells in the nodules of PLCH express membrane maturation markers that are similar to those on the surface of DCs after being activated by cytokines or pathogens [92]. Direct cytotoxic damage by pulmonary macrophages, natural killer cells and cytotoxic CD8 T cells that have been aberrantly activated by the abnormal DCs likely contribute to destructive remodeling [84]. Expression of the BRAF V600E mutation in CD11c myeloid cells was recently shown to result in secretion of CCL7, increased responsiveness to CCL20, and enhanced cellular survival and recruitment [93]. There are several different metalloproteinases in PLCH nodules that are thought to participate in tissue destruction [75, 94, 95].

Radiographically, PLCH lesions are typically bilateral, symmetric, upper-lobe predominant nodules and cysts that spare the bases, especially the costophrenic sulci (Fig. 20.2) [96–98]. In the early stages of disease, small and irregular nodules can predominate [74]. As disease progresses, the nodules form, cavitate, and evolve into thin-walled, irregular, bilobed, clover leafed, or branched cystic structures [98]. Longitudinal studies have shown that the nodules can completely resolve without obvious sequela, but the cysts tend to persist or enlarge [99]. Ground-glass opacities, linear densities, and emphysematous bullae can also be seen as part of the known spectrum of cigarette smoke-induced lung injury [100].