This is “Advance Publication Article”

Case Report

Kurume Medical Journal, 66, 00-00, 2019

A Case of Autoimmune Pulmonary Alveolar Proteinosis withPulmonary Fibrosis and Asbestosis-Like Features
MASAYUKI NAKAMURA, MASAKI OKAMOTO, KIMINORI FUJIMOTO *, SHIGEKI SHIMIZU **,MASAKI TOMINAGA, SHINGO TSUNEYOSHI, YOSHIAKI ZAIZEN, TAKASHI NOUNO,SATOSHI SAKAMOTO, TOMOTAKA KAWAYAMA AND TOMOAKI HOSHINODivision of Respirology, Neurology and Rheumatology, Department of Internal Medicine, * Department of Radiology andCenter for Diagnostic Imaging, Kurume University School of Medicine, Kurume 830-0011,** Department of Pathology, Kindai University Faculty of Medicine, Osakasayama 589-8511, Japan
Received 2 August 2018, accepted 15 January 2019
J-STAGE advance publication 24 April 2020

Edited by MASAHIRO MITSUOKA
Summary: A 78-year-old man who had worked in the building industry visited our hospital because of groundglass opacity with smoothly thickened, intralobular interstitial lines and interlobular septal lines on chest high-resolution computed tomography (HRCT). HRCT image also showed a focal area of reticulation and pleural thickening. Lung specimens obtained by surgical lung biopsy showed accumulations of intra-alveolar periodic acid-Schiffpositive materials, usual interstitial pneumonia (UIP)-like subpleural lung fibrosis and asbestos bodies (1 body/cm2in high-power field, ×400). Serum granulocyte-macrophage colony stimulating factor autoantibody was positive.
The patient was diagnosed as having autoimmune pulmonary alveolar proteinosis (PAP) and needed differential
diagnosis from secondary PAP caused from pulmonary asbestosis and UIP. Careful observation of the manifestations of pulmonary asbestosis and the progression of fibrosis using HRCT will be necessary in this patient.
Key words autoimmune pulmonary alveolar proteinosis, usual interstitial pneumonia, anti-granulocyte-macrophage colony-stimulating factor antibody

INTRODUCTION

Pulmonary alveolar proteinosis (PAP) is a lung dis-ease characterized by accumulation of lipid-rich proteinaceous materials that stain positive with periodic
acid-Schiff (PAS) in the pulmonary alveolar space[1,2]. Although autoimmune PAP, pulmonary asbestosis, and idiopathic pulmonary fibrosis/usual interstitialpneumonia (IPF/UIP) are independent pulmonary disorders, cases of secondary PAP caused by asbestosis
or PAP-leading pulmonary fibrosis may occur occasionally. Differential diagnosis among these diseases
is important but difficult.
Here we report a case of autoimmune PAP withpulmonary asbestosis-like features including asbestos
bodies in the lung tissue and pleural thickening on
high-resolution computed tomography (HRCT), and ahistologically possible UIP pattern.
CASE REPORT
A 78-year-old man visited a local hospital in May
2016 because of persistent productive cough andground-glass opacities (GGOs) were observed on achest radiograph and HRCT at a nearby hospital inMay 2016. The productive cough eventually resolved,
but the chest radiograph and HRCT showed expansion

Corresponding Author: Masaki Okamoto, Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University
School of Medicine, Kurume, Fukuoka 830-0011, Japan. Tel: +81-942-31-7560, Fax: +81-942-31-7703, E-mail: okamoto_masaki@med.kurume-u.ac.jp
Abbreviations: GGOs, ground-glass opacities; GM-CSF, granulocyte-macrophage colony-stimulating factor; HRCT, high-resolution computed tomography;
IPF/UIP, idiopathic pulmonary fibrosis/usual interstitial pneumonia; MDS, myelodysplastic syndrome; PAP, pulmonary alveolar proteinosis; PAS, periodic
acid-Schiff; SLB, surgical lung biopsy.

