relapse after lung transplantation [107]. Indeed PAP and ILD may be related to a macrophage dysfunction, not treated by lung transplantation though the exact pathophysiology of PAP is unknown [100].

Lysosomal Diseases

Hermansky-Pudlak Syndrome

Hermansky-Pudlak Syndrome (HPS) refers to a heterogeneous group of autosomal recessive disorders of intracellular traf cking that result in oculocutaneous albinism, clotting dysfunction secondary to defective platelets, and, in some subtypes that affect alveolar type II cells, ILD. To date, eight different subtypes have been described in humans associated with different genetic abnormalities that lead to abnormal protein traf cking associated with dysfunction of lysosome-­ related organelles [108]. The disease is most prevalent in Puerto Rico due to a founder effect.

Among HPS subtypes, ILD and pulmonary brosis occur in HPS-1 and HPS-4. HPS-1 is the most common subtype of this disease, accounting for approximately 50% of HPS cases outside the Puerto Rican population.

In most individuals with HPS-1 or HPS-4 who survive to adulthood, ILD can be found, with many patients having severe progressive pulmonary brosis resulting in respiratory failure [109, 110]. Patients who present with lung brosis have a mean age of onset of symptoms of 35 and an average age of death related to respiratory failure of 37, consistent with very rapidly progressive disease [110].

Lung biopsy in HPS can not only reveal a pathologic pattern similar to UIP but can also show hyperplastic AECslled with phospholipid-rich droplets and enlarged lamellar bodies, suggestive of possible defects in the surfactant secretory pathway [111]. Compared to HPS-1, HPS-4 is much less common, but lung manifestations occur in the same pattern as noted in HPS-1 [112]. Two small trials evaluated the effect of pirfenidone vs. placebo in these patients and contradictory results were reported. One report, including 35 patients, did not nd a difference between the two groups, while the other study of 21 patients reported decreased lung function decline in treated patients [113].

Lysosomal Storage Disorders

Gaucher disease is an autosomal recessive disease secondary to mutations in the glucocerebrosidase gene resulting in de ciency of the lysosomal hydrolase acid β-glucosidase and in accumulation of its substrate, glucosylceramide [114]. The most frequent manifestations of type 1 Gaucher disease are related to the in ltration of bone marrow, liver, spleen, and lung by lipid-engorged macrophages (Gaucher

cells). Type 2 and 3 Gaucher disease manifests with primary central nervous system (CNS) involvement expressed as spasticity, oculomotor apraxia, and seizures with onset in infancy and premature death [114]. In the few cases of lung involvement of Gaucher disease that have been speci cally reported, the chest CT showed a predominant ground-glass pattern with superimposed thickening of interlobular septa [115]. The natural history of Gaucher disease has been dramatically modi ed by the development of enzyme replacement therapy [116].

Acid sphingomyelinase defciency (ASMD, ex-Nie- mann-Pick disease) is an autosomal recessive disease secondary to acid sphingomyelinase de ciency. The most frequent clinical presentation is a neurovisceral infantile form in type A, but a chronic visceral form presenting with hepatosplenomegaly and pulmonary involvement may also encountered in adults in type B disease [117]. ASMD-B Niemann-Pick disease is a autosomal recessive inherited condition related to mutation within SMPD1 [117]. The most frequent CT patterns are interlobular septal thickening and ground-glass opacities, and bronchoalveolar lavage shows characteristic Niemann-Pick cells (Fig. 24.6) [118, 119]. Although pulmonary manifestations eventually worsen, the results of a clinical trial with enzyme replacement therapy should soon be available (NCT02004691).

Fabry disease is an X-linked lysosomal storage disorder caused by mutation of the α-galactosidase gene (GLA) causing de ciency of α-galactosidase A activity [120]. This enzymatic defect leads to the progressive accumulation of glycosphingolipids resulting in neurological, ocular, skin, renal, and cardiac manifestations in classical type of the disease [120]. Respiratory symptoms are most frequently related to cardiac involvement. A few cases of ILD and ground-glass pulmonary in ltrations on CT scan in patients with Fabry disease have been reported [121]. Enzyme replacement therapy may improve or stabilize respiratory manifestations [121].

FAM111B, NDUFAF6, PEPD

At least ve families with poikiloderma associated with tendon contractures and pulmonary brosis were found to have FAM111B mutations [122]. In this series, CT seems to be inconsistent with UIP.

Acadian variant of Fanconi syndrome refers to a speci c condition characterized by proximal tubular dysfunction in newborns, resulting in chronic kidney disease and pulmonary interstitial brosis. It has been associated with biallelic intronic variants of NDUFAF6 encoding a mitochondrial enzyme. Pulmonary data are sparse, but the age of