By Ilaria Campo, Francesco Bonella

Pulmonary Alveolar Proteinosis (PAP) State of the art

Introduction

Pulmonary alveolar proteinosis (PAP) is an extremely rare lung disease, occurring with an estimated prevalence of 0.3 per 100,000 individuals worldwide. It was first described by Rosen and Castleman in 1958 [1] and is characterized by the accumulation of periodic acid-Schiff (PAS)-positive lipoproteinaceous material, primarily phospholipid surfactant and surfactant apoproteins, in the distal air spaces, which could lead to impaired gas-exchange and progressive respiratory failure.

The clinical course of PAP is variable, ranging from asymptomatic respiratory insufficiency to respiratory failure and death. The onset of clinical disease is insidious, with a subacute indolent course that often delays the diagnosis by months to years. This delay is secondary to the time required for sufficient surfactant accumulation in the alveoli to impair gas exchange. In fact, decreased clearance of surfactant from the alveoli has been postulated as the basis of PAP pathogenesis.

PAP occurs in distinct clinical forms: autoimmune (the most frequent, associated to the presence of GM-CSF autoantibodies), secondary (associated with hematologic or solid malignancies, inhalation of dusts and lysinuric protein intolerance), congenital (caused by mutations in genes coding for the granulocyte-macrophage colony-stimulating factor receptor, GM-CSF-R), and PAP-like syndrome (cased by mutation in the genes coding for surfactant protein -B or -C or ABCA3).

The autoimmune form accounts for more than 90% of PAP cases and is characterized by the presence of autoantibodies directed towards the GM-CSF, which lead to a defective maturation of alveolar macrophages and thus impair their function in surfactant clearance. Moreover, the anti GM-CSF autoantibodies impair the microbicidal activity of neutrophils [2], possibly explaining the basis for recurrent infections in PAP. When highly purified GM-CSF autoantibodies, isolated from a patient with autoimmune PAP, were administered to healthy nonhuman primates, the human disorder was reproduced, thus demonstrating the role of these autoantibodies as causative agent [3].

Clinical presentation

Autoimmune PAP patients usually present as young to middle-aged adults with progressive exertional dyspnea of insidious onset, or dyspnea and cough. However a large fraction of autoimmune PAP patients are asymptomatic (up to 31%) [4,5] and the disorder is detected as an incidental finding or on annual health examination. Secondary PAP, especially associated with haematological disorders, occurs in elderly patients and is complicated by the symptoms related to the underlying disorder. The prognosis is worse than in autoimmune PAP. In congenital PAP, typically presenting in children between the ages of 1 and 11, the clinical signs appear worse and frequently results in progressive respiratory insufficiency. It is often fatal within the first year of life, with a significant number of patients developing a chronic lung disease throughout life.

The physical examination in autoimmune PAP is typically unremarkable but may reveal inspiratory crackles and in most severe cases, cyanosis. Routine laboratory tests are usually normal except for an increase in lactate dehydrogenase (LDH). Pulmonary function tests are normal but in patients with more severe disease, may reveal a restrictive ventilatory defect with impairment of forced vital capacity, total lung capacity, and a marked decrease in lung diffusing capacity. Hypoxia, either with exertion or at rest in severe cases, is frequently present [6] and causes an increased alveolar- arteriolar diffusion gradient.

Due to defects in alveolar macrophage host defense functions, caused by the accumulated surfactant, an increased frequency of secondary infections has been reported in association with PAP. In particular, opportunistic agents, including Nocardia aster­oides, mycobacteria, Cryptococcus neoformans, Aspergillus, Mucor, and Pneumocystis jiroveci, have been isolated [5,7,8-11].

Diagnostics

In autoimmune PAP the chest radiograph typically reveals widespread, usually but not always bilateral air-space disease that is patchy and asymmetric in nature [12] (Figure 1).

High-resolution computed tomography (HRCT) of the chest shows a characteristic pattern of ground-glass opacities with sharply defined straight and angulated margins with a geographic appearance superimposed over a pattern of fine overlapping lines forming irregular polygonal shapes typically in a patchy distribution throughout both lungs (Figure 2) [13]. This pattern is commonly referred to as “crazy paving” and is characteristic but not diagnostic of PAP. The chest HRCT in PAP varies with disease severity, having a more homogeneous or consolidative pattern with advanced disease, and is altered by superimposition of parenchymal infection, with confluent, well-demarcated areas of consolidation. The chest HRCT in congenital PAP has a similar appearance [14], while the appearance in secondary PAP can vary considerably [15].

Lung biopsy is generally not required to diagnose PAP since bronchoalveolar lavage shows characteristic macro and microscopic findings (a milky appearance and foamy alveolar macrophages, cell debris and positivity for periodic acid-Schiff (PAS) staining). Histopathologically, alveoli are filled with eosinophilic material, which is PAS positive. Foamy alve­olar macrophages are often present within the alveolar spaces and ghost cells may be seen. Ghost cells are rem­nant cells in which the cell membrane is still visible but the nucleus has dissolved. A preservation of the parenchymal architecture and no inflammatory response are usual. Ultrastructurally, electron microscopy demon­strates numerous lamellar bodies within type II cells and tubular myelin within alveolar spaces [16].

Biomarkers

Autoimmune PAP patients are characterized by increased levels of GM-CSF autoantibodies in serum. Values above 3 mg/ml (with a polyclonal standard [17-19]) or 0.5 mg/ml (with a monoclonal standard [20]) are considered diagnostic, with the sensitivity and specificity approach 100% [4, 21, 22].

