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Current Pulmonology Reports

Erschienen in:

16.05.2024 | REVIEW

Autoimmune Pulmonary Alveolar Proteinosis: A Review of Pathogenesis and Emerging Therapies

verfasst von: Akshay Mathavan, Akash Mathavan, Swaminathan Perinkulam Sathyanarayanan, Cormac McCarthy, Ali Ataya

Erschienen in: Current Pulmonology Reports | Ausgabe 3/2024

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Abstract

Purpose of Review

Autoimmune pulmonary alveolar proteinosis is a heterogenous clinical syndrome of disordered surfactant clearance due to a dysfunctional granulocyte–macrophage colony-stimulating factor signaling axis in the setting of polyclonal autoantibody generation. Recent advancements identifying key mechanistic drivers of this disease have been made. This clinical review summarizes current knowledge of autoimmune pulmonary alveolar proteinosis with an emphasis on contemporary findings on pathogenesis and emerging therapies.

Recent Findings

A disturbed granulocyte–macrophage colony-stimulating factor signaling axis leads to downstream dysregulation of cholesterol export within alveolar macrophages. Accumulation of cholesterol impedes surfactant clearance and propagates the syndrome’s disease process.

Summary

Whole lung lavage therapy is an invasive procedure performed under general anesthesia which remains the standard of care for autoimmune pulmonary alveolar proteinosis. Augmentation of the defective signaling axis with recombinant human granulocyte-macrophage colony-stimulating factor is a promising treatment modality.

Miyashita K, Hozumi H, Inoue Y, Suzuki T, Suda T. Nationwide survey of adult patients with pulmonary alveolar proteinosis using the National Database of designated intractable diseases of Japan. Respir Investig. 2023;61:364–70. https://doi.org/10.1016/j.resinv.2023.02.011.CrossRefPubMed

McCarthy C, Avetisyan R, Carey BC, Chalk C, Trapnell BC. Prevalence and healthcare burden of pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2018;13:129. https://doi.org/10.1186/s13023-018-0846-y.CrossRefPubMedPubMedCentral

Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958;258:1123–42. https://doi.org/10.1056/NEJM195806052582301.CrossRefPubMed

Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003;349:2527–39. https://doi.org/10.1056/NEJMra023226.CrossRefPubMed

• McCarthy C, Carey BC, Trapnell BC. Autoimmune Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2022;205:1016–35. https://doi.org/10.1164/rccm.202112-2742SO. State of the art comprehensive review of autoimmune pulmonary alveolar proteinosis.CrossRefPubMed

Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med. 2008;177:752–62. https://doi.org/10.1164/rccm.200708-1271OC.CrossRefPubMedPubMedCentral

Han S, Mallampalli RK. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections. Ann Am Thorac Soc. 2015;12:765–74. https://doi.org/10.1513/AnnalsATS.201411-507FR.CrossRefPubMedPubMedCentral

Gschwend J, Sherman SPM, Ridder F, Feng X, Liang H-E, Locksley RM, et al. Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth. J Exp Med. 2021. https://doi.org/10.1084/jem.20210745.CrossRefPubMedPubMedCentral

Schneider C, Nobs SP, Kurrer M, Rehrauer H, Thiele C, Kopf M. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014;15:1026–37. https://doi.org/10.1038/ni.3005.CrossRefPubMed

10.

Wojcik AJ, Skaflen MD, Srinivasan S, Hedrick CC. A critical role for ABCG1 in macrophage inflammation and lung homeostasis. J Immunol. 2008;180:4273–82. https://doi.org/10.4049/jimmunol.180.6.4273.CrossRefPubMed

11.

Wang B, Tontonoz P. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol. 2018;14:452–63. https://doi.org/10.1038/s41574-018-0037-x.CrossRefPubMedPubMedCentral

12.

Trapnell BC, Nakata K, Bonella F, Campo I, Griese M, Hamilton J, et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers. 2019;5:16. https://doi.org/10.1038/s41572-019-0066-3.CrossRefPubMed

13.

