Pulmonary Alveolar Phospholipoproteinosis: Experience With 34 Cases and a Review

doi:10.1016/S0025-6196(12)65477-9

Mayo Clinic Proceedings

Volume 62, Issue 6, June 1987, Pages 499-518

https://doi.org/10.1016/S0025-6196(12)65477-9 Get rights and content

A retrospective review of Mayo Clinic records through 1983 revealed 34 patients (24 male and 10 female; mean age, 41 years) with the diagnosis of pulmonary alveolar phospholipoproteinosis. The major clinical features were dyspnea, cough, fever, and chest pain. Chest roentgenograms usually showed bilateral symmetric alveolar infiltrates, but asymmetric, unilateral, and chronic patchy patterns were also noted. Diagnosis was established by thoracotomy-lung biopsy in 26 patients. Histologic analysis revealed uniform filling of the alveoli by periodic acid-Schiff-positive material and maintenance of normal alveolar architecture. Electron microscopy showed enlarged alveolar macrophages with lamellar osmiophilic inclusions, dense granules, and myeloid bodies. Of the 21 patients who underwent therapeutic bronchoalveolar lavage, 13 had no recurrence of the disease during a mean follow-up of 8.8 years. In patients who underwent pulmonary function testing both before and after lavage, significant restrictive dysfunctions present before the procedure were alleviated afterward. Three deaths occurred among the 34 patients. Pulmonary alveolar phospholipoproteinosis may result from defective clearance of phospholipids by the alveolar macrophages, excessive production of phospholipids by type II pneumocytes, or both. It is likely a nonspecific response to a variety of injuries to the alveolar macrophage or type II pneumocyte or both, including exposure to certain dusts and chemicals and occurrence of hematologic diseases or infections. The uncommon occurrence of this disorder suggests individual susceptibility.

Section snippets

MATERIAL AND METHODS

Retrospective review of clinical records through 1983 at our medical center revealed that pulmonary alveolar proteinosis had been diagnosed in 39 patients, 34 of whom had the typical clinical features of PAP.¹ The five other patients had PAP-like changes in their lungs, but these changes were focal and associated with infections or hematologic malignant lesions. The clinical features, roentgenographic changes, laboratory abnormalities, pathologic features, and results of long-term follow-up

Clinical Features.

The mean age (± SD) of our study group (24 male and 10 female patients) was 41 ± 11.8 years (range, 6 to 67 years); all these patients were white. The major clinical features of these 34 patients with PAP are shown in Table 1. Mild dyspnea was the most common symptom, but significant dyspnea (grade 2 or higher) was present in 48% of the patients. A persistent dry cough was the second most common symptom, and streaky hemoptysis associated with hard coughing was noted by almost a fourth of the

Etiopathogenesis.

The diagnosis of PAP is based on the pulmonary pathologic findings and substantiated by clinical and roentgenographic features. Of importance, PAP-like changes occur in a variety of clinical situations, and at times it may be difficult to distinguish the “idiopathic” or “primary” form of PAP from the “secondary” form of the disease that results from nonpulmonary conditions, exposure to chemicals, and infections. In some instances, PAP may have a genetic basis.⁸ Further confusion is added by the

ACKNOWLEDGMENT

We thank Pamela J. Langrfor secretarial assistance, Bernard Gilles for assistance in performing therapeutic lavage, Patrice C. Abell-Aleff for assistance with the elemental analysis, and Dr. Ralph D. Ellefson for performance of the lipid analysis and chromatography.

REFERENCES (103)

WD Claypool et al.
Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis)
Chest
(1984)
JM Davidson et al.
Pulmonary alveolar proteinosis
Br J Dis Chest
(1969)
HA Buechner et al.
Acute silico-proteinosis: a new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis
Dis Chest
(1969)
G Singh et al.
Pulmonary alveolar proteinosis: staining for surfactant apoprotein in alveolar proteinosis and in conditions simulating it
Chest
(1983)
AR Spurr
A low-viscosity epoxy resin embedding medium for electron microscopy
J Ultrastruct Res
(1969)
AG Bhagwat et al.
Observations on the relationship of desquamative interstitial pneumonia and pulmonary alveolar proteinosis in childhood: a pathologic and experimental study
Chest
(1970)
R Schober et al.
On the origin of the membranous intraalveolar material in pulmonary alveolar proteinosis
Exp Mol Pathol
(1974)
DD McEuen et al.
Particulate concentrations in pulmonary alveolar proteinosis
Environ Res
(1978)
H Jacobs et al.
The significance of reutilization of surfactant phosphatidylcholine
J Biol Chem
(1983)
L Gluck et al.
Diagnosis of the respiratory distress syndrome by amniocentesis
Am J Obstet Gynecol
(1971)

JR Webster et al.

