Sections

Pathology of Pulmonary Alveolar Proteinosis

Sections Pathology of Pulmonary Alveolar Proteinosis
Definition
Etiology and Pathophysiology
Clinical Features and Imaging
Differential Diagnosis
Gross and Microscopic Findings
Treatment and Prognosis
Questions & Answers
Show All
Media Gallery
References

Definition

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of granular eosinophilic material within alveolar spaces.^[1] PAP has also been referred to as pulmonary alveolar phospholipoproteinosis or alveolar lipoproteinosis, reflecting the abundance of lipids within the granular exudate. PAP has a worldwide distribution and an estimated incidence of 0.2 case per million population.^[1]

Etiology and Pathophysiology

Animal and human studies indicate that more than one pathway exists for the different forms of pulmonary alveolar proteinosis (PAP). The congenital form of PAP results from multiple genetic abnormalities. These include defects in genes encoding for surfactan protein B or C, transporter molecules within type II pneumocytes, and the beta chain receptor of granulocyte-macrophage colony-stimulating factor (GM-CSF).^{[2, 3, 4, 5]}

Autoimmune PAP is characterized by the presence of anti-GM-CSF antibodies. This leads to a deficiency or malfunction of GM-CSF, which is an integral component of surfactant homeostasis.^{[6, 7, 8, 9, 10, 11]}Analysis of bronchoalveolar lavage (BAL) fluid suggests that the pathogenesis of autoimmune PAP may also involve abnormal clearance rather than excessive production of pulmonary surfactant.^{[12, 13]}

Clinical Features and Imaging

Pulmonary alveolar proteinosis (PAP) is classified into two main categories: congenital (neonatal) and acquired. Acquired PAP is subdivided into an autoimmune form (previously termed idiopathic/primary) and secondary form (ie, due to an underlying disease).^[14]Most cases of PAP are the autoimmune form (90%),^{[1, 14, 15]}followed by secondary (4%), and congenital (1%), with the remaining 5% consisting of undetermined PAP-like disease.^[1]Adults between aged 39 and 51 years are most commonly affected, with a 2:1 male-to-female predominence.^[1]Infants and children can also be affect.^[1]

Secondary PAP is associated with various underlying diseases. These include various infections, hematologic malignancies, inorganic dust exposure (silica, aluminum, or titanium), and immunodeficiency states such as infection with human immunodeficiency virus (HIV) and lung transplantation.^{[16, 17, 18, 19, 20, 21, 22, 23]}Less common causes include Fanconi anemia, lysinuric protein intolerance, and surfactant protein B deficiency.^{[24, 25, 26]}

The onset of clinical disease is usually insidious, with a varying presentation and nonspecific symptoms, which may delay the diagnosis of PAP by months to years. Most patients experience progressive dyspnea and dry cough.^[1]White sputum production, weight loss, hemoptysis, and fever have also been described in patients with PAP.^{[14, 27, 28]}Patients with the congenital form of PAP (see Etiology and Pathophysiology) usually present with an acute onset of rapidly progressive respiratory distress immediately after birth.^[14]

Chest radiographs demonstrate bilateral and symmetric areas of airspace consolidation that primarily involve the perihilar regions and lower lobes.^{[6, 29]}These areas of consolidation tend to have a vaguely nodular configuration. With high-resolution computed tomography (HRCT) scanning, the characteristic finding is the presence of ground glass opacities associated with interlobular septal thickening, imparting a “crazy paving” appearance to the lung parenchyma.^{[30, 31]}

The diagnosis of PAP can be confirmed by various methods. In patients with autoimmune PAP, measurement of the autoantibody level against granulocyte macrophage colony-stimulating factor (GM-CFS) has been used to identify this disease. Using an enzyme-linked immunosorbent assay (ELISA)–based testing platform, Uchida and colleagues were able determine that a serum level of 5 ug/mL as the optimal cutoff value for distinguishing autoimmune PAP from normal serum.^[32]Confirmation of PAP can also be obtained through examination of tissue specimens obtained by one of several methods. Previously, an open biopsy was considered the criterion standard to establish the diagnosis of PAP. However, transbronchial biopsies or cytologic evaluation of bronchoalveolar lavage (BAL) samples are now routinely used to diagnose this disease.^{[1, 6, 7, 33, 34, 35]}

Differential Diagnosis

The differential diagnosis of pulmonary alveolar proteinosis (PAP) includes other diseases associated with intra-alveolar exdudates. These include pulmonary edema, pneumocystis pneumonia, and alveolar mucinosis. Pulmonary edema has a homogeneous appearance and lacks the granularity typical of PAP (see the images below). The exudate of pneumocystis pneumonia has a frothy or foamy appearance due to the negative image of the cyst form of Pneumocystisjiroveci (formally known as carinii).

Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (A) (hematoxylin and eosin, x400) and broncheoalveolar lavage (BAL).

View Media Gallery

Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (B) (Papanicolaou, x600). Note the negative images of the cysts impart the foamy characteristic of the exudate.

View Media Gallery

Gross findings

The lungs of patients with pulmonary alveolar proteinosis (PAP) are heavy with a firm consistency. The cut surface oozes yellow fluid due to the marked accumulation of lipid.

Microscopic findings

The characteristic finding in tissue sections is the presence of eosinophilic granular material within the alveolar spaces. The overall lung architecture is preserved, and a mild chronic inflammatory infiltrate within the pulmonary interstitium may be present (see the images below).

Pathology of pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hematoxylin and eosin, x200).

View Media Gallery

Pathology of pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal tissue with minimal reaction (hematoxylin and eosin, x400).

View Media Gallery

This material is strongly periodic-acid-Shiff positive and diastase-resistant (DPAS) (see the image below).

Pathology of pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase [D]-PAS, x200).

View Media Gallery

The diagnosis of PAP can also be established by cytologic evaluation of bronchoavleolar lavage (BAL) specimens.

Pathology of pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-Schiff [DPAS], x400).

View Media Gallery

In addition, another finding reported in BAL samples from patients with PAP is the presence of dense globules that have well-defined borders (see the image below).^{[36, 37]}

Pathology of pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar proteinosis (PAP) (Papanicolaou, x400).

View Media Gallery

Quantitative analysis of these globules has shown that the presence of 18 or more in BAL samples is a highly sensitive and specific marker for PAP.^[38]These globules are believed to represent the multilaminated structures characteristic of PAP that are visible by electron microscopy.^[37]

Treatment and Prognosis

The most widely accepted and effective treatment for PAP is therapeutic whole-lung lavage(WLL).^{[1, 6, 7, 39]}This form of therapy is instituted when significant dyspnea limits activity and progressive deterioration of arterial oxygenation.^{[40, 41]} Bronchoscopic serial lobar lavages have also been used to treat patients with PAP.^[42]

The patient’s respiratory function improves due to the removal of proteinaceous material and local anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. This helps restore the migration and phagocytic functions of alveolar macrophages.^{[43, 44]}Although a significant number of patients exhibit clinical, radiologic, and functional improvement after a single treatment, most require repeat lavage at intervals between 6 and 15 months.^{[45, 46]}Patients receiving whole-lung lavage have shown a significant improvement in their 5-year survival rate compared to those who do not receive this form of therapy.^{[1, 45]}For patients with secondary PAP, in addition to whole-lung lavage, treatment of the underlying condition should also be instituted.^{[6, 7]}

The administration of exogenous GM-CSF or suppression of ant-GM-CSF antibodies has been used to treat those patients with autoimmune PAP. The goal of this treatment is to relieve the deficiency of functional GM-CSF, and this can be administered simultaneously or as an alternate to whole-lung lavage.^{[47, 48, 49, 50]}Although predictors of response to treatment with GM-CSF have yet to be established, those patients with pretreatment variables such as longer time from diagnosis, high vital capacity, normal serum lactate dehydrogenase level, and higher plasma surfactant-protein-B level appear to respond better to GM-CSF.^[50]

Novel forms of therapy are being explored for those patients who do not respond to GM-CSF or whole-lung lavage. Plasmapharesis, rituximab, trypsin, chymotrypsin, ambroxol, immunoglobulin G, and antibiotics have been investigated.^{[51, 52, 53, 54, 55, 56]}For refractory PAP, rituximab, plasmapheresis, and lung transplantation may be therapeutic considerations.^[6]

Attempts have also been made to use stem cells to treat some forms of PAP. Lachmann et al have investigated the use of induced pluripotent stem cells derived from monocytes and macrophages to treat patients with the hereditary form of PAP.^[57]

As a means to monitor disease progression, research has evaluated several ancillary tests, including high molecular weight human MUC-1 mucin and serum KL-6. Both of these makers are increased in most patients with PAP. Based on the work of Bonella et al, it appears that serum KL-6 levels are a strong predictor of disease progression in patients with PAP.^[58]

Questions & Answers

Overview

What is pulmonary alveolar proteinosis (PAP)?

