Review
Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach

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Summary

Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease that results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homoeostasis. Identification of the granulocyte–macrophage colony-stimulating factor (GM-CSF) as an indispensable mediator of macrophage maturation and surfactant catabolism was the key discovery leading to the current understanding of the pathogenesis of most forms of PAP. Impaired GM-CSF bioavailability due to anti-GM-CSF autoimmunity is the cause of approximately 90% of adult PAP cases. Abnormal macrophage function due to endogenous or exogenous triggers, GM-CSF receptor defects, and other genetic abnormalities of surfactant production account for the remainder of causes. The usual physiological consequence of PAP is impairment of gas exchange, which can lead to dyspnoea, hypoxaemia, or even respiratory failure and death. Pulmonary fibrosis occurs occasionally in patients with PAP. For patients with moderate to severe disease, whole lung lavage is still the first-line treatment of choice. Supplemental GM-CSF is also useful, but details about indications, choice of agent, and dosing remain unclear. Other therapies, including rituximab, plasmapheresis, and lung transplantation have been described but should be reserved for refractory cases.

Introduction

Since its first description in 1958 by Rosen and colleagues,1 our understanding of the pathogenesis, natural history, and treatment of pulmonary alveolar proteinosis (PAP) has evolved considerably. PAP is characterised by the accumulation of surfactant in alveolar macrophages and alveoli, resulting in impaired gas exchange. Clinically, patients with PAP can be asymptomatic or present with progressive dyspnoea, worsening oxygen requirements, and have an increased susceptibility to infections. PAP has a variable clinical course, ranging from spontaneous resolution to death from infections or progressive respiratory failure. In this Review, we elucidate current knowledge of the pathogenesis of PAP, and also discuss the diagnosis, treatment, and future developments.

Section snippets

Pathogenesis and classification of PAP

The principal abnormalities in adult PAP result from poor surfactant clearance and altered surfactant homoeostasis in the lung due to impaired alveolar macrophage function (figure 1). Attenuated alveolar macrophage maturation is typically caused by inadequate granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling, which is crucial for development of the full range of alveolar macrophage metabolic and immune functions.2 Autoimmune PAP, formerly known as idiopathic PAP, occurs when

Role of GM-CSF in PAP

One of the major breakthroughs in our understanding of the pivotal role of GM-CSF for alveolar macrophage function was the near fortuitous discovery that GM-CSF knock-out mice developed intra-alveolar accumulation of surfactants, remarkably similar in phenotype to human PAP.14, 15 Mice deficient in the GM-CSF receptor β chain also developed a lung phenotype similar to that of GM-CSF-deficient mice.16 Replacement of the GM-CSF gene and treatment with aerosolised GM-CSF were found to correct the

Clinical features

PAP typically presents in the third to sixth decade of life.4 The disease is more common in men, with a prevalence ratio of approximately 2:1.4, 8 However, women might have an earlier age of presentation than men.4 There is no known racial predilection. Although a causal relationship between tobacco use or environmental triggers and PAP has not been established, there is a higher than expected proportion of smokers (50–70%) and dust exposure (20–50%) in reported cohorts.4, 8, 41 It is possible

Diagnosis of PAP

Although clinical presentation and HRCT pattern alone can be fairly suggestive in typical cases, the first step in confirming PAP is usually a bronchoscopy. Broncho-alveolar lavage might demonstrate characteristic opalescent or milky-appearing fluid (figure 3). The milky consistency is due to the high lipoproteinaceous content of the amorphous material that accumulates in the alveolar spaces. Under light microscopy, characteristic acellular oval bodies that are basophilic on May–Grünwald–Giemsa

Treatment

There are no international consensus guidelines for treatment of PAP. Conventionally, therapeutic decisions are largely based on disease severity and type of PAP. Patients with mild symptoms and no evidence of substantial physiological impairment can be monitored by serial assessment of symptoms, pulmonary function testing, oxygenation, and chest radiography. Patients with moderate-to-severe disease warrant a more aggressive approach. Similar to recommendations for patients with other chronic

Corticosteroids

By analogy with other autoimmune diseases, corticosteroid therapy seems logical for treatment of autoimmune PAP. However, most data from patients with PAP treated with corticosteroids suggest more harm than benefit. In a retrospective study,82 patients treated with steroids had a dose-dependent worsening of their Disease Severity Scores. Although the exact explanation is unknown, it is likely that the negative effect corticosteroids exert on macrophage phagocytosis and catabolism account for

Lung transplantation

There is minimal experience with lung transplantation in patients with PAP. Recurrence in the lung allograft is one of the major concerns with transplantation in PAP.91, 92, 93 Recurrence in transplant recipients could be attributed to the immune dysregulation that is persistent in patients with PAP, particularly those with underlying genetic mutations.91 Secondary PAP can also develop de novo in some transplant recipients, and is probably related to disruption of the native immune system by

Treatment of hereditary and secondary PAP

For patients with secondary PAP, the initial therapeutic focus should generally be on removing offending exposures or treating the underlying medical disorder. For individuals with myelodysplastic syndrome, the development of PAP is associated with poor survival.99 In patients with advanced respiratory compromise, WLL could be useful.100 Bone-marrow transplantation has been considered in myelodysplastic syndrome complicated by secondary PAP, but the data are limited to case reports.101, 102

Prognosis

The clinical course of PAP is highly variable, ranging from spontaneous resolution to death due to progressive respiratory failure or infection.4 Although observations from early cohorts suggested that spontaneous resolution occurs in 25–30% of patients, more recent studies observed resolution in only 7–8% of patients.4, 103, 104 There are no known reliable clinical features that can predict which patients will have spontaneous remission. In a large study starting in the 1950s by Seymour and

Future research

One of the major impediments to estimating prevalence, ascertaining diagnosis, and defining the actual effect of therapies in PAP is the rarity of the condition. A US registry for patients with PAP is currently recruiting and should provide further insights into the prevalence and genetic risk factors for development of the disease. The registry also aims to demonstrate the feasibility of measuring GM-CSF antibodies with a diagnostic blood spot card (NCT02461615).

The indications and benefits of

Conclusions

Since the original description of PAP, our understanding of the pathogenesis and classification of the disorder have evolved substantially. Impaired alveolar macrophage maturation and surfactant clearance due to abnormal GM-CSF signalling are now recognised as the fundamental defects in autoimmune PAP, which constitutes the majority of adult cases. However, PAP can be secondary to other triggers, particularly bone-marrow disorders or inhalational exposures, and is rarely hereditary. Although

Search strategy and selection criteria

We searched Medline and PubMed for reviews and original articles about pulmonary alveolar proteinosis published in English from Jan 1, 1950, to July 1, 2017. We used the terms “pulmonary alveolar proteinosis” in combination with “pathogenesis”, “diagnosis” and “treatment”. We also searched individual terms such as “GM-CSF”, “alveolar macrophages”, “whole lung lavage”, “recombinant GM-CSF”, “rituximab”, “plasmapheresis”, and “lung transplantation”. We chose studies mostly published within the

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