Pulmonary alveolar proteinosis is a rare and often underdiagnosed condition. It has been associated with infections and systemic diseases but most cases are idiopathic. The clinical presentation is usually nonspecific. The cause is a deficiency in granulocyte-macrophage colony-stimulating factor (GM-CSF) activity which may lead to this surfactant accumulation. It is likely this is an autoimmune disease since anti-GM-CSF antibodies have been found in PAP patients. Patients are treated with lung lavage or immunomodulatory agents.
Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION MYELODYSPLASTIC SYNDROME
Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome.
Ohnishi T, Yamada G, Shijubo N, Takagi-Takahashi Y, Itoh T, Takahashi H, Satoh M, Koba H, Nakata K, Abe S.
Third Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo.
Intern Med 2003 Feb;42(2):187-90 Abstract quote
A 47-year-old man, who had been diagnosed as myelodysplastic syndrome (MDS), complained of a severe cough and a high-grade fever. Chest CT disclosed scattered small nodules and ground-glass opacities with interlobular septal thickening in both lung fields and a mass lesion in the right lower lobe.
Pathological findings of the ground-glass opacities and the mass lesion obtained by video-assisted thoracoscopic surgery revealed the accumulation of eosinophilic amorphous material in the alveoli and confirmed the diagnosis of pulmonary alveolar proteinosis (PAP).
Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in sera were below sensitivity, while the GM-CSF level was elevated in bronchoalveolar lavage fluid. He was diagnosed as secondary PAP associated with MDS.
Pulmonary alveolar proteinosis as a terminal complication in myelodysplastic syndromes: a report of four cases detected on autopsy.
Shoji N, Ito Y, Kimura Y, Nishimaki J, Kuriyama Y, Tauchi T, Yaguchi M, Payzulla D, Ebihara Y, Ohyashiki K.
First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishijuku, Shinjuku-ku, 160-0023, Tokyo, Japan.
Leuk Res 2002 Jun;26(6):591-5 Abstract quote
Secondary pulmonary alveolar proteinosis (PAP) is one of the complications of hematologic malignancy and immunosuppressive diseases.
We encountered four cases of myelodysplastic syndrome (MDS) associated with PAP detected on autopsy. They consisted of two refractory anemia (RA) and two patients with refractory anemia with excess blasts in transformation (RAEBt) at the time of MDS diagnosis, but all of them developed leukemic phase and were resistant to chemotherapy at the time of pulmonary episodes. Of the four MDS patients, two also had pulmonary aspergillosis. Previously, 69 patients with PAP associated with hematologic disorders have been reported, but there have been only seven cases with MDS, including our four patients. Of the 69 reported cases of PAP in hematologic malignancies, 24/63 (38%) informative patients with infection had fungal infections of the lung; 2/7 (29%) MDS cases had fungal infection.
We should, therefore, pay careful attention to this possibility in cases of MDS with lung complications, including PAP, especially in patients in the leukemic phase of MDS.
PATHOGENESIS CHARACTERIZATION GENERAL
Proteomic analysis of human bronchoalveolar lavage fluid: expression profiling of surfactant-associated protein A isomers derived from human pulmonary alveolar proteinosis using immunoaffinity detection.
Lung Research Group, Dr. Hauner children's hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
Proteomics 2003 Jan;3(1):87-94 Abstract quote
Human bronchoalveolar lavage fluid (BALF) proteins from pulmonary alveolar proteinosis (PAP) obtained by washing the epithelial lining of the lung with phosphate-buffered saline, were separated using high resolution two-dimensional gel electrophoresis (2-DE) under denaturing and reducing conditions.
By Western blotting, the proteins were transferred from polyacrylamide gel onto a chemical resilient membrane. The surfactant-associated protein A (SP-A) isomers were then identified with enhanced chemiluminescence detection (ECL) using antibody-antigen reaction. Some of the gels were treated with silver staining after 2-DE. The molecular masses of SP-A isomers in BALF from PAP ranged from 20.5 to 26, 26 to 32, and 32 to 42 kDa, respectively; and isoelectric points (pI) were in pH range of 4.5-5.4 under denaturing and reducing conditions.