What is the pathophysiology of pulmonary alveolar proteinosis (PAP)?

How is pulmonary alveolar proteinosis (PAP) classified?

What causes secondary pulmonary alveolar proteinosis (PAP)?

What are the signs and symptoms of pulmonary alveolar proteinosis (PAP)?

Which imaging findings are characteristic of pulmonary alveolar proteinosis (PAP)?

How is the diagnosis of pulmonary alveolar proteinosis (PAP) confirmed?

Which conditions are included in the differential diagnoses of pulmonary alveolar proteinosis (PAP)?

Which macroscopic findings are characteristic of pulmonary alveolar proteinosis (PAP)?

Which histologic findings are characteristic of pulmonary alveolar proteinosis (PAP)?

How is pulmonary alveolar proteinosis (PAP) treated?

Carrington JM, Hershberger DM. Pulmonary alveolar proteinosis. 2019 Jan. [QxMD MEDLINE Link]. [Full Text].
Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993 Feb 11. 328(6):406-10. [QxMD MEDLINE Link].
Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001 Feb 22. 344(8):573-9. [QxMD MEDLINE Link].
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004 Mar 25. 350(13):1296-303. [QxMD MEDLINE Link].
Dirksen U, Hattenhorst U, Schneider P, Schroten H, Gobel U, Bocking A. Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure. Blood. 1998 Aug 15. 92(4):1097-103. [QxMD MEDLINE Link].
Kumar A, Abdelmalak B, Inoue Y, Culver DA. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir Med. 2018 Jul. 6 (7):554-65. [QxMD MEDLINE Link].
Griese M. Pulmonary alveolar proteinosis: a comprehensive clinical perspective. Pediatrics. 2017 Aug. 140 (2):[QxMD MEDLINE Link]. [Full Text].
Kitamura T, Tanaka N, Watanabe J, Uchida, Kanegasaki S, Yamada Y. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. 1999 Sep 20. 190(6):875-80. [QxMD MEDLINE Link].
Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med. 2008 Apr 1. 177(7):752-62. [QxMD MEDLINE Link].
Uchida K, Nakata K, Trapnell BC, Terakawa T, Hamano E, Mikami A. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood. 2004 Feb 1. 103(3):1089-98. [QxMD MEDLINE Link].
Trapnell BC, Whitsett JA. Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol. 2002. 64:775-802. [QxMD MEDLINE Link].
Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25. 349(26):2527-39. [QxMD MEDLINE Link].
Ramirez J, Harlan WR Jr. Pulmonary alveolar proteinosis. Nature and origin of alveolar lipid. Am J Med. 1968 Oct. 45(4):502-12. [QxMD MEDLINE Link].
Khan A, Agarwal R. Pulmonary alveolar proteinosis. Respir Care. 2011 Jul. 56(7):1016-28. [QxMD MEDLINE Link].
Myers JL. Other diffuse lung diseases. Churg AM, Myers JL, Tazelaar HD, Wright JL (editors). Thurlbeck’s pathology of the lung. 3rd ed. New York: Thieme; 2005. 601-73.
Pascual J, Gomez Aguinaga MA, Vidal R, Maudes A, Sureda A, Gomez Mampaso E. Alveolar proteinosis and nocardiosis: a patient treated by bronchopulmonary lavage. Postgrad Med J. 1989 Sep. 65(767):674-7. [QxMD MEDLINE Link].
Ranchod M, Bissell M. Pulmonary alveolar proteinosis and cytomegalovirus infection. Arch Pathol Lab Med. 1979 Mar. 103(3):139-42. [QxMD MEDLINE Link].
Ito K, Iwabe K, Okai T, Kouda S, Tadokoro M, Isiko T. Rapidly progressive pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. Intern Med. 1994 Nov. 33(11):710-3. [QxMD MEDLINE Link].
Carnovale R, Zornoza J, Goldman AM, Luna M. Pulmonary alveolar proteinosis: its association with hematologic malignancy and lymphoma. Radiology. 1977 Feb. 122(2):303-6. [QxMD MEDLINE Link].