McCarthy C, Lee E, Bridges JP, Sallese A, Suzuki T, Woods JC, et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nat Commun. 2018;9:3127. https://doi.org/10.1038/s41467-018-05491-z.CrossRefPubMedPubMedCentral

14.

Sakagami T, Uchida K, Suzuki T, Carey BC, Wood RE, Wert SE, et al. Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N Engl J Med. 2009;361:2679–81. https://doi.org/10.1056/NEJMc0904077.CrossRefPubMedPubMedCentral

15.

Dhagat U, Hercus TR, Broughton SE, Nero TL, Cheung Tung Shing KS, Barry EF, et al. The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities. MAbs. 2018;10:1018–29. https://doi.org/10.1080/19420862.2018.1494107.CrossRefPubMedPubMedCentral

16.

Uchida K. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood. 2003;103:1089–98. https://doi.org/10.1182/blood-2003-05-1565.CrossRefPubMed

17.

Hwang JA, Song JH, Kim JH, Chung MP, Kim DS, Song JW, et al. Clinical significance of cigarette smoking and dust exposure in pulmonary alveolar proteinosis: a Korean national survey. BMC Pulm Med. 2017;17:147. https://doi.org/10.1186/s12890-017-0493-4.CrossRefPubMedPubMedCentral

18.

Uchida K, Nakata K, Suzuki T, Luisetti M, Watanabe M, Koch DE, et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood. 2009;113:2547–56. https://doi.org/10.1182/blood-2009-05-155689.CrossRefPubMedPubMedCentral

19.

Seymour JF, Doyle IR, Nakata K, Presneill JJ, Schoch OD, Hamano E, et al. 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. Thorax. 2003;58:252–7. https://doi.org/10.1136/thorax.58.3.252.CrossRefPubMedPubMedCentral

20.

Ataya A, Knight V, Carey BC, Lee E, Tarling EJ, Wang T. The Role of GM-CSF Autoantibodies in Infection and Autoimmune Pulmonary Alveolar Proteinosis: A Concise Review. Front Immunol. 2021;12: 752856. https://doi.org/10.3389/fimmu.2021.752856.CrossRefPubMedPubMedCentral

21.

Mabo A, Borie R, Wemeau-Stervinou L, Uzunhan Y, Gomez E, Prevot G, et al. Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort. Thorax. 2023;79:68–74. https://doi.org/10.1136/thorax-2023-220040.CrossRefPubMed

22.

Trapnell BC, Carey BC, Uchida K, Suzuki T. Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages. Curr Opin Immunol. 2009;21:514–21. https://doi.org/10.1016/j.coi.2009.09.004.CrossRefPubMedPubMedCentral

23.

Trapnell BC, Whitsett JA. GM-CSF Regulates Pulmonary Surfactant Homeostasis and Alveolar Macrophage-Mediated Innate Host Defense. Annu Rev Physiol. 2002;64:775–802. https://doi.org/10.1146/annurev.physiol.64.090601.113847.CrossRefPubMed

24.

Campo I, Mariani F, Rodi G, Paracchini E, Tsana E, Piloni D, et al. Assessment and management of pulmonary alveolar proteinosis in a reference center. Orphanet J Rare Dis. 2013;8:40. https://doi.org/10.1186/1750-1172-8-40.CrossRefPubMedPubMedCentral

25.

Hawkins P, Chawke L, Cormican L, Wikenheiser-Brokamp KA, Fabre A, Keane MP, et al. Autoimmune pulmonary alveolar proteinosis: a discrepancy between symptoms and CT findings. Lancet. 2021;398: e7. https://doi.org/10.1016/S0140-6736(21)01254-X.CrossRefPubMed

26.

Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002;166:215–35. https://doi.org/10.1164/rccm.2109105.CrossRefPubMed

27.

Punatar AD, Kusne S, Blair JE, Seville MT, Vikram HR. Opportunistic infections in patients with pulmonary alveolar proteinosis. J Infect. 2012;65:173–9. https://doi.org/10.1016/j.jinf.2012.03.020.CrossRefPubMed

28.