In the mass range of 20.5-26 kDa and pI of 4.5-5.4, there were five isomers, and in mass range of 26-32 kDa and pI of 4.5 to 5.4, there were at least eight isomers on the ECL detection film. However, in the mass range of 32-42 kDa and pI of 4.5-5.4, there were three isomers separated one from another but there was also a cluster of overlapping spots on the ECL detection film.
Thus, this communication describes a characteristic 2-DE pattern of SP-A isomers in BALF from PAP as follows. (1) The five isomers of mass 20.5-26 kDa and pI of 4.5-5.4; (2) the eight isomers of mass 26-32 kDa and pI of 4.5-5.4; and (3) the three isomers of mass 32-42 kDa and pI of 4.5-5.4.
CT features of pulmonary alveolar proteinosis.
Holbert JM, Costello P, Li W, Hoffman RM, Rogers RM.
Department of Radiology, University of Pittsburgh, St. Margaret, 815 Freeport Rd., Pittsburgh, PA 15215, USA.
AJR Am J Roentgenol 2001 May;176(5):1287-94 Abstract quote
OBJECTIVE: This investigation describes the CT features of pulmonary alveolar proteinosis in a large group of patients.
MATERIALS AND METHODS: A retrospective review of 139 chest CT scans (79 thick-section scans and 60 thin-section scans) from 27 patients with pathologically proven pulmonary alveolar proteinosis was performed. Two independent observers assessed the intraslice patterns and zonal distribution of disease on three CT images of each lung. The observers also graded the percentage of ground-glass opacities, air-space opacities, fibrosis, interlobular opacities, intralobular opacities, and emphysema in each slice. CT scans obtained before and after lavage related to 12 whole-lung lavage treatments on nine patients were evaluated.
RESULTS: The dominant intraslice pattern was geographic, but a diffuse pattern was sometimes seen. The most common zonal pattern was uniform; a lower zone predominance was next most frequent. Ground-glass, air-space, and fibrotic opacities had a generally homogeneous craniocaudal distribution, but there was a trend toward more interlobular opacities at the lung bases (p < 0.002). Ground-glass opacities were seen on at least one scan in 100% of the patients. Interlobular opacities (85%), air-space opacities (78%), substantial fibrosis (7%), and intralobular opacities (7%) occurred less frequently. Compared with thick-section images, thin-section images showed more interlobular opacities, but no difference in ground-glass, air-space, or fibrotic disease. The proportion of lung affected by ground-glass and interlobular opacities decreased significantly (p < 0.05) after lavage.
CONCLUSION: Pulmonary alveolar proteinosis does not present only with alveolar disease. The CT appearance typically combines different types of opacities with a geographic pattern and a uniform zonal distribution with variation over time.
LABORATORY MARKERS GM-CSF AUTOANTIBODIES
Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis.
Bonfield TL, Russell D, Burgess S, Malur A, Kavuru MS, Thomassen MJ.
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Ohio 44195, USA.
Am J Respir Cell Mol Biol 2002 Oct;27(4):481-6 Abstract quote
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of phospholipids and surfactant proteins in the lung. The central role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in surfactant homeostasis has been established in mice lacking the GM-CSF gene, which results in murine pulmonary alveolar proteinosis. No GM-CSF gene defect has been defined in adult patients with idiopathic PAP.
Previous studies indicated that the human disease differs from the murine model by the presence of circulating, neutralizing autoantibodies against GM-CSF. Therefore, the final common pathway between the GM-CSF knockout and human PAP appears to be the deficiency of functionally active GM-CSF. In the present study, all patients with idiopathic PAP were found to have systemic and localized antibodies against GM-CSF. Anti-GM-CSF titers were a specific and sensitive marker for PAP. In addition, we present data showing that the absence of active GM-CSF is associated with enhanced levels of macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and interleukin-8.
