Hospital Practice: Volume 38: No.1

An Overview for Internists and Hospital Physicians

Monisha Das, MD And Gary A. Salzman, MD

Abstract: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by abnormal accumulation of surfactant-associated phospholipoproteinaceous material in the pulmonary alveoli. The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of “bat-wing configuration” and “crazy paving” appearance in high-resolution computed tomography are suggestive, but not diagnostic of PAP. The current gold standard of PAP diagnosis involves histopathological examination of alveolar specimens obtained from bronchoalveolar lavage and transbronchial lung biopsy. The characteristic histopathological features are intraalveolar periodic acid Schiff (PAS)-positive eosinophilic homogeneous material with well-preserved architecture of alveolar septa. The current standard medical treatment of PAP involves the physical removal of the surfactant-associated phospholipoproteinaceous alveolar deposit by whole lung lavage, which causes clinical and radiological improvement in a majority of patients. Some patients have been successfully treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF).

Keywords: pulmonary alveolar proteinosis; periodic acid Schiff; granulocyte-macrophage colony-stimulating factor; bronchoalveolar lavage

Pulmonary alveolar proteinosis (PAP) is a relatively rare clinicopathological entity with an estimated annual incidence of 0.36 and a prevalence of 3.7 per million population in the United States and internationally.^1,2 This usually manifests as a diffuse lung disease and is characterized by the accumulation of a large amount of periodic acid Schiff (PAS)-positive material, surfactant-associated phospholipoproteins, in the lung alveoli.³ The pulmonary architecture is generally well preserved with minimal or no interstitial inflammation or fibrosis.^2,4 This intraalveolar deposit blocks the alveolar sacs and interferes with the normal diffusion of gases between the alveoli and the capillaries. Patients commonly present with progressive dyspnea of gradual onset or dyspnea on exertion, at times associated with persistent dry cough or fatigue.^1,2,4,5 The clinical course is variable, however, ranging from spontaneous resolution (reported in ~8%–30% of patients) to death due to pneumonia or respiratory failure.² Approximately 30% of patients with PAP may remain asymptomatic with relatively minor nonspecific physical findings,^2,4,5 even with diffuse radiographic chest abnormalities. The physician is generally faced with a patient complaining of slow onset of breathlessness or dyspnea with chest radiograph (CXR) showing bilateral, asymmetrical consolidation.^2,5-7 A wide range of differential diagnoses should be considered, including a large number of pulmonary diseases and some systemic disorders (Table 1). Thus, diagnosis and management of PAP may involve all or many areas of medicine. As PAP is a relatively rare lung disease presenting clinically and radiographically with nonspecific features, misdiagnosis or delayed diagnosis is possible, leading to inappropriate therapy and unnecessary morbidity. Considerable advances have been made during the past 8 years in the understanding of the etiopathogenesis of this rare and puzzling lung disease, offering newer approaches to its diagnosis and management.^2,4,5 This review aims to provide an overview of various aspects of pulmonary alveolar proteinosis, highlighting some interesting aspects of emerging scientific findings.

Pulmonary alveolar proteinosis was finally recognized as a distinctive disease entity in 1958 following the publication of a report of 27 cases of this disorder by Rosen et al.⁸ Rosen did, however, recognize the distinctive pathology of the first case of this series as early as 1953, and several other similar cases were described earlier.^2,9,10 Epidemiological studies of PAP have been difficult because of its relative rarity. Approximately 500 patients with PAP have been described in the literature, mostly as single case reports and a few short series of ≥ 10 cases.^1,2,4 No particular racial or geographic predilection has been described and about 72% of patients were smokers.^2,4

The pathogenesis of this clinicopathological syndrome remained unclear for almost 3 decades since its initial description in 1958. During the last 10 years newer scientific evidence has lead to a greater understanding of the pathophysiological basis of this syndrome. Etiologically, PAP constitutes a heterogeneous group with similar clinicopathological expressions. Accordingly, PAP is classified into 3 distinct forms (Table 2).^2,4,5

Although the majority of PAP patients are adults aged 25 to 50 years, it is recognized that PAP may occur as a congenital/hereditary disorder in some infants and neonates. Although the histological appearance of the alveolar lesions in these cases is similar to that of PAP in adults, the congenital/hereditary forms of this disorder appear to follow a different clinical course, and most infants with this form of PAP do not survive after the first year of life despite the maximum medical therapy available.^11,12 These abnormalities appear to be mostly transmitted in an autosomal recessive manner, and the disease is manifested only in the homozygous state.^13,14-18 A large number of different mutations relevant to hereditary PAP have been described that are of special interest to the geneticists.^15-24

The secondary form of PAP occurs in patients in association with various infective disorders, exposure to numerous environmental agents,^25,26 and some systemic disorders including hematopoietic malignancies and immunological deficiencies^27-30 (Table 3); the possible pathophysiological relationship between PAP and these underlying agents or conditions remains poorly understood.