Pulmonary alveolar proteinosis in two siblings with decreased immunoglobulin A

Am J Med

(1980)

DW Golde

Alveolar proteinosis and the overfed macrophage (editorial)

Chest

(1979)

CC Jones

Pulmonary alveolar proteinosis with unusual complicating infections: a report of two cases

Am J Med

(1960)

RA Vidone et al.

The diagnosis of pulmonary alveolar proteinosis by sputum examination

Dis Chest

(1966)

RH Greenspan

Chronic disseminated alveolar diseases of the lung

Semin Roentgenol

(1967)

AR Hudson et al.

Pulmonary interstitial fibrosis following alveolar proteinosis

Chest

(1974)

HC Anton et al.

Pulmonary alveolar proteinosis presenting with pneumothorax

Clin Radiol

(1967)

MB Divertie et al.

Pulmonary alveolar proteinosis: two cases studied by electron microscopy

Am J Med

(1966)

GH Rupp et al.

Bronchopulmonary fluids in pulmonary alveolar proteinosis

J Allergy Clin Immunol

(1973)

SN Bhattacharyya et al.

Characterization of the collagen- and non-collagen-like regions present in a glycoprotein isolated from alveoli of patients with alveolar proteinosis

Biochim Biophys Acta

(1980)

K Wasserman et al.

Lung lavage (alveolar washing) in alveolar proteinosis

Am J Med

(1968)

PL Arora et al.

Alveolar proteinosis: experience with trypsin therapy

Am J Med

(1968)

JO Harris et al.

Lobar lavage: therapeutic benefit in pulmonary alveolar filling disorders

Chest

(1974)

BB Brach et al.

Alveolar proteinosis: lobar lavage by fiberoptic bronchoscopic technique

Chest

(1976)

SH Rosen et al.

Pulmonary alveolar proteinosis

N Engl J Med

(1958)

J Ramirez-R et al.

Pulmonary alveolar proteinosis

Am J Med

(1968)

S Sahu et al.

Lipids found in pulmonary lavage of patients with alveolar proteinosis and in rabbit lung lamellar organelles

Am Rev Respir Dis

(1976)

T Akino et al.

Phospholipids of the lung in normal, toxic, and diseased states

CRC Crit Rev Toxicol

(1981)

CWM Bedrossian et al.

Alveolar proteinosis as a consequence of immunosuppression: a hypothesis based on clinical and pathologic observations

Hum Pathol

(1980)

K Teja et al.

Pulmonary alveolar proteinosis in four siblings

N Engl J Med

(1981)

B Corrin et al.

Pathogenesis of experimental pulmonary alveolar proteinosis

Thorax

(1970)

AG Heppleston et al.

Experimental alveolar lipo-proteinosis following the inhalation of silica

J Pathol

(1970)

KP Lee et al.

Pulmonary response to glass fiber by inhalation exposure

Lab Invest

(1979)

PM Suratt et al.

Acute silicosis in tombstone sandblasters

Am Rev Respir Dis

(1977)

JM Xipell et al.

Acute silicolipoproteinosis

Thorax

(1977)

TR Martin et al.

Pulmonary toxicity of Mt. St. Helens volcanic ash: a review of experimental studies

Am Rev Respir Dis

(1983)

RR Miller et al.

Pulmonary alveolar proteinosis and aluminum dust exposure

Am Rev Respir Dis

(1984)

J Ramirez-R et al.

Pulmonary alveolar proteinosis: diagnostic technics and observations

N Engl J Med

(1963)

J Ramirez-R

Bronchopulmonary lavage: new techniques and observations

Dis Chest

(1966)

EM McDowell et al.

Histologic fixatives suitable for diagnostic light and electron microscopy

Arch Pathol Lab Med

(1976)

AG Heppleston

Atypical reaction to inhaled silica

Nature

(1967)

P Gross et al.

Alveolar proteinosis: its experimental production in rodents

Arch Pathol

(1968)

D Heath et al.

Effects of chlorphentermine on the rat lung

Thorax

(1973)

J Gough

Silicosis and alveolar proteinosis (letter to the editor)

Br Med J

(1967)

WA Littler et al.

