Pulmonary alveolar proteinosis

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Pulmonary alveolar proteinosis
Synonyms alveolar proteinosis
Pulmonary alveolar proteinosis -3- high mag.jpg
Micrograph of pulmonary alveolar proteinosis, showing the characteristic airspace filling with focally dense globs referred to as chatter or dense bodies. H&E stain.
Specialty Pulmonology Edit this on Wikidata

Pulmonary alveolar proteinosis (PAP) is a group of rare lung disorders characterized by abnormal accumulation of surfactant-derived lipoprotein compounds within the alveoli of the lung. The accumulated substances interfere with the normal gas exchange and expansion of the lungs, ultimately leading to difficulty breathing and a predisposition to developing lung infections. The causes of PAP may be grouped into primary and secondary causes, although the most common etiology is a primary autoimmune condition (see below).

Signs and symptoms[edit]

The signs and symptoms of PAP include shortness of breath,[1] a cough, low grade fever, and weight loss.

The clinical course of PAP is unpredictable. Spontaneous remission is recognized, and some patients have stable symptoms. Death may occur due to the progression of PAP or of any underlying associated disease. Individuals with PAP are more vulnerable to lung infections such as bacterial pneumonia, mycobacterium avium-intracellulare infection, or a fungal infection.

Causes[edit]

The abnormal accumulation of lipoproteinaceous compounds in PAP is due to impaired surfactant regulation and clearance. This is usually related to impaired alveolar macrophage function.[2]

In adults, the most common cause of PAP is an autoimmunity to granulocyte-macrophage colony stimulating factor (GM-CSF), a critical factor in development of alveolar macrophages. Decreased bioavailability of GM-CSF results in poor alveolar macrophages development and function, which results in accumulation of surfactant and related products.[2]

Secondary causes of PAP are those in which the accumulation of lipoproteinaceous compounds is secondary to another disease process. This has been recognized in the settings of certain cancers (such as myeloid leukemia), lung infections, or environmental exposure to dusts or chemicals.

Although the cause of PAP was not originally understood, a major breakthrough in the understanding of the cause of the disease came by the chance observation that mice bred for experimental study to lack a hematologic growth factor known as granulocyte-macrophage colony stimulating factor (GM-CSF) developed a pulmonary syndrome of abnormal surfactant accumulation resembling human PAP.[3]

The implications of this finding are still being explored, but significant progress was reported in February 2007. Researchers in that report discussed the presence of anti-GM-CSF autoantibodies in patients with PAP, and duplicated that syndrome with the infusion of these autoantibodies into mice.[4]

Familial or sporadic inactivating mutations in one of the two parental GATA2 genes produces an autosomal dominant disorder termed GATA2 deficiency. The GATA2 gene produces the GATA2 transcription factor which is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming cells. Individuals with a single GATA2 inactivating mutation present with a wide range of disorders including pulmonary alveolar proteinosis. GATA2 mutation-based pulmonary alveolar proteinosis is associated with normal levels of GM-CSF and commonly improves or is avoided in afflicted individuals who successfully receive a hematopoietic stem cell transplantation.[5][6]

Genetics[edit]

Abnormalities in CSF2 receptor alpha have been shown to cause hereditary pulmonary alveolar proteinosis. This gene is located on chromosome 5 in the 5q31 region. This gene product is also known as granulocyte macrophage colony-stimulating factor receptor.[7]

Diagnosis[edit]

Intermediate magnification micrograph of pulmonary alveolar proteinosis. H&E stain.

The diagnosis of PAP is made using a combination of a person's symptoms, chest imaging, and microscopic evaluation of lung washing/tissue. Additional testing for serum anti-GM-CSF antibodies are helpful for confirmation.[8]

Although both the symptoms and imaging findings are stereotypical and well-described, they are non-specific and indistinguishable from many other conditions. For example, chest x-ray may show alveolar opacities, and a CT may show a "crazy paving" lung pattern, both of which are seen more commonly in numerous other conditions.[9] Thus, the diagnosis primarily depends on the pathology findings.