More than 90% of PAP cases in the adult are considered to be acquired disorders in which no familial predisposition or any other known association are present, and are apparently of unknown etiology.^2,3,7 In recent years, autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) have been detected in the sera and bronchoalveolar lavage (BAL) fluid of patients with acquired PAP,^31-35 which are not present in the sera of patients with congenital or secondary PAP. These antibodies were found to cause inactivation of GM-CSF in vitro as well as in vivo, and impair the ability of macrophages to catabolize and remove surfactant-associated phospholipoproteins from the pulmonary alveoli of patients with acquired PAP.^34,35

A few comprehensive and excellent reviews have been published on the clinical features of PAP.^1,2,4,5 More than 90% of PAP cases were described as primary acquired disorders of unknown etiology before the discovery of autoantibodies against GM-CSF in the sera and BAL fluid of many of these patients. Approximately 30% of such patients were without any symptoms for a long time.^1,4,5 The median duration of symptoms before diagnosis was reported to be about 7 months. The median age at diagnosis was 39 years for men and 33.5 years for women. There was a preponderance of men, with a male-to-female ratio of approximately 3:1. Most patients (~72%; 85% for men and 39% for women) were smokers at the onset of symptoms. When patients develop symptoms, they commonly present with slowly progressive shortness of breath or dyspnea on exertion and persistent dry cough with little or no sputum. Rarely, cough may be productive with expectoration of gelatinous, gummy, or chunky sputum.^2,36 Some patients have symptoms of generalized illness such as malaise, fatigue, weight loss, and low-grade fever and night sweats at onset. Rarely, patients complain of pleuritic chest pain and hemoptysis. Physical examination often yields normal features or relatively minor, nonspecific findings, such as end-inspiratory rales, in about half of patients. Clubbing of fingers has been reported in about 25% and cyanosis in 20% of patients. Rarely, features suggestive of pulmonary hypertension and cor pulmonale have been observed, particularly at a late stage. Because of the apparently mild and nonspecific nature of the presenting features, it becomes necessary to invoke a host of pulmonary and nonpulmonary conditions for differential diagnosis, and carry out numerous investigations to establish a correct diagnosis. Pulmonary function testing reveals decrease in total lung capacity, and forced vital capacity; carbon dioxide diffusing capacity is disproportionately reduced relative to other pulmonary function parameters.^1,2,4 Various degrees of hypoxia occur and worsen with exercise. This may be due to a right-to-left shunt through poorly ventilated areas with preserved perfusion.³⁷ The possible major clinical complications include lung infections with bacteria, including Mycobacterium tuberculosis (M tuberculosis) and Nocardia asteroides. Pulmonary fibrosis and cor pulmonale may complicate PAP at a late stage.

Plain CXR shows bilateral asymmetrical perihilar infiltrates appearing either as ground-glass opacity or frank consolidation, giving a “bat-wing configuration” (Figure 1).^5,6 These changes are nonspecific and may mimic pulmonary edema with typical absence of cardiomegaly or pleural effusion; there is no mediastinal widening. Unilateral involvement has also been described.

High-resolution computed tomography (HRCT) of the chest reveals areas of patchy ground-glass opacity with smooth interlobar thickening that produces a polygonal pattern, referred to as “crazy paving” (Figure 2).^6,7 However, crazy paving appearance is suggestive but not specific for PAP, because this can be observed in several other lung diseases, such as lipoid pneumonia, pulmonary sarcoidosis, acute respiratory distress syndrome, mucinous bronchoalveolar carcinoma, diffuse pulmonary infections including M tuberculosis, other bacterial pneumonia, and hydrostatic pulmonary edema. In addition, atypical PAP may not present as crazy paving.^2,6,7

The lactic dehydrogenase (LDH) level in the sera of patients with PAP is consistently elevated, and serial measurement of serum LDH levels in individual cases suggests that this enzyme level may be a useful indicator of disease severity.³⁸

It is important to establish a tissue diagnosis utilizing transbronchial biopsy, video-assisted thorascopic surgery, or open lung biopsy. The procedure used is dependent on the clinical status of the patient. Histopathological examination of alveolar sections show complete or near complete filling of alveolar spaces and terminal bronchioles with PAS-positive (eosinophilic) acellular lipoproteinaceous material with relatively well-preserved interalveolar septa in the pulmonary architecture (Figure 3). These features remain the gold standard of PAP diagnosis.