These studies confirm and strengthen previous studies and support the concept that adult idiopathic PAP is an autoimmune disease defined by the presence of anti-GM-CSF. Further, using anti-GM-CSF as an indicator of pulmonary alveolar proteinosis may avoid the use of more invasive means of evaluating patients with pulmonary disease characterized by alveolar infiltrates.
Serological diagnosis of idiopathic pulmonary alveolar proteinosis.
Kitamura T, Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y, Hanaoka K, Seymour JF, Schoch OD, Doyle I, Inoue Y, Sakatani M, Kudoh S, Azuma A, Nukiwa T, Tomita T, Katagiri M, Fujita A, Kurashima A, Kanegasaki S, Nakata K.
Department of Pulmonary Diseases, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Am J Respir Crit Care Med 2000 Aug;162(2 Pt 1):658-62 Abstract quote
Previously, we reported the specific occurrence of neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchoalveolar lavage fluid from 11 Japanese patients with idiopathic pulmonary alveolar proteinosis (I-PAP).
The autoantibody was also detected in sera from all 5 I-PAP patients examined. To determine that the existence of the autoantibody is not limited to the Japanese patients, we examined sera from 24 I-PAP patients in five countries and showed that the autoantibody was consistently and specifically present in such patients.
Thus, detection of the autoantibody in sera can be used for diagnosis of I-PAP. To establish a simple and convenient method for diagnosis of I-PAP, we developed a novel latex agglutination test using latex beads coupled with recombinant human GM-CSF. GM-CSF binding proteins isolated from the sera using the latex beads were identified as the autoantibodies of IgG(1) and IgG(2). The titer of the autoantibody determined by this test correlated with that determined by ELISA. Agglutination was positive in 300-fold diluted sera from all 24 I-PAP patients, but negative in sera from four secondary PAP patients, two congenital PAP patients, 40 patients with other lung diseases, and 38 of 40 normal subjects.
These results establish that the latex agglutination test is a reliable method for serological diagnosis of I-PAP with high sensitivity (100%) and specificity (98%).
Pulmonary alveolar proteinosis: progress in the first 44 years.
Seymour JF, Presneill JJ.
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, and the Intensive Care Unit, The Royal Melbourne Hospital, Parkville, Australia.
Am J Respir Crit Care Med 2002 Jul 15;166(2):215-35 Abstract quote
Pulmonary alveolar proteinosis is a rare clinical syndrome that was first described in 1958. Subsequently, over 240 case reports and small series have described at least 410 cases in the literature.
Characterized by the alveolar accumulation of surfactant components with minimal interstitial inflammation or fibrosis, pulmonary alveolar proteinosis has a variable clinical course ranging from spontaneous resolution to death with pneumonia or respiratory failure.
The most effective proven treatment--whole lung lavage--was described soon after the first recognition of this disease. In the last 8 years, there has been rapid progress toward elucidation of the molecular mechanisms underlying both the congenital and acquired forms of pulmonary alveolar proteinosis, following serendipitous discoveries in gene-targeted mice lacking granulocyte-macrophage colony-stimulating factor (GM-CSF). Impairment of surfactant clearance by alveolar macrophages as a result of inhibition of the action of GM-CSF by blocking autoantibodies may underlie many acquired cases, whereas congenital disease is most commonly attributable to mutations in surfactant protein genes but may also be caused by GM-CSF receptor defects.
Therapy with GM-CSF has shown promise in approximately half of those acquired cases treated, but it is unsuccessful in congenital forms of the disease, consistent with the known differences in disease pathogenesis.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES IDIOPATHIC PULMONARY FIBROSIS
Pulmonary alveolar proteinosis mimicking idiopathic pulmonary fibrosis.
Arbiser ZK, Guidot DM, Pine JR, Giltman LI, Gal AA.
Departments of Pathology and Laboratory Medicine and Pulmonary and Critical Care Medicine, Emory University Hospital, Atlanta; and the Departments of Pulmonary and Critical Care Medicine and Pathology and Laboratory Medicine, Atlanta Veterans Affairs Medical Center, Decatur, GA.