Mariani F, Infusino C, Lettieri S, Piloni D, Bosio M, De Silvestri A, et al. Lung fibrosis in Pulmonary Alveolar Proteinosis (PAP): different stages of a syndrome or distinct diseases? Rare ILD / DPLD. European Respiratory Society. 2021. https://doi.org/10.1183/13993003.congress-2021.PA2369.CrossRef

29.

Hunt AN, Malur A, Monfort T, Lagoudakis P, Mahajan S, Postle AD, et al. Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis. Am J Respir Cell Mol Biol. 2017;57:448–58. https://doi.org/10.1165/rcmb.2016-0242OC.CrossRefPubMedPubMedCentral

30.

Seymour JF. Extra-pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte-macrophage colony-stimulating factor-deficient mice. Respirology. 2006. https://doi.org/10.1111/j.1440-1843.2006.00801.x.CrossRefPubMed

31.

Da Nam B, Kim TJ, Chung MP, Chung MJ, Kim TS, Lee KS. CT findings in pulmonary alveolar proteinosis: serial changes and prognostic implications. J Thorac Dis. 2018;10:5774–83. https://doi.org/10.21037/jtd.2018.09.86.CrossRefPubMedPubMedCentral

32.

Fijołek J, Wiatr E, Radzikowska E, Bestry I, Langfort R, Polubiec-Kownacka M, et al. Pulmonary alveolar proteinosis during a 30-year observation. Diagnosis and treatment Pneumonol Alergol Pol. 2014;82:206–17. https://doi.org/10.5603/PiAP.2014.0028.CrossRefPubMed

33.

Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, et al. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2014;402:57–70. https://doi.org/10.1016/j.jim.2013.11.011.CrossRefPubMed

34.

•• McCarthy C, Carey B, Trapnell BC. Blood Testing for Differential Diagnosis of Pulmonary Alveolar Proteinosis Syndrome. Chest. 2019;155:450–2. https://doi.org/10.1016/j.chest.2018.11.002. Paper highlighting the importance of blood GM-CSF testing in diagnosing autoimmune pulmonary alveolar proteinosis.CrossRefPubMedPubMedCentral

35.

Nakata K, Sugi T, Kuroda K, Yoshizawa K, Takada T, Tazawa R, et al. Validation of a new serum granulocyte-macrophage colony-stimulating factor autoantibody testing kit. ERJ Open Res. 2020. https://doi.org/10.1183/23120541.00259-2019.CrossRefPubMedPubMedCentral

36.

Carey B, Chalk C, Stock J, Toth A, Klingler M, Greenberg H, et al. A dried blood spot test for diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2022;511: 113366. https://doi.org/10.1016/j.jim.2022.113366.CrossRefPubMedPubMedCentral

37.

Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE, Zimmerman SL, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med. 2008;205:2703–10. https://doi.org/10.1084/jem.20080990.CrossRefPubMedPubMedCentral

38.

Kusakabe Y, Uchida K, Hiruma T, Suzuki Y, Totsu T, Suzuki T, et al. A standardized blood test for the routine clinical diagnosis of impaired GM-CSF signaling using flow cytometry. J Immunol Methods. 2014;413:1–11. https://doi.org/10.1016/j.jim.2014.07.009.CrossRefPubMedPubMedCentral

39.

Salvator H, Cheng A, Rosen LB, Williamson PR, Bennett JE, Kashyap A, et al. Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis. Respir Res. 2022;23:280. https://doi.org/10.1186/s12931-022-02103-9.CrossRefPubMedPubMedCentral

40.

Lee E, Miller C, Ataya A, Wang T. Opportunistic Infection Associated With Elevated GM-CSF Autoantibodies: A Case Series and Review of the Literature. Open Forum Infect Dis. 2022;9:ofac146. https://doi.org/10.1093/ofid/ofac146.CrossRefPubMedPubMedCentral

41.

Campo I, Meloni F, Gahlemann M, Sauter W, Ittrich C, Schoelch C, et al. An exploratory study investigating biomarkers associated with autoimmune pulmonary alveolar proteinosis (aPAP). Sci Rep. 2022;12:8708. https://doi.org/10.1038/s41598-022-11446-8.CrossRefPubMedPubMedCentral

42.