2NAKAMURA ET AL.

of GGOs. In February 2017, he visited our hospital.
He had an occupational history of working in thebuilding industry from 20 to 58 years of age, during
which time he might have been exposed to asbestos
and other materials. He had no additional history ofenvironmental exposure. He was an ex-smoker with a
5-year smoking history of 0.75 pack/years. Before
presentation, he had also been treated for hypertension
and benign prostatic hyperplasia. Vital signs on admission were as follows: respiratory rate, 22/min;heart rate, 66/min; blood pressure, 124/76 mmHg;
body temperature, 36.1°C. No fine crackles were auscultated, and there were no clubbed fingers, or otherabnormal physical findings. Blood hematological andbiochemical examinations revealed no abnormal findings. Arterial blood gas analysis indicated mild hypoxemia (PaO2 75.9 torr) and widening of the A-aDO2(21.0 torr). There were no physical or hematologicalfindings suggesting any complication with connective
tissue diseases or hematologic diseases including myelodysplastic syndrome (MDS) and multiple myeloma. Chest radiograph showed bilateral GGOs with apatchy distribution predominantly in the right perihilar region (figure 1). Areas of GGO with smoothly
thickened, intralobular interstitial lines and interlobular septal lines on HRCT were expanded at the first
visit to our hospital compared with the findings 6months earlier (figure 2A, B). HRCT images also
demonstrated a focal area of reticulation with small air
cysts in subpleural lung parenchyma of the right basal
segments, and pleural plaque with calcification (figure2C, D, E). No typical radiological features of pulmonary asbestosis including a subpleural dotlike opacity,
subpleural curvilinear line, or parenchymal band wereevident on HRCT images. Pulmonary function tests
demonstrated no restrictive ventilatory impairment or
reduction of diffusion capacity (forced vital capacity
89.5%, predicted; diffusing capacity of the lungs forcarbon monoxide 123.6%, predicted). A six-minutewalking test yielded a distance of 276.3 m and a minimum SpO2 of 94%. Analysis of bronchoalveolar lavage fluid showed no sign of milky appearance, bacterial or fast-acid bacillus bodies or atypical cells.
Transbronchial lung biopsy revealed no specific findings of lung disease. In May 2017, we performed asurgical lung biopsy (SLB) using video-assisted thoracoscopy from the anterior segment of right upper lobe(S3) and the lateral segment of right middle lobe (S4) toestablish a diagnosis. Histological examination revealed accumulations of intra-alveolar lightly eosinophilic finely granular material that stained positive
with PAS, slightly foamy intra-alveolar macrophages
and mild infiltration of the alveolar septa. There wasalso a histologically possible UIP pattern including
lung fibrosis with a predominantly subpleural distribution and fibroblastic foci. Asbestos bodies (1 body/cm2 in high-power field, ×400) were found in a lungspecimen obtained from right S4 (figure 3). A high serum level of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody at 56.4 μg/mL(cut-off level 1.0 μg/mL) was found after SLB examination. On the basis of these findings, we diagnosed
this patient as having autoimmune PAP with pulmonary fibrosis. The subtype of PAP in this case was considered to be idiopathic PAP on the basis of the clinicalfeatures. We are now observing carefully the progression of fibrosis and the manifestation of the clinicalfeatures of pulmonary asbestosis by HRCT. The patient’s disease is currently stable.
DISCUSSION

Fig. 1. Chest radiograph at the first visit to our hospital showed ground-glass opacities with a patchy
distribution predominantly in right perihilar region.

PAP is a rare pulmonary disorder, with a minimum
incidence and prevalence of 0.49 and 6.2 per million,respectively. [3] Rosen et al. first reported 27 patientswith PAP in 1958. [1] Three types of PAP have been
described: idiopathic, secondary, and congenital. [4,5]The causes of secondary PAP include hematologic
diseases such as MDS and multiple myeloma, inhalation exposure to dust, and infectious disease. [6] Congenital PAP is caused by gene mutations of SP-B or C
or the GM-CSF receptor [2]. Idiopathic PAP is considered to be an autoimmune disorder caused by dysfunc-Kurume Medical Journal Vol. 66, No. 1 2019

PULMONARY ALVEOLAR PROTEINOSIS WITH FIBROSIS

Fig. 2. Chest high-resolution computed tomography
images at the first visit to our hospital (B, C, D) and 6
months before (A). Images at the first visit showed
areas of ground-glass opacity (GGO) with thickened,
intralobular interstitial lines and interlobular septal
lines with a patchy distribution predominantly inright perihilar region and inner lung zone (B, whitearrowheads), focal area of reticulation with small aircysts in the right lower lobe (C, D, black arrowheads), and a pleural plaque with calcification (E,white arrow) in the right lower lung zone. Note progression of extent areas of GGO on image B compared with those on image A.