Ann Diagn Pathol 2003 Apr;7(2):82-86 Abstract quote
Pulmonary alveolar proteinosis (PAP) is a rare disorder of unknown etiology. While most biopsies from patients with PAP disclose a prominent positive periodic acid-Schiff, diastase-resistant intra-alveolar exudate, and minimal interstitial thickening, interstitial fibrosis and honeycombing can be the predominant histologic findings.
We recently identified two patients with PAP who initially were thought to have idiopathic pulmonary fibrosis, but whose biopsies ultimately disclosed PAP with considerable interstitial fibrosis.
Because the clinical and radiographic presentation of PAP can overlap with other interstitial lung disorders, it should be considered in the differential diagnosis of unexplained idiopathic interstitial pneumonias in young patients.
PROGNOSIS CHARACTERIZATION ANTI-GM-CSF TITERS
Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis.
Bonfield TL, Kavuru MS, Thomassen MJ.
Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195-5038, USA.
Clin Immunol 2002 Dec;105(3):342-50 Abstract quote
Pulmonary alveolar proteinosis (PAP) is an idiopathic disease characterized by the accumulation of surfactant in the pulmonary airspaces.
The development of a PAP-like syndrome in the GM-CSF knockout mouse and resolution of disease by local GM-CSF expression strongly implicates GM-CSF in surfactant homeostasis and disease pathogenesis. Based on murine data, GM-CSF therapy was administered to PAP patients, with a subset responding to therapy. The lack of response to GM-CSF therapy in some patients is unexplained. In adult idiopathic PAP there appears to be no intrinsic cellular defect in synthesizing or secreting GM-CSF and/or function in the GM-CSF receptor. Subsequent studies have shown the presence of circulating, neutralizing anti-GM-CSF antibodies in all adult PAP patients studied to date. Whether the anti-GM-CSF is causally related to the PAP disease and whether it should be the target of manipulation remains to be determined. The present study quantified the anti-GM-CSF levels sequentially in PAP patients receiving GM-CSF therapy.
The data indicate that titers of circulating anti-GM-CSF predict response to GM-CSF therapy. In addition, we present data from a patient undergoing plasmapheresis in which anti-GM-CSF titer decreased with improvement in the lung disease.
Together, these data support the hypothesis that PAP is an anti-GM-CSF autoimmune disease due to the development of antibodies, which results in the deactivation or neutralization of GM-CSF.
TREATMENT CHARACTERIZATION GENERAL AMBROXOL
Pulmonary alveolar proteinosis successfully treated with ambroxol.
Department of Internal Medicine, Yokohama Sakaekyosai Hospital, Yokohama.
Intern Med 2002 Dec;41(12):1175-8 Abstract quote
A 79-year-old woman was admitted to hospital due to a four-month history of a cough and dyspnea on exertion. Chest CT scans revealed ground glass opacity with thickened interlobular septa in both lungs.
Bronchoalveolar lavage fluid (BALF) had milky appearance and revealed large acellular eosinophilic amorphous bodies positively stained with periodic acid-Schiff (PAS).
Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) were present in sera and BALF from the patient. Ambroxol was started in a daily dose of 45 mg orally. Her oxygen saturation improved and abnormal shadows in CT scan disappeared 6 months after beginning the therapy.
Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis.
Seymour JF, Doyle IR, Nakata K, Presneill JJ, Schoch OD, Hamano E, Uchida K, Fisher R, Dunn AR.
Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, Melbourne, Australia.
Thorax 2003 Mar;58(3):252-7 Abstract quote
BACKGROUND: Conventional measures of the severity of alveolar proteinosis (AP) include alveolar-arterial oxygen gradient ([A - a]DO(2)), vital capacity (VC), and carbon monoxide transfer factor (TLCO), but alternative serological measures have been sought. Granulocyte-macrophage colony stimulating factor (GM-CSF) neutralising autoantibody is found in patients with idiopathic acquired AP. We have investigated the interrelationships between the levels of this antibody and those of surfactant protein (SP)-A and -B, lactate dehydrogenase (LDH), and conventional measures of disease severity, and the capacity of these parameters to predict the response to rhGM-CSF treatment.