Campo I, Luisetti M, Griese M, Trapnell BC, Bonella F, Grutters J, et al. Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures. Orphanet J Rare Dis. 2016;11:115. https://doi.org/10.1186/s13023-016-0497-9.CrossRefPubMedPubMedCentral

43.

Wayne MT, Ali MS, Roller L, Gay SE, Maldonado F, De Cardenas J. Safety of Bilateral Whole Lung Lavage for Pulmonary Alveolar Proteinosis. J Bronchology Interv Pulmonol. 2023;30:188–91. https://doi.org/10.1097/LBR.0000000000000897.CrossRefPubMed

44.

Mariani F, Salvaterra E, Lettieri S, De Silvestri A, Corino A, Bosio M, et al. A mini-whole lung lavage to treat autoimmune pulmonary alveolar proteinosis (PAP). Respir Res. 2022;23:60. https://doi.org/10.1186/s12931-022-01982-2.CrossRefPubMedPubMedCentral

45.

Ra SW, Park SE, Lee HK, Han IS, Park SH. Whole lung lavage using a rapid infusion system to treat a patient with pulmonary alveolar proteinosis. Yeungnam Univ J Med. 2020;37:67–72. https://doi.org/10.12701/yujm.2019.00360.CrossRefPubMed

46.

Gómez-Sánchez R, Santa-Teresa P, García López JJ, Duque P, García-Carreño J, Jaspe A. Pulmonary alveolar proteinosis treated with whole-lung lavage under veno-venous extracorporeal membrane oxygenation, clinical case series and review of the literature. Med Intensiva. 2024;48:59–61. https://doi.org/10.1016/j.medine.2023.11.005.CrossRefPubMed

47.

Bonella F, Bauer PC, Griese M, Wessendorf TE, Guzman J, Costabel U. Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis. Eur Respir J. 2012;40:1468–74. https://doi.org/10.1183/09031936.00017612.CrossRefPubMed

48.

Kinthala S, Liang M, Khusid F, Harrison S. The Use of High-Frequency Percussive Ventilation for Whole-Lung Lavage: A Case Report. A A Pract. 2018;11:205–7. https://doi.org/10.1213/XAA.0000000000000778.CrossRefPubMed

49.

McCarthy C, Bartholmai BJ, Woods JC, McCormack FX, Trapnell BC. Automated Parenchymal Pattern Analysis of Treatment Responses in Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2019;199:1151–2. https://doi.org/10.1164/rccm.201810-1918IM.CrossRefPubMedPubMedCentral

50.

Zhang H-T, Wang C, Wang C-Y, Fang S-C, Xu B, Zhang Y-M. Efficacy of Whole-Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis. Am J Ther. 2016;23:e1671–9. https://doi.org/10.1097/MJT.0000000000000239.CrossRefPubMed

51.

Kaenmuang P, Navasakulpong A. Efficacy of whole lung lavage in pulmonary alveolar proteinosis: a 20-year experience at a reference center in Thailand. J Thorac Dis. 2021;13:3539–48. https://doi.org/10.21037/jtd-20-3308.CrossRefPubMedPubMedCentral

52.

Kiani A, Parsa T, Adimi Naghan P, Dutau H, Razavi F, Farzanegan B, et al. An eleven-year retrospective cross-sectional study on pulmonary alveolar proteinosis. Adv Respir Med. 2018;86:7–12. https://doi.org/10.5603/ARM.2018.0003.CrossRefPubMed

53.

Chuang C-H, Cheng C-H, Tsai Y-C, Tsai M-J, Sheu C-C, Chong I-W. Pulmonary alveolar proteinosis in Taiwan. J Formos Med Assoc. 2023;122:1061–8. https://doi.org/10.1016/j.jfma.2023.04.002.CrossRefPubMed

54.

Seymour JF, Dunn AR, Vincent JM, Presneill JJ, Pain MC. Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor in Acquired Alveolar Proteinosis. N Engl J Med. 1996;335:1924–5. https://doi.org/10.1056/NEJM199612193352513.CrossRefPubMed

55.