Elevated serum LDH, carcinoembryonic antigen (CEA), cytokeratin 19, CYFRA 21-1, mucin KL-6, and SP-A, and -D can be frequently found but are non-specific for PAP. Interestingly an increase in serum levels of KL-6, CYFRA 21-1, CEA and surfactant proteins seems to correlate with lung disease severity [4, 23-25].

PAP Therapy
Whole lung lavage

Bilateral sequential whole lung lavage (WLL) is the gold standard of care for PAP. In the pre-WLL era, PAP was fatal mostly because of progressive respiratory failure and, to a lesser extent, superimposed respiratory opportunistic infections. The introduction of the WLL occurred in the mid 60s and changed the natural history of PAP, with significant improvements in symptoms and radiographic results. However, it induces complete resolution of the disorder only in 30% of patients and it is associated with a very variable response. In contrast with the 80% rate reported by Seymour and Presneill in 2002 [5], in the series of Beccaria et al [26] the recurrence rate was 28% in prolonged follow up.

The technique is performed under general anaesthesia in the intensive care unit. The patient is intubated, one lung is lavaged by infusing aliquots of saline warmed to body temperature, while the non lavaged lung is mechanically ventilated. At the end of the infusion, fluid is collected by gravity. Chest wall percussion is generally added. Lavage and percussion are continued until the outflow fluid became completely clear, which may take 3 hours and a total of 15–20 L saline for a single lung.

The principal criticism of this procedure is that WLL has not been standardized in terms of the procedure itself (i.e., volume infused, use of mechanical percussion, the endpoint of an individual lavage procedure), the indications for its use, methods for determining the endpoint evaluating the treatment effectiveness, or timing of repeated procedures. Moreover, no perspective clinical trials have been performed. As a result, WLL has been modified by each center [27] and a number of publications deal step by step with the technical issues [28-30].

Reasonable indications for when to perform WLL, collected from available reports, include: presence of persistent or progressive respiratory failure; absence of respiratory difficulty at rest, but presence of exercise desaturation (>5% points); in selected cases, WLL may be discussed if a PAP patient, in particular a young adult, reports a significant limitation in daily or sport activities [27].

WLL is generally well tolerated. The major adverse effect of WLL is hypoxemia, especially during the emptying phase. Other more common and less dangerous complications include pneumothorax, pleural effusion and hydropneumothorax. Nevertheless, over time the WLL technique has been continuously improved, thus allowing even severely impaired PAP patients to be treated successfully.

Bronchofiberscopiclobar lavage

Multiple segmental or lobar lavage by fiberoptic bronchoscopy is an alternative used in patients in whom whole lung lavage under general anesthesia is considered risky due to severe hypoxemia [31] or in paediatric patients, where the use of WLL is less well established mainly because of the technical difficulties associated with the use of large endotracheal tube [27, 32].

GM-CSF substitution therapy

Although WLL is still considered the gold standard for treatment, the discovery of alveolar macrophage involvement and anti GM-CSF neutralizing antibodies led to the use of GM-CSF as a potential therapeutic approach for PAP.

So far, only a limited number of PAP patients have been treated with subcutaneously administered GM-CSF therapy. In one such study, 14 autoimmune PAP patients received subcutaneously administered GM-CSF in escalating doses (5-20 mg/kg/day) over a 3-month-period [33]. In another study, 21 autoimmune PAP patients were treated with escalating subcutaneous doses of 5 – 18 mg/kg/day for 6-12-months [34]. Other small series and case reports using a similar approach. Summarizing the subcutaneous administration results in: improvement in about 50% of patients; a variable response among patients, depends on the dose and duration of treatment; presents a lag of about 8 weeks before a response.

Aerosolized GM-CSF has been used to treat 35 autoimmune PAP patients in Japan using an induction dose (250 mg on days 1-8 of 14, x 6 cycles) followed by maintenance dose (125 mg on days 1-4 of 14, x 6 cycles [35]. The overall response rate was 62%, somewhat higher than the response rate in patients treated with subcutaneous GM-CSF. This approach was not accompanied by drug-related adverse effects.

Finally, a clinical trial on a combination therapy for the treatment of autoimmune PAP, with WLL followed by inhaled recombinant GM-CSF (Sargramostim), has been recently started in Italy, at the IRCCS Policlinico San Matteo Foundation (AIFA FARM7MCPK4). Preliminary results seem to be promising, showing that inhaled GM-CSF is well tolerated, safe, and efficacious as therapy of aPAP and that WLL followed by inhaled Sargramostim is more efficacious than WLL alone.

Other therapeutic options

Other potential therapeutic strategies for autoimmune PAP include plasmapheresis and B-lymphocyte-depletion by Rituximab, which both target decrease in GM-CSF autoantibody levels. Only a few patients have been treated with such approaches [36, 37].

Lung transplantation has been also performed successfully in one patient with PAP, but the clinical course was characterized by disease recurrence 3 years later [38].

chest
Figure 1. Appearance of the Chest Radiograph in Autoimmune PAP

tomography
Figure 2. High Resolution Computed Tomography of the Chest in Autoimmune PAP


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Editor in chief
Bonella

Dr. med. Francesco Bonella
Senior Clinical Researcher
Interstitial and Rare Lung Disease Unit
Ruhrlandklinik, Essen
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