The detection and measurement of antibodies (usually immunoglobulin G) against GM-CSF are of great diagnostic help in patients with acquired PAP and may indicate the autoimmune nature of the disease process.^31-35

The effective treatment of PAP has gradually evolved over the past decade. The most important principle and practice of medical treatment of PAP involves mechanical removal of the intraalveolar lipoproteinaceous material by whole lung lavage39 under general anesthesia, and bronchoscopy through a double-lumen fiberoptic endobronchial tube;^4-7,40-45 this has become the standard therapeutic procedure.^2,30,39-45 The double-lumen tube allows simultaneous ventilation and lavage. The lungs are briefly ventilated with 100% oxygen before lavage, and isotonic saline solution is used to flush out the alveolar deposits. After completing the procedure, the lung is suctioned off most of the isotonic saline solution and the patient is allowed time to recover before the other lung is lavaged. The procedure for each lung may take several hours. Recently, lung lavages have been performed in hyperbaric oxygen chambers, which have made lavage of both lungs possible on the same day. Following therapeutic lavages, significant clinical, physiological, and radiological improvements occurred in approximately 84% of the evaluated patients.² The median duration of clinical benefit from lavage was 15 months with < 20% of those patients followed beyond 3 years; patients were reported as free from recurrent manifestations of PAP.

The recent detection of autoantibodies against GM-CSF in acquired PAP and their possible pathophysiological role in this disorder have also indicated their novel therapeutic potentials. The subcutaneous administration of recombinant GM-CSF has been envisaged to augment the catabolism and clearance of surfactant-associated phospholipoproteins from the alveoli. Subcutaneous injection of GM-CSF at a dose of 5 to 9 μg/kg/day has been reported to have produced symptomatic, physiologic, and radiological improvement in 75% of patients.^46-48 In another large multicenter study, approximately 50% of patients treated with GM-CSF showed significant clinical response despite the presence of GM-CSF-neutralizing antibodies. ⁴⁹ However, long-term follow-up data are needed as these patients have not yet been followed for > 5 years.^46-49 The overall prognosis for primary acquired PAP is good, with achievement of complete or almost complete clinical remission in many patients (~84% of evaluated patients). There are several reports of spontaneous resolution of primary acquired PAP (10%-24% of patients) occurring 1 to 3 years after diagnosis.^2,43 In secondary PAP, appropriate treatment for the underlying cause is mandatory and inpatient care may be necessary. In the congenital/hereditary form of PAP, the overall prognosis is poor; lung transplantation has been recommended with reasonable anticipation of clinical improvements in some patients.^2,50 Patients with PAP should be referred for regular follow-up with a pulmonologist.

Pulmonary alveolar proteinosis is a relatively rare and enigmatic disorder. It is characterized by abnormal intraalveolar accumulation of surfactant-associated phospholipoproteins. The pathophysiologic basis of this abnormal deposition of proteinaceous material in the lung alveoli remains obscure, although scientific findings will provide a better understanding of this disorder. The majority of PAP cases (~90%) are of the primary acquired variety, but a minority of cases may be associated with or are secondary to various infective disorders, exposure to environmental conditions, and systemic diseases, including hematologic malignancies. A small number of congenital PAP cases may occur in neonates and infants, and are caused by several heterogeneous mutations. A typical patient with PAP clinically presents with gradual-onset dyspnea or dyspnea on exertion with dry cough or fatigue, and with minimal or minor nonspecific physical findings. Plain CXR shows bilateral consolidation, giving a “bat-wing configuration,” and HRCT reveals areas of patchy ground-glass opacity with smooth interlobar septal images described as crazy paving. Neither the clinical presentations nor the radiographic findings are specific for PAP, and a wide range of differential diagnoses must be considered. If the diagnosis is missed or delayed it could lead to inappropriate therapy and unnecessary morbidity. At present, the gold standard of diagnosis is based on histopathological examinations of lung alveolar specimens obtained under general anesthesia by BAL and transbronchial biopsy. This reveals deposits of PAS-positive acellular eosinophilic material in the pulmonary alveoli with otherwise well-preserved architecture of interalveolar septa. The standard treatment in most cases of PAP is physical removal of the surfactant-associated phospholipoproteinaceous material from the pulmonary alveoli by BAL. The overall prognosis for acquired PAP is generally good. A favorable clinical response has been claimed for 85% of patients after therapeutic lavage, although a small proportion of patients may need repeated lavages; the prognosis in the latter cases may be relatively poor, and some of these cases may progress to pulmonary fibrosis. Spontaneous resolution has been reported to occur in 10% to 20% of patients with primary acquired PAP. Recently, autoantibodies against GM-CSF have been detected in the sera and BAL fluid of patients with acquired PAP. These antibodies may inhibit the functions of GM-CSF on macrophages, and impair the ability of the latter to catabolize and remove alveolar lipoproteinaceous deposits in patients with primary acquired PAP. These observations have revealed novel therapeutic options for patients with acquired PAP. Preliminary results of administering recombinant GM-CSF to patients with acquired PAP have yielded encouraging results. Lowering the antibody level through plasmapheresis or immunosuppression are emerging therapeutic treatment options.

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