Kavuru MS, Sullivan EJ, Piccin R, Thomassen MJ, Stoller JK. Exogenous Granulocyte-Macrophage Colony-Stimulating Factor Administration for Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2000;161:1143–8. https://doi.org/10.1164/ajrccm.161.4.9906044.CrossRefPubMed

56.

Seymour JF, Presneill JJ, Schoch OD, Downie GH, Moore PE, Doyle IR, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med. 2001;163:524–31. https://doi.org/10.1164/ajrccm.163.2.2003146.CrossRefPubMed

57.

Venkateshiah SB, Yan TD, Bonfield TL, Thomassen MJ, Meziane M, Czich C, et al. An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis. Chest. 2006;130:227–37. https://doi.org/10.1378/chest.130.1.227.CrossRefPubMed

58.

Khan A, Agarwal R, Aggarwal AN, Bal A, Sen I, Yaddanapuddi LN, et al. Experience with treatment of pulmonary alveolar proteinosis from a tertiary care centre in north India. Indian J Chest Dis Allied Sci. 2012;54:91–7.PubMed

59.

Hadda V, Tiwari P, Madan K, Mohan A, Gupta N, Bharti S, et al. Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature. Lung India. 2016;33:626. https://doi.org/10.4103/0970-2113.192876.CrossRefPubMedPubMedCentral

60.

Arai T, Hamano E, Inoue Y, Ryushi T, Nukiwa T, Sakatani M, et al. Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. Respir Med. 2004;98:1227–30. https://doi.org/10.1016/j.rmed.2004.08.011.CrossRefPubMed

61.

Tazawa R, Hamano E, Arai T, Ohta H, Ishimoto O, Uchida K, et al. Granulocyte-Macrophage Colony-Stimulating Factor and Lung Immunity in Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2005;171:1142–9. https://doi.org/10.1164/rccm.200406-716OC.CrossRefPubMed

62.

Wylam ME. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006;27:585–93. https://doi.org/10.1183/09031936.06.00058305.CrossRefPubMed

63.

Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2010;181:1345–54. https://doi.org/10.1164/rccm.200906-0978OC.CrossRefPubMedPubMedCentral

64.

Ohashi K, Sato A, Takada T, Arai T, Nei T, Kasahara Y, et al. Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis. Respir Med. 2012;106:284–93. https://doi.org/10.1016/j.rmed.2011.10.019.CrossRefPubMed

65.

Papiris SA, Tsirigotis P, Kolilekas L, Papadaki G, Papaioannou AI, Triantafillidou C, et al. Long-Term Inhaled Granulocyte Macrophage–Colony-Stimulating Factor in Autoimmune Pulmonary Alveolar Proteinosis: Effectiveness, Safety, and Lowest Effective Dose. Clin Drug Investig. 2014;34:553–64. https://doi.org/10.1007/s40261-014-0208-z.CrossRefPubMed

66.

Campo I, Mariani F, Paracchini E, Kadija Z, Zorzetto M, Tinelli C, et al. Inhaled sargramostim and whole lung lavage (WLL) as therapy of autoimmune pulmonary alveolar proteinosis (aPAP). Diffuse Parenchymal Lung Disease European Respiratory Society. 2016. https://doi.org/10.1183/13993003.congress-2016.PA3870.CrossRef

67.

Ohkouchi S, Akasaka K, Ichiwata T, Hisata S, Iijima H, Takada T, et al. Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis A Report of Five Intractable Cases. Ann Am Thorac Soc. 2017;14:1298–304. https://doi.org/10.1513/AnnalsATS.201611-892BC.CrossRefPubMed

68.

Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, et al. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019;381:923–32. https://doi.org/10.1056/NEJMoa1816216.CrossRefPubMed

69.

Zhen G, Li D, Jiang J, Weng Y. Granulocyte-Macrophage Colony-Stimulating Factor Inhalation Therapy for Severe Pulmonary Alveolar Proteinosis. Am J Ther. 2020;28:e171–8. https://doi.org/10.1097/MJT.0000000000001053.CrossRefPubMed

70.