Kurume Medical Journal Vol. 66, No. 1 2019

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NAKAMURA ET AL.

tion of surfactant catabolism due to neutralization ofGM-CSF by autoantibodies. [7,8]The present patient was diagnosed as having autoimmune PAP with pulmonary fibrosis because of thepresence of anti-GM-CSF autoantibody in serum andthe features revealed by HRCT. The present caseshould be distinguished from pulmonary asbestosis. Aprevious study has revealed that rats developed PAP
after inhalation of quartz dust. [9] The mechanism ofPAP development in patients with asbestos exposureis unclear. Some previous reports suggested that thepathogenesis of secondary PAP caused from dust exposure may be attributed to impaired alveolar surfactant disposal by macrophages. [10-11] Beuchner etal. reported 4 patients with acute silicosis who were all
diagnosed as having PAP. [12] Moreover, previous
studies suggested that an exposure to material can leadto the production of anti-GM-GSF autoantibody [1314]. The percentage of autoimmune PAP patients who
also had inhalational exposure varies between 26%
and 54% in studies [3,15-18]. Although the present
case had asbestosis-like findings including asbestos
bodies and pleural thickening on HRCT, no typical ra-

diological findings such as a subpleural dotlike opacity, subpleural curvilinear line, or parenchymal band
were observed. [19] In this patient, there was notenough evidence to determine that his pulmonary fibrosis has been caused by asbestosis. Asbestos-likefindings may suggest a simple asbestos exposure.
The present case demonstrated a focal subpleuralarea of reticulation with small air cysts on HRCT andpossible UIP pattern on SLB histological specimens.
The typical feature of PAP is accumulation of proteinaceous materials within the air spaces, without thickening and fibrosis of the alveolar septa. [2] On theother hand, Rosen et al. in their first report of PAPstated that 2 of their 27 patients showed developmentof mild alveolar fibrosis. [1] Interstitial fibrosis thatrarely develops secondary to PAP had been describedin several previous reports. [3,20-27] The present casemay show a natural course of PAP, distinct from IPF/
UIP and asbestosis-related pulmonary fibrosis.
In the present case, a differential diagnosis wasneeded to distinguish idiopathic PAP from secondary
PAP caused by pulmonary asbestosis and IPF/UIP. It
is necessary to monitor disease behavior to establish aFig. 3. Histological findings in the lung specimen obtained by surgical lung biopsy shows accumulations ofintra-alveolar lightly eosinophilic finely granular materials (A; hematoxylin and eosin (HE) stain, right S3, original, ×400). Asbestos bodies (1 body/cm2 in high-power field, white arrow) were found (B; HE stain, right S4,original, ×400). Histological UIP pattern including lung fibrosis in a predominantly subpleural distribution andfibroblastic foci (arrow head) were shown (C; HE stain, D; Elastica van Gieson stain, right S4, original, ×100).
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diagnosis in this type of case.
The standard therapy for PAP is whole lung lavage. GM-CSF inhalation is a new non-invasive treatment for autoimmune PAP. However, the patient did
not receive such treatment because he was asymptomatic and had only mild hypoxemia with no abnormal
pulmonary function. We are carefully observing theprogression of respiratory symptoms and fibrosis byHRCT and are watching for any decline of pulmonary
function in this patient.
In summary, autoimmune PAP with asbestosislike features and UIP-like pulmonary fibrosis is a raredisease combination. Accumulation of similar case reports and studies of the pathogenesis are important.
ACKNOWLEDGEMENT: We are grateful to all the members
who contributed to medical care in this case.
CONFLICT OF INTEREST: The authors of this manuscript
have no conflicts of interest to declare.

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Kurume Medical Journal Vol. 66, No. 1 2019