Buechner HA, Ansari A. Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis. Dis Chest. 1969 Apr. 55(4):274-8. [QxMD MEDLINE Link].
Keller CA, Frost A, Cagle PT, Abraham JL. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest. 1995 Jul. 108(1):277-80. [QxMD MEDLINE Link].
Ruben FL, Talamo TS. Secondary pulmonary alveolar proteinosis occurring in two patients with acquired immune deficiency syndrome. Am J Med. 1986 Jun. 80(6):1187-90. [QxMD MEDLINE Link].
Yousem SA. Alveolar lipoproteinosis in lung allograft recipients. Hum Pathol. 1997 Dec. 28(12):1383-6. [QxMD MEDLINE Link].
Eldar M, Shoenfeld Y, Zaizov R, Fogel R, Asherov J, Liban E. Pulmonary alveolar proteinosis associated with fanconi's anemia. Respiration. 1979. 38(3):177-9. [QxMD MEDLINE Link].
McManus DT, Moore R, Hill CM, Rodgers C, Carson DJ, Love AH. Necropsy findings in lysinuric protein intolerance. J Clin Pathol. 1996 Apr. 49(4):345-7. [QxMD MEDLINE Link].
Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993 Feb 11. 328(6):406-10. [QxMD MEDLINE Link].
Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest. 1998 Nov. 114(5):1357-62. [QxMD MEDLINE Link].
Rubinstein I, Mullen JB, Hoffstein V. Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisited. Arch Intern Med. 1988 Apr. 148(4):813-6. [QxMD MEDLINE Link].
Alavuk Kundovic S, Popovic L. Congenital pulmonary alveolar proteinosis: from birth to ten-years of age. Indian J Pediatr. 2017 Sep. 84 (9):721-3. [QxMD MEDLINE Link].
Wang BM, Stern EJ, Schmidt RA, Pierson DJ. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest. 1997 Feb. 111(2):460-6. [QxMD MEDLINE Link].
Lee KN, Levin DL, Webb WR, Chen D, Storto ML, Golden JA. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest. 1997 Apr. 111(4):989-95. [QxMD MEDLINE Link].
Uchida K, Nakata K, Carey B, et al. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2014 Jan 15. 402(1-2):57-70. [QxMD MEDLINE Link].
Suzuki T, Trapnell BC. Pulmonary alveolar proteinosis syndrome. Clin Chest Med. 2016 Sep. 37 (3):431-40. [QxMD MEDLINE Link]. [Full Text].
Shattuck TM, Bean SM. Pulmonary alveolar proteinosis. Diagn Cytopathol. 2013 Jul. 41(7):620-2. [QxMD MEDLINE Link].
Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest. 1998 Nov. 114(5):1357-62. [QxMD MEDLINE Link].
Laucirica R, Ostrowski ML. Cytology of nonneoplastic occupational and environmental diseases of the lung and pleura. Arch Pathol Lab Med. 2007 Nov. 131(11):1700-8. [QxMD MEDLINE Link].
Mikami T, Yamamoto Y, Yokoyama M, Okayasu I. Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid. J Clin Pathol. 1997 Dec. 50(12):981-4. [QxMD MEDLINE Link]. [Full Text].
Chou CW, Lin FC, Tung SM, Liou RD, Chang SC. Diagnosis of pulmonary alveolar proteinosis: usefulness of papanicolaou-stained smears of bronchoalveolar lavage fluid. Arch Intern Med. 2001 Feb 26. 161(4):562-6. [QxMD MEDLINE Link].
Wang T, Lazar CA, Fishbein MC, Lynch JP 3rd. Pulmonary alveolar proteinosis. Semin Respir Crit Care Med. 2012 Oct. 33(5):498-508. [QxMD MEDLINE Link].
Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest. 1984 Apr. 85(4):550-8. [QxMD MEDLINE Link].
Selecky PA, Wasserman K, Benfield JR, Lippmann M. The clinical and physiological effect of whole-lung lavage in pulmonary alveolar proteinosis: a ten-year experience. Ann Thorac Surg. 1977 Nov. 24(5):451-61. [QxMD MEDLINE Link].
Baldi MM, Nair J, Athavale A, Gavali V, Sarkar M, Divate S, et al. Serial lobar lung lavage in pulmonary alveolar proteinosis. J Bronchology Interv Pulmonol. 2013 Oct. 20(4):333-7. [QxMD MEDLINE Link].