Tian X, Yang Y, Chen L, Sui X, Xu W, Li X, et al. Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up. Orphanet J Rare Dis. 2020;15:174. https://doi.org/10.1186/s13023-020-01450-4.CrossRefPubMedPubMedCentral

71.

•• Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, et al. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020;383:1635–44. https://doi.org/10.1056/NEJMoa1913590. The largest randomized clinical trial in autoimmune PAP to date showing inhaled GM-CSF therapy was superior to placebo in improving multiple endpoints including change in arterial-alveolar gradient and diffusion capacity to carbon monoxide (DLCO).CrossRefPubMedPubMedCentral

72.

Livingstone C, Corallo C, Siemienowicz M, Pilcher D, Stirling RG. Nebulised sargramostim in pulmonary alveolar proteinosis. Br J Clin Pharmacol. 2022;88:3523–8. https://doi.org/10.1111/bcp.15266.CrossRefPubMed

73.

Tazawa R, Inoue Y, Arai T, Takada T, Kasahara Y, Hojo M, et al. Duration of Benefit in Patients With Autoimmune Pulmonary Alveolar Proteinosis After Inhaled Granulocyte-Macrophage Colony-Stimulating Factor Therapy. Chest. 2014;145:729–37. https://doi.org/10.1378/chest.13-0603.CrossRefPubMed

74.

Sheng G, Chen P, Wei Y, Chu J, Cao X, Zhang H-L. Better approach for autoimmune pulmonary alveolar proteinosis treatment: inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor: a meta-analyses. Respir Res. 2018;19:163. https://doi.org/10.1186/s12931-018-0862-4.CrossRefPubMedPubMedCentral

75.

Zhang F, Weng D, Su Y, Yin C, Shen L, Zhang Y, et al. Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis. Respir Res. 2020;21:1. https://doi.org/10.1186/s12931-019-1261-1.CrossRefPubMedPubMedCentral

76.

Munsif M, Sweeney D, Leong TL, Stirling RG. Nebulised granulocyte–macrophage colony-stimulating factor (GM-CSF) in autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis. Eur Respir Rev. 2023;32: 230080. https://doi.org/10.1183/16000617.0080-2023.CrossRefPubMedPubMedCentral

77.

Campo I, Carey BC, Paracchini E, Kadija Z, De Silvestri A, Rodi G, et al. Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients. Eur Respir J. 2024. https://doi.org/10.1183/13993003.01233-2023.CrossRefPubMedPubMedCentral

78.

Trapnell BC, McCarthy C. The Alveolar Lipidome in Pulmonary Alveolar Proteinosis. A New Target for Therapeutic Development? Am J Respir Crit Care Med. 2019;200:800–2. https://doi.org/10.1164/rccm.201905-1009ED.CrossRefPubMedPubMedCentral

79.

Yan X, Gao Y, Zhao Q, Qiu X, Tian M, Dai J, et al. Correlation of Lipid Ratios With the Severity of Pulmonary Alveolar Proteinosis: A Cross-Sectional Study. Front Nutr. 2021. https://doi.org/10.3389/fnut.2021.610765.CrossRefPubMedPubMedCentral

80.

Griese M, Bonella F, Costabel U, de Blic J, Tran N-B, Liebisch G. Quantitative Lipidomics in Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2019;200:881–7. https://doi.org/10.1164/rccm.201901-0086OC.CrossRefPubMed

81.

Shi S, Wang R, Chen L, Li Y, Zhang Y, Xin X, et al. Long-term follow-up and successful treatment of pulmonary alveolar proteinosis without hypercholesterolemia with statin therapy: a case report. J Int Med Res. 2021;49:3000605211010046. https://doi.org/10.1177/03000605211010046.CrossRefPubMed

82.

Takano T, Takeda K, Nakamura S, Akiyama G, Ando N, Komori M. A case of autoimmune pulmonary alveolar proteinosis with severe respiratory failure treated with segmental lung lavage and oral statin therapy. Respir Med Case Rep. 2022;38: 101684. https://doi.org/10.1016/j.rmcr.2022.101684.CrossRefPubMedPubMedCentral

83.