METHODS: Blood levels of anti-GM-CSF antibodies, SP-A, SP-B, LDH, and [A - a]DO(2), VC, and TLCO were measured before rhGM-CSF treatment and every 2 weeks thereafter in 14 patients with AP.
RESULTS: At baseline, high levels of anti-GM-CSF antibodies and increased SP-A and SP-B levels were seen in all patients, and LDH was raised in 83%. SP-A was highly correlated with [A - a]DO(2), VC, and TLCO (p</=0.02), but other markers were not. Only a normal LDH level was predictive of a response to rhGM-CSF treatment (p=0.03). During treatment a correlation between conventional and serological variables within patients was seen only between SP-A and [A - a]DO(2) (p=0.054), LDH levels and [A - a]DO(2) (p=0.010), and LDH levels and VC (p=0.019).
CONCLUSIONS: Of the serological parameters studied, only SP-A and LDH levels were correlated with conventional measures of disease severity, with LDH most accurately reflecting [A - a]DO(2) and vital capacity. Only a normal LDH level predicted a higher likelihood of response to treatment with GM-CSF.
Pulmonary alveolar proteinosis: treatment by bronchofiberscopic lobar lavage.
Cheng SL, Chang HT, Lau HP, Lee LN, Yang PC.
Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan.
Chest 2002 Oct;122(4):1480-5 Abstract quote
The current mainstay of treatment for pulmonary alveolar proteinosis (PAP) is whole-lung lavage. Therapy with granulocyte-macrophage colony-stimulating factor is a possibility, although its long-term safety has not been determined. An alternative procedure is selected lobar lavage by fiberoptic bronchoscopy (FOB).
We report here our experiences with lobar lavage by FOB in treating three patients with PAP. PAP was diagnosed in three patients (two men, one woman) who had dyspnea and hypoxemia after undergoing open-lung biopsy. The patients underwent lobar lavage by FOB under local anesthesia. The bronchoscope was wedged into a lobar bronchus. Approximately 2,000 mL warm normal saline solution was instilled via syringe in 50-mL aliquots through a fiberoptic bronchoscope. After undergoing multiple lobar lavages, two patients showed clinical, physiologic, and radiologic improvement. The third patient, who had more advanced disease, showed improvement only in oxygenation.
The major complications were severe cough and hypoxemia during lavage. Our experience suggests that bronchoscopic lobar lavage is simple and safe, and may find application in patients in whom a whole-lung lavage with generalized anesthesia may be hazardous, and in patients with less advanced disease whose proteinaceous substances can be removed with a small volume of lavage fluid.
Pulmonary alveolar proteinosis: step-by-step perioperative care of whole lung lavage procedure.
Ben-Abraham R, Greenfeld A, Rozenman J, Ben-Dov I.
Department of Anesthesiology and Critical Care, Faculty of Medicine, Tel Aviv University, Israel.
Heart Lung 2002 Jan-Feb;31(1):43-9 Abstract quote
BACKGROUND: Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of surfactant-like material within the alveolar spaces that causes progressive respiratory failure. Improvement can be achieved with whole lung lavage.
OBJECTIVE: Our objective was to conduct a study of the feasibility of treating pulmonary alveolar proteinosis in a community hospital.
METHODS: Five patients were treated. We assessed procedure pulmonary functions.
RESULTS: No major sequelae occurred. Each lung was lavaged with 12 to 20 L of normal saline in cycles of 970 +/- 150 mL each (mean +/- standard deviation), over 106 +/- 49 minutes. Extubation was performed when compliance of the lavaged lung was restored. All patients showed subjective improvement. Resting and exercise oxygen saturation improved within 1 week after the lavage. A significant improvement was also noted in forced expiratory volume in 1 second, forced vital capacity, and maximal oxygen uptake, whereas total lung capacity and carbon monoxide single-breath diffusion capacity remained unchanged.
CONCLUSION: Although retrospective and based on a small sample size, our results suggest that whole lung lavage may be performed safely even in medical centers that have limited experience, if strict adherence to a protocol is maintained.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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