Assessment and management of pulmonary alveolar proteinosis in a reference center.

Pulmonary alveolar proteinosis (PAP) is a term defining an ultra-rare group of disorders characterised by a perturbation in surfactant homeostasis, resulting in its accumulation within airspaces and impaired gas transfer. In this report we provide data from a cohort of PAP patients (n=81) followed for more than two decades at the San Matteo University Hospital of Pavia, Italy. In agreement with other large series in PAP individuals, 90% of the study subjects were affected by autoimmune/idiopathic PAP, while the remaining subjects were divided as follow: congenital 1%, secondary 4% and PAP-like 5%. The disease affected males and females with a ratio of 2:1 and approximately one third of PAP patients were lifelong nonsmokers. Occupational exposure was reported in 35% of subjects in this series. With reference to the PAP clinical course, in 29 patients (7% with spontaneous remission) disease severity did not necessitate whole lung lavage (WLL) in the long-term follow up. On the other hand, 44 PAP patients underwent therapeutic WLL: in 31 subjects a single WLL was sufficient to provide long term, durable benefit, whereas 13 patients required multiple WLLs. The intra-patient mean interval between two consecutive WLLs was 15.7±13.6 months. When baseline data among never lavaged and PAP patients lavaged at least once were compared, the need for lavage was significantly associated with serum biomarkers (CEA, Cyfra, LDH), lung function parameters forced vital capacity (FVC), and lung diffusing capacity (Dlco). We conclude that patient cohorts with an ultra-rare disease, such as PAP, referred to a single reference center, can provide useful information on the natural history and clinical course of the disease.

Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe.

The approach to treating a rare disease is different to that taken for more common diseases. Small patient cohorts alter clinical trial design and limit enrollment, and the picture for rare lung diseases is further complicated by the fact that most are composed of a variety of clinical phenotypes. Since the outcome measures of lung impairment have considerable test-to-test variability, potential new therapies face a substantial challenge. In this paper we will review the current sources of clinical data for rare lung diseases and the regulatory challenges encountered by their treatment, with particular reference to alpha(1)-antitrypsin deficiency, lymphangioleiomyomatosis, cystic fibrosis, and pulmonary alveolar proteinosis. Strategies will also be identified for the better utilization of available data from patients with rare lung diseases, recognizing that the development cost of new therapies and the number of patients who will ultimately use them may not be aligned. Also important is improved communication between patients and their organizations, basic researchers, clinicians and their registries, drug developers, regulators such as the European Medicines Agency, and national health services. At present, licensing and reimbursement requirements are not aligned, either nationally or internationally, and variations also exist in drug availability between countries because of different national licensing and reimbursement rules. The changes needed to optimize European rare lung disease therapies include a commitment to develop empowered patient communities as advocates for therapy, the development of novel trial designs with new endpoints, and for regulatory bodies to be willing to accept nontraditional models of efficacy for orphan drugs.

alpha1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note.

The use of IV augmentation therapy with plasma-derived alpha1-antitrypsin (AAT) has become the standard of care for the treatment of pulmonary disease associated with the severe genetic deficiency of AAT. The Medical and Scientific Advisory Committee of the Alpha-1 Foundation has become aware that physicians are prescribing this expensive blood product for the treatment of individuals with a single abnormal AAT gene, primarily the PI*MZ genotype. We are aware of no evidence that such therapy is effective in this patient population. The most important therapeutic interventions in such patients remain smoking cessation and elimination of other risk factors for lung disease. This commentary discusses the treatment of AAT deficiency and the concerns regarding treatment of PI*MZ individuals. We conclude that clinicians should avoid prescribing augmentation therapy for this heterozygote population.

Endocytic internalization of adenovirus, nonspecific phagocytosis, and cytoskeletal organization are coordinately regulated in alveolar macrophages by GM-CSF and PU.1.

GM-CSF gene-targeted (GM(-/-)) mice have impaired pulmonary clearance of bacterial and fungal pathogens by alveolar macrophages (AMs). Because AMs also clear adenovirus from the lung, the role of GM-CSF in endocytic internalization of adenovirus by AMs was evaluated. Pulmonary clearance of adenovirus was severely impaired in GM(-/-) mice compared to wild-type (GM(+/+)) mice as determined by Southern analysis of viral DNA. Internalization of adenovirus by AMs was deficient in GM(-/-) mice in vivo and in vitro as determined by uptake of fluorescently labeled adenovirus or by PCR quantification of adenoviral DNA internalized within AMs. An AM cell line previously established from GM(-/-) mice (mAM) had impaired internalization of adenovirus and transferrin-coated 100-nm latex beads compared to MH-S, a GM(+/+) AM cell line. Phagocytosis of 4- micro m latex beads was also impaired in mAM cells as determined by confocal and fluorescence microscopy. Retroviral vector-mediated reconstitution of PU.1 expression in cultured GM(-/-) AMs restored phagocytosis of 4- micro m beads, endocytosis of adenovirus, and transferrin-coated 100-nm beads (independent of integrin alpha(V) and transferrin receptors, respectively), and restored normal cytoskeletal organization, filamentous actin distribution, and stimulated formation of filopodia. Interestingly, mRNA for the phosphoinositide 3 kinase p110gamma isoform, important in macrophage phagocytic function, was absent in GM(-/-) AMs and was restored by PU.1 expression. These data show that GM-CSF, via PU.1, regulates endocytosis of small ( approximately 100 nm) pathogens/inert particles and phagocytosis of very large inert particles and suggests regulation of cytoskeletal organization by GM-CSF/PU.1 as the molecular basis of this control.