Shi S, Gui X, Ding J, Yang S, Xin X, Xu K, et al. Assessment of Statin Treatment for Pulmonary Alveolar Proteinosis without Hypercholesterolemia: A 12-Month Prospective, Longitudinal, and Observational Study. Biomed Res Int. 2022;2022:1589660. https://doi.org/10.1155/2022/1589660.CrossRefPubMedPubMedCentral

84.

Shi S, Zou R, Chen L, Yang S, Xu K, Xin X, et al. Quantitative chest CT assessment of pulmonary alveolar proteinosis with deep learning: a real-world longitudinal study. Quant Imaging Med Surg. 2022;12:5394–403. https://doi.org/10.21037/qims-22-205.CrossRefPubMedPubMedCentral

85.

Sallese A, Suzuki T, McCarthy C, Bridges J, Filuta A, Arumugam P, et al. Targeting cholesterol homeostasis in lung diseases. Sci Rep. 2017;7:10211. https://doi.org/10.1038/s41598-017-10879-w.CrossRefPubMedPubMedCentral

86.

Dupin C, Hurtado M, Cazes A, Taille C, Debray MP, Guenée C, et al. Pioglitazone in pulmonary alveolar proteinosis: promising first clinical experience. Respir Med Res. 2020;78: 100756. https://doi.org/10.1016/j.resmer.2020.100756.CrossRefPubMed

87.

Vis DC, Kelly MM, De Heuvel E, MacEachern PR. Reduction in Alveolar Macrophage Size in Refractory Autoimmune Pulmonary Alveolar Proteinosis After Treatment With Pioglitazone. J Bronchology Interv Pulmonol. 2020;27:219–22. https://doi.org/10.1097/LBR.0000000000000686.CrossRefPubMed

88.

Lee E, Williams KJ, McCarthy C, Bridges JP, Redente EF, de Aguiar Vallim TQ, et al. Alveolar macrophage lipid burden correlates with clinical improvement in patients with pulmonary alveolar proteinosis. J Lipid Res. 2024;65: 100496. https://doi.org/10.1016/j.jlr.2024.100496.CrossRefPubMedPubMedCentral

89.

Seabloom DE, Galbraith AR, Haynes AM, Antonides JD, Wuertz BR, Miller WA, et al. Safety and Preclinical Efficacy of Aerosol Pioglitazone on Lung Adenoma Prevention in A/J Mice. Cancer Prev Res (Phila). 2017;10:124–32. https://doi.org/10.1158/1940-6207.CAPR-16-0174.CrossRefPubMed

90.

Huang J, Lin Z, Lin J, Xie S, Xia S, Chen G, et al. Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study. Thorax. 2024;79:135–43. https://doi.org/10.1136/thorax-2023-220789.CrossRefPubMed

91.

Akasaka K, Tanaka T, Kitamura N, Ohkouchi S, Tazawa R, Takada T, et al. Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study. BMC Pulm Med. 2015;15:88. https://doi.org/10.1186/s12890-015-0085-0.CrossRefPubMedPubMedCentral

92.

Ishimoto H, Sakamoto N, Yura H, Hara A, Kido T, Yamaguchi H, et al. Autoimmune pulmonary alveolar proteinosis exacerbated by steroid therapy due to misdiagnosis as anti-aminoacyl-tRNA synthetase (ARS) antibody positive- interstitial pneumonia: a case report. BMC Pulm Med. 2022;22:120. https://doi.org/10.1186/s12890-022-01909-z.CrossRefPubMedPubMedCentral

93.

Asami-Noyama M, Ito K, Harada M, Hisamoto Y, Kunihiro Y, Ikeda E, et al. A case of development of autoimmune pulmonary alveolar proteinosis during the treatment of hypersensitivity pneumonitis. Respir Med Case Rep. 2023;44: 101862. https://doi.org/10.1016/j.rmcr.2023.101862.CrossRefPubMedPubMedCentral

94.