Lung washings or tissue for histopathologic analysis are most commonly obtained using bronchoalveolar lavage and/or lung biopsy.[10] Characteristic biopsy findings show filling of the alveoli (and sometimes terminal bronchioles) with an amorphous eosinophilic material, which stains strongly positive on PAS stain and the PAS diastase stain. The surrounding alveoli and pulmonary interstitium remain relatively normal.[11] Electron microscopy of the sample, although not typically performed due to impracticality, shows lamellated bodies representing surfactant.[12] An alternative diagnosis with similar histomorphologic findings is Pneumocystis jirovicii pneumonia.[12]

Lung washings characteristically yield a fluid which is "milky"composition. Under the microscope, samples show 20-50 micrometer PAS-positive globules on a background of finely granular or amorphous PAS-positive material. There is typically a low numbers of macrophages and inflammatory cells (although this is variable).[11][12]

Treatment[edit]

The standard treatment for PAP is whole-lung lavage,[13][14] in which the lung is filled with sterile fluid with subsequent removal of the fluid along with the abnormal surfactant material. This is generally effective at improving PAP symptoms, often for a prolonged period of time.

Since the mouse discovery noted above, the use of GM-CSF injections has also been attempted, with variable success.

Lung transplantation may be performed in refractory cases.

Epidemiology[edit]

The disease is more common in males and in tobacco smokers.

In a recent epidemiologic study from Japan,[15] Autoimmune PAP has an incidence and prevalence higher than previously reported and is not strongly linked to smoking, occupational exposure, or other illnesses.

Endogenous lipoid pneumonia and non-specific interstitial pneumonitis has been seen prior to the development of PAP in a child.[16]

History[edit]

PAP was first described in 1958[17] by the physicians Samuel Rosen, Benjamin Castleman, and Averill Liebow.[18] In their case series published in the New England Journal of Medicine on June 7 of that year, they described 27 patients with pathologic evidence of periodic acid Schiff positive material filling the alveoli. This lipid rich material was subsequently recognized to be surfactant.

The reported treatment of PAP using therapeutic bronchoalveolar lavage was in 1960 by Dr. Jose Ramirez-Rivera at the Veterans' Administration Hospital in Baltimore,[19] who described repeated "segmental flooding" as a means of physically removing the accumulated alveolar material.[20]

Research[edit]

PAP is one of the rare lung diseases currently being studied by The Rare Lung Diseases Consortium (RLDC). The RLDC is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), of the National Center for Advancing Translational Sciences (NCATS). The RLDC is dedicated to developing new diagnostics and therapeutics for patients with rare lung diseases, through collaboration between the National Institutes of Health, patient organizations and clinical investigators.

Patient registry[edit]

PAP patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

References[edit]