Bracci L. Role of physical therapy in management of pulmonary alveolar proteinosis. A case report. Phys Ther. 1988 May. 68(5):686-9. [QxMD MEDLINE Link].
Hoffman RM, Dauber JH, Rogers RM. Improvement in alveolar macrophage migration after therapeutic whole lung lavage in pulmonary alveolar proteinosis. Am Rev Respir Dis. 1989 Apr. 139(4):1030-2. [QxMD MEDLINE Link].
Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002 Jul 15. 166(2):215-35. [QxMD MEDLINE Link].
Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000 Jan. 55(1):67-77. [QxMD MEDLINE Link].
de Vega MG, Sanchez-Palencia A, Ramirez A, Cervera S, Aneiros J. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax. 2002 Sep. 57(9):837. [QxMD MEDLINE Link].
Venkateshiah SB, Yan TD, Bonfield TL, Thomassen MJ, Meziane M, Czich C. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest. 2006 Jul. 130(1):227-37. [QxMD MEDLINE Link].
Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006 Mar. 27(3):585-93. [QxMD MEDLINE Link].
Seymour JF, Presneill JJ, Schoch OD, Downie GH, Moore PE, Doyle IR. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med. 2001 Feb. 163(2):524-31. [QxMD MEDLINE Link].
Bonfield TL, Kavuru MS, Thomassen MJ. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol. 2002 Dec. 105(3):342-50. [QxMD MEDLINE Link].
Borie R, Debray MP, Laine C, Aubier M, Crestani B. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J. 2009 Jun. 33(6):1503-6. [QxMD MEDLINE Link].
Brodsky I, Mayock RL. Pulmonary alveolar proteinosis. Remission after therapy with trypsin and chymotrypsin. N Engl J Med. 1961 Nov 9. 265:935-8. [QxMD MEDLINE Link].
Hashizume T. Pulmonary alveolar proteinosis successfully treated with ambroxol. Intern Med. 2002 Dec. 41(12):1175-8. [QxMD MEDLINE Link].
Cho K, Nakata K, Ariga T, Okajima S, Matsuda T, Ueda K. Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration. Respirology. 2006 Jan. 11 Suppl:S74-7. [QxMD MEDLINE Link].
Gumpert BC, Nowacki MR, Amundson DE. Pulmonary alveolar lipoproteinosis. Remission after antibiotic treatment. West J Med. 1994 Jul. 161(1):66-8. [QxMD MEDLINE Link].
Lachmann N, Happle C, Ackermann M, et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2014 Jan 15. 189(2):167-82. [QxMD MEDLINE Link].
Bonella F, Ohshimo S, Miaotian C, Griese M, Guzman J, Costabel U. Serum KL-6 is a predictor of outcome in pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2013 Apr 4. 8:53. [QxMD MEDLINE Link]. [Full Text].
Sakai Y, Abo W, Yoshimura H, Sano H, Kuroki Y, Satoh M. Pulmonary alveolar proteinosis in infants. Eur J Pediatr. 1999 May. 158(5):424-6. [QxMD MEDLINE Link].

Media Gallery

Pathology of pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hematoxylin and eosin, x200).
Pathology of pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal tissue with minimal reaction (hematoxylin and eosin, x400).
Pathology of pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase [D]-PAS, x200).
Pathology of pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-Schiff [DPAS], x400).
Pathology of pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar proteinosis (PAP) (Papanicolaou, x400).
Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (A) (hematoxylin and eosin, x400) and broncheoalveolar lavage (BAL).
Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (B) (Papanicolaou, x600). Note the negative images of the cysts impart the foamy characteristic of the exudate.