Hirose M, Arai T, Sugimoto C, Takimoto T, Sugawara R, Minomo S, et al. B cell-activating factors in autoimmune pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2021;16:115. https://doi.org/10.1186/s13023-021-01755-y.CrossRefPubMedPubMedCentral

95.

Borie R, Debray M-P, Laine C, Aubier M, Crestani B. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J. 2009;33:1503–6. https://doi.org/10.1183/09031936.00160908.CrossRefPubMed

96.

Amital A, Dux S, Shitrit D, Shpilberg O, Kramer MR. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis. Thorax. 2010;65:1025–6. https://doi.org/10.1136/thx.2010.140673.CrossRefPubMed

97.

Bird D, Evans J, Pahoff C. Rituximab rescue therapy for autoimmune pulmonary alveolar proteinosis. Respir Med Case Rep. 2022;37: 101637. https://doi.org/10.1016/j.rmcr.2022.101637.CrossRefPubMedPubMedCentral

98.

Kavuru MS, Malur A, Marshall I, Barna BP, Meziane M, Huizar I, et al. An open-label trial of rituximab therapy in pulmonary alveolar proteinosis. Eur Respir J. 2011;38:1361–7. https://doi.org/10.1183/09031936.00197710.CrossRefPubMed

99.

Malur A, Kavuru MS, Marshall I, Barna BP, Huizar I, Karnekar R, et al. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis. Respir Res. 2012;13:46. https://doi.org/10.1186/1465-9921-13-46.CrossRefPubMedPubMedCentral

100.

Soyez B, Borie R, Menard C, Cadranel J, Chavez L, Cottin V, et al. Rituximab for auto-immune alveolar proteinosis, a real life cohort study. Respir Res. 2018;19:74. https://doi.org/10.1186/s12931-018-0780-5.CrossRefPubMedPubMedCentral

101.

Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med. 2003;167:1036–7. https://doi.org/10.1164/ajrccm.167.7.950.CrossRefPubMed

102.

Luisetti M, Rodi G, Perotti C, Campo I, Mariani F, Pozzi E, et al. Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J. 2009;33:1220–2. https://doi.org/10.1183/09031936.00097508.CrossRefPubMed

103.

Garber B, Albores J, Wang T, Neville TH. A Plasmapheresis Protocol for Refractory Pulmonary Alveolar Proteinosis. Lung. 2015;193:209–11. https://doi.org/10.1007/s00408-014-9678-2.CrossRefPubMed

104.

Keske A, Destrampe EM, Barksdale B, Rose WN. Pulmonary Alveolar Proteinosis Refractory to Plasmapheresis and Rituximab despite GM-CSF Antibody Reduction. Case Reports Immunol. 2022;2022:2104270. https://doi.org/10.1155/2022/2104270.CrossRefPubMedPubMedCentral

105.

Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest. 1997;111:1457–8. https://doi.org/10.1378/chest.111.5.1457.CrossRefPubMed

106.

Wang YB, Li FK, Ding ZD, Zhao K, Fang ZM, Feng M, et al. Lung transplantation for pulmonary alveolar proteinosis: a case report and literature review. Zhonghua Jie He He Hu Xi Za Zhi. 2022;45:667–70. https://doi.org/10.3760/cma.j.cn112147-20220302-00165.CrossRefPubMed

Titel: Autoimmune Pulmonary Alveolar Proteinosis: A Review of Pathogenesis and Emerging Therapies
verfasst von: Akshay Mathavan
Akash Mathavan
Swaminathan Perinkulam Sathyanarayanan
Cormac McCarthy
Ali Ataya
Publikationsdatum: 16.05.2024
Verlag: Springer US
Erschienen in: Current Pulmonology Reports / Ausgabe 3/2024
Elektronische ISSN: 2199-2428
DOI: https://doi.org/10.1007/s13665-024-00356-x

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Autoimmune Pulmonary Alveolar Proteinosis: A Review of Pathogenesis and Emerging Therapies

Abstract

Purpose of Review

Recent Findings

Summary

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