  1. ^ Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C (January 2000). "Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis". Thorax. 55 (1): 67–77. doi:10.1136/thorax.55.1.67. PMC 1745595Freely accessible. PMID 10607805. 
  2. ^ a b Kumar, Anupam; Abdelmalak, Basem; Inoue, Yoshikazu; Culver, Daniel A (2018). "Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach". The Lancet Respiratory Medicine. doi:10.1016/s2213-2600(18)30043-2. 
  3. ^ Stanley E, Lieschke GJ, Grail D, et al. (June 1994). "Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology". Proc. Natl. Acad. Sci. U.S.A. 91 (12): 5592–6. doi:10.1073/pnas.91.12.5592. PMC 44042Freely accessible. PMID 8202532. 
  4. ^ Uchida K, Beck D, Yamamoto T, Berclaz P, Abe S, Staudt M, Carey B, Filippi M, Wert S, Denson L, Puchalski J, Hauck D, Trapnell B (2007). "GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis". N Engl J Med. 356 (6): 567–79. doi:10.1056/NEJMoa062505. PMID 17287477. 
  5. ^ Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC 5391620Freely accessible. PMID 28179280. 
  6. ^ Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM (August 2017). "Heterogeneity of GATA2-related myeloid neoplasms". International Journal of Hematology. 106 (2): 175–182. doi:10.1007/s12185-017-2285-2. PMID 28643018. 
  7. ^ Whitsett, JA; Wert, SE; Weaver, TE (2015). "Diseases of pulmonary surfactant homeostasis". Annual Review of Pathology. 10: 371–93. doi:10.1146/annurev-pathol-012513-104644. PMC 4316199Freely accessible. PMID 25621661. 
  8. ^ Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, Koch DE, Stevens C, Inoue Y, Yamada Y, Trapnell BC (Jan 15, 2014). "Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis". J Immunol Methods. 402 (1–2): 57–70. doi:10.1016/j.jim.2013.11.011. PMID 24275678. 
  9. ^ Holbert, J. M.; Costello, P.; Li, W.; Hoffman, R. M.; Rogers, R. M. (May 2001). "CT features of pulmonary alveolar proteinosis". AJR. American journal of roentgenology. 176 (5): 1287–1294. doi:10.2214/ajr.176.5.1761287. ISSN 0361-803X. PMID 11312196. 
  10. ^ Monisha Das, MD & Gary A. Salzman, MD (February 2010). "Pulmonary Alveolar Proteinosis: An Overview for Internists and Hospital Physicians". Hospital Practice. 38 (1): 43–49. doi:10.3810/hp.2010.02.277. PMID 20469623. 
  11. ^ a b Mikami, T.; Yamamoto, Y.; Yokoyama, M.; Okayasu, I. (December 1997). "Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid". Journal of Clinical Pathology. 50 (12): 981–984. doi:10.1136/jcp.50.12.981. ISSN 0021-9746. PMC 500376Freely accessible. PMID 9516877. 
  12. ^ a b c Maygarden, S. J.; Iacocca, M. V.; Funkhouser, W. K.; Novotny, D. B. (June 2001). "Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid". Diagnostic Cytopathology. 24 (6): 389–395. doi:10.1002/dc.1086. ISSN 8755-1039. PMID 11391819. 
  13. ^ Ceruti M, Rodi G, Stella GM, et al. (2007). "Successful whole lung lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance: a case report". Orphanet J Rare Dis. 2: 14. doi:10.1186/1750-1172-2-14. PMC 1845139Freely accessible. PMID 17386098. 
  14. ^ Menard KJ (April 2005). "Whole lung lavage in the treatment of pulmonary alveolar proteinosis". J. Perianesth. Nurs. 20 (2): 114–26. doi:10.1016/j.jopan.2005.01.005. PMID 15806528. 
  15. ^ Inoue Y, Trapnell BC, Tazawa R, et al. (April 2008). "Characteristics of a Large Cohort of Patients with Autoimmune Pulmonary Alveolar Proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118Freely accessible. PMID 18202348. 
  16. ^ Antoon JW, Hernandez ML, Roehrs PA, Noah TL, Leigh MW, Byerley JS (2014). "Endogenous lipoid pneumonia preceding diagnosis of pulmonary alveolar proteinosis". Clin Respir J. 10: 246–9. doi:10.1111/crj.12197. PMID 25103284. 
  17. ^ Seymour JF, Presneill JJ (July 2002). "Pulmonary alveolar proteinosis: progress in the first 44 years". Am. J. Respir. Crit. Care Med. 166 (2): 215–35. doi:10.1164/rccm.2109105. PMID 12119235. 
  18. ^ Rosen SH, Castleman B, Liebow AA (1958). "Pulmonary alveolar proteinosis". N. Engl. J. Med. 258 (23): 1123–1142. doi:10.1056/NEJM195806052582301. PMID 13552931. 
  19. ^ Ramirez-Rivera J, Nyka W, McLaughlin J (1963). "Pulmonary Alveolar Proteinosis: Diagnostic Technics and Observations". New England Journal of Medicine. 268 (4): 165–71. doi:10.1056/NEJM196301242680401. PMID 13990655. 
  20. ^ Ramirez-Rivera J, Schultz RB, Dutton RE (1963). "Pulmonary Alveolar Proteinosis: A New Technique and Rational for Treatment". Archives of Internal Medicine. 112: 419–31. doi:10.1001/archinte.1963.03860030173021. 

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