Pulmonary alveolar proteinosis☆
Section snippets
Medical history
Based on several analyses of published case reports and case series that together included more than 400 patients, the common clinical features of patients with PAP are relatively well established [1], [8], [9], [10], [11]. Although the diagnosis has been reported at all ages, a patient who has PAP is typically a previously healthy adult of median age 39 years who describes a history of slowly progressive dyspnea, with these symptoms being present for a median of 7 months. There is a wide range
Differential diagnosis
The differential diagnosis of an adult who has PAP is wide, because the clinical presentation of this syndrome is nonspecific [11], [28]. Although the adult age group excludes congenital PAP as a possibility, acquired PAP occasionally can be secondary to underlying hematopoietic malignancy [5], [29], intrinsic or iatrogenic immunodeficiency disorders [30], [31], lysinuric protein intolerance [32], acute silicosis, and other industrial inhalational syndromes [33].
On first presentation, acquired
Algorithm for investigation
The diagnostic evaluation of a patient with possible PAP begins with a clinical and occupational history and physical examination that focuses on exercise tolerance and exclusion of cardiac disease or systemic disorders, such as sepsis, vasculitis, and malignancy. Blood and differential leukocyte counts help to detect any underlying hematopoietic malignancy, and blood chemistry tests, including renal and liver function assessment, help detect other systemic disorders. Moderately elevated LDH
Therapeutic lung lavage
Physical removal of excess alveolar surfactant material by repeated segmental flooding with saline was first shown to be beneficial in 1960. Modern whole lung lavage using general anesthesia and single lung ventilation via a double lumen endotracheal tube has been standard therapy for several decades in symptomatic patients. This procedure usually is fairly well tolerated, with significant clinical, physiologic, and radiologic improvements expected in up to 84% of cases after the first lavage
Outcome
Deaths directly related to PAP usually have involved respiratory failure (72%) or uncontrolled infection (18%), and most of these events occur within 1 year of diagnosis. Survival prospects for patients who have PAP seem to have improved consistently in the four decades since the condition was first described, such that survival rates approach 100% for cases reported within the last decade [1]. Spontaneous resolution has been reported in a small number of patients, and it seems likely that the
Discovery of the role of granulocyte-macrophage colony-stimulating factor
GM-CSF was chemically purified in the late 1970s [41], and in 1984 it was one of the first human cytokines to be cloned [42]. It was an intense focus of clinical and laboratory investigation through the 1980s and 1990s because of its potent capacity to stimulate the proliferation and differentiation of neutrophilic and monocyte/macrophage lineage hematopoietic cells in vitro, an action that had remained unexplained since its recognition in 1964 [43]. This capacity provides the basis for its
Gene-targeted mice that lack granulocyte-macrophage colony-stimulating factor
In 1994, two independent publications described the creation and analysis of animals that lack GM-CSF (GM-CSF−/−) [59], [60]. The phenotype was identical, with normal viability and apparently normal fertility [61] and normal steady-state hematopoiesis. The dominant abnormality, not found in GM-CSF+/− animals, was “alveolar-proteinosis”–like lung pathology with surfactant accumulation, which manifested as early as 4 to 8 weeks of age and was associated with an increased frequency of pulmonary
Quantification of surfactant protein and lipid abnormalities
The healthy alveolar surface is lined by a thin liquid layer of surfactant, which lowers its surface tension and serves to stabilize alveoli against collapse [66]. Pulmonary surfactant is structurally heterogeneous complex lipid-protein mixture rich in phospholipids [67], [68], [69]. It is composed of 90% to 95% lipid by mass, predominantly di-saturated forms of phosphatidylcholine (SatPC) (approximately 45%), such as dipalmitoylphosphatidylcholine (DPPC), unsaturated PC (approximately 20%),
Surfactant metabolism and kinetic studies
The surfactant lipids and individual proteins are maintained in dynamic equilibrium through incompletely understood regulatory mechanisms that control synthesis, recycling, and catabolism in a coordinated fashion at the whole lung level [82], [83], [84], [85], [86], [87]. Type II alveolar cells, with a large intracellular storage pool of surfactant within their lamellar bodies, are the sole source of surfactant lipid production, whereas type II cells and Clara cells can produce SPs [85], [88].
Phenotypic and functional studies of lung macrophages
Lung macrophages—alveolar and interstitial—are a critical component of immunologic defense of the lung and provide a pivotal link between the innate and acquired immune systems [7], [94]. They are derived from bone marrow (BM) monocyte precursors [95], [96] and have some limited local proliferative capacity [96], but they are responsive in vitro to M-CSF [97], GM-CSF [97], [98], [99], and IL-3 [100]. The effects of these cytokines vary, however, with differential gene expression and
Bone marrow transplantation
Transplantation of wild-type bone marrow cells into irradiated βc−/− recipients resulted in morphologic clearance of surfactant [126], [127]. BAL cellularity and macrophage morphology were normalized and BAL protein levels were corrected. Several abnormalities persisted, however, including focal alveolar macrophage aggregates, periluminal lymphocytic infiltration, and limited areas of fibrosis. Even at 6 months after transplantation, dynamic pulmonary compliance, a measure of lung
Granulocyte-macrophage colony-stimulating factor antibodies and new diagnostic tests
Most reported serologic tests for PAP are based on small series of patients and lack specificity. No specific marker for the serologic diagnosis of PAP was available until the recent discovery of the autoantibody against GM-CSF. The discovery of this antibody provided the explanatory link between the pulmonary phenotype in GM-CSF−/− mice and patients with PAP.
Role of granulocyte-macrophage colony-stimulating factor in alveolar macrophage development and function
Alveolar macrophages from GM-CSF−/− mice do not express the differentiation-inducing transcription factor, PU.1. Retroviral-mediated PU.1 expression in cultured GM-CSF−/− alveolar macrophages corrects most of the observed defects, including SP catabolism. GM-CSF plays a critical role in surfactant homeostasis by acting locally in the murine lung and stimulating alveolar macrophage terminal differentiation.
GM-CSF in the lung also is likely to be critical for surfactant homeostasis in humans, as
Granulocyte-macrophage colony-stimulating factor as therapy for pulmonary alveolar proteinosis
Although the enormous body of data that clarified the pathogenetic link between GM-CSF neutralizing antibodies and PAP was not known at the time, clinical trials that explored the therapeutic role of GM-CSF commenced in the mid 1990s. The first treated patient in the world responded favorably, with improved oxygenation, which prompted early reporting of this new phenomenon [157]. At the completion of this initial study using 5 μg/kg/day subcutaneous GM-CSF with the potential for later dose
Acknowledgements
The authors wish to thank the following investigators, who made substantial and critical contributions to the work performed in Dr. Nakata's laboratory described herein: Dr. Kanji Uchida, Dr. Emi Hamano, and Dr. Inoue's clinical laboratory described herein: Dr. Toru Arai, Ms. Miho Oka, Ms. Eri Kurokawa, and Ms. Yukiko Hashimoto.
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Thiswork was supported by a grant-in-aid for translational research, Japanese Ministry of Labor (H114-trans-014).