Busulphan lung

Thorax

(1969)

FB Smith

Alveolar proteinosis: atypical pulmonary response to injury

NY State J Med

(1980)

S Sato et al.

A new myelin-like laminated body found in two cases of pulmonary alveolar proteinosis

Tohoku J Exp Med

(1978)

K Bensch et al.

Granular pneumocytes: electron microscopic evidence of their exocrinic function

Science

(1964)

M Hallman et al.

Analysis of labeling and clearance of lung surfactant phospholipids in rabbit: evidence of bidirectional surfactant flux between lamellar bodies and alveolar lavage

J Clin Invest

(1981)

RH Rao et al.

Deacylation of dipalmitoyllecithin by phospholipases A in alveolar macrophages

Exp Lung Res

(1981)

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Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome characterized by the accumulation of surfactant in the alveolar space resulting in impaired gas exchange. Primary PAP, the most common form of disease, is caused by disruption in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling due to acquired neutralizing autoantibodies. PAP often presents as progressive dyspnea of insidious onset with a widely variable clinical course, ranging from spontaneous remission to respiratory failure and death. While whole lung lavage remains the mainstay of therapy, there are several proposed novel and promising targeted therapies.
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Conversely, those with more progressive and dramatic PAP populated many of the postoperative PFTs. Despite this, improvement in PFT data found in this study is consistent with prior reports by Prakash et al.24 Previous studies report similar findings including a systematic review of 68 patients who underwent 73 WLL procedures reported improvement in clinical symptoms and improved postoperative diffusing capacity in most patients.30
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^*: Present address: University of Illinois, Urbana, Illinois.

^†: Emeritus staff.

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Pulmonary Alveolar Phospholipoproteinosis: Experience With 34 Cases and a Review

Section snippets

MATERIAL AND METHODS

Clinical Features.

Etiopathogenesis.

ACKNOWLEDGMENT

Chest

Br J Dis Chest

Dis Chest

Chest

J Ultrastruct Res

Chest

Exp Mol Pathol

Environ Res

J Biol Chem

Am J Obstet Gynecol

Am J Med

Chest

Am J Med

Dis Chest

Semin Roentgenol

Chest

Clin Radiol

Am J Med

J Allergy Clin Immunol

Biochim Biophys Acta

Am J Med

Am J Med

Chest

Chest

Pulmonary alveolar proteinosis

N Engl J Med

Pulmonary alveolar proteinosis

Am J Med

Lipids found in pulmonary lavage of patients with alveolar proteinosis and in rabbit lung lamellar organelles

Am Rev Respir Dis

Phospholipids of the lung in normal, toxic, and diseased states

CRC Crit Rev Toxicol

Alveolar proteinosis as a consequence of immunosuppression: a hypothesis based on clinical and pathologic observations

Hum Pathol

Pulmonary alveolar proteinosis in four siblings

N Engl J Med

Pathogenesis of experimental pulmonary alveolar proteinosis

Thorax

Experimental alveolar lipo-proteinosis following the inhalation of silica

J Pathol

Pulmonary response to glass fiber by inhalation exposure

Lab Invest

Acute silicosis in tombstone sandblasters

Am Rev Respir Dis

Acute silicolipoproteinosis

Thorax

Pulmonary toxicity of Mt. St. Helens volcanic ash: a review of experimental studies

Am Rev Respir Dis

Pulmonary alveolar proteinosis and aluminum dust exposure

Am Rev Respir Dis

Pulmonary alveolar proteinosis: diagnostic technics and observations

N Engl J Med

Bronchopulmonary lavage: new techniques and observations

Dis Chest

Histologic fixatives suitable for diagnostic light and electron microscopy

Arch Pathol Lab Med

Atypical reaction to inhaled silica

Nature

Alveolar proteinosis: its experimental production in rodents

Arch Pathol

Effects of chlorphentermine on the rat lung

Thorax

Silicosis and alveolar proteinosis (letter to the editor)

Br Med J

Busulphan lung

Thorax

Alveolar proteinosis: atypical pulmonary response to injury

NY State J Med

A new myelin-like laminated body found in two cases of pulmonary alveolar proteinosis

Tohoku J Exp Med

Granular pneumocytes: electron microscopic evidence of their exocrinic function

Science

Analysis of labeling and clearance of lung surfactant phospholipids in rabbit: evidence of bidirectional surfactant flux between lamellar bodies and alveolar lavage

J Clin Invest