RARE DISEASE
Autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis
Synonyms: Autoimmune PAP, aPAP
Synonyms: Autoimmune PAP, aPAP
Synonyms: Autoimmune PAP, aPAP
Drug discovery
5
drugs
With orphan designations
Overview
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease caused by neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to impaired surfactant clearance and progressive respiratory insufficiency. Diagnosis relies on high-resolution CT findings, bronchoalveolar lavage with PAS-positive material, and serum GM-CSF autoantibody detection [1][5][6]. Clinical presentation typically includes insidious dyspnea, cough, and fatigue, with variable progression from spontaneous remission to respiratory failure [7][12]. Current management includes whole-lung lavage, inhaled GM-CSF therapy, and emerging biologic therapies [3][8][13].
Categories: rare respiratory diseases, rare transplant-related disorders
Research Papers
227 drug discovery papers about Autoimmune pulmonary alveolar proteinosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
227 drug discovery papers about Autoimmune pulmonary alveolar proteinosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-02 | Progressive Fibrosing Lung Disease Treated With Nintedanib in a Patient With Long-Standing Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is caused by impaired surfactant clearance due to neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor. Although whole-lung lavage and inhaled granulocyte-macrophage colony-stimulating factor therapy are established treatment options, pulmonary fibrosis is increasingly recognized as a clinically relevant complication in a subset of patients with APAP. However, the clinical behavior of APAP-associated fibrosing lung disease and the role of antifibrotic therapy remain unclear. A 54-year-old man with a 15-year history of APAP was referred to our institution. High-resolution computed tomography images obtained before referral showed slow progression of reticulation and traction bronchiectasis, suggesting fibrotic progression rather than recurrence of APAP. At presentation, forced vital capacity (FVC) was 3.31 L (80.0% predicted), and diffusion capacity for carbon monoxide (DLCO) was preserved. During 6 months of observation, FVC declined to 3.03 L (73.5% predicted), accompanied by worsening dry cough and exertional dyspnea. Nintedanib was initiated for a progressive fibrosing phenotype in the context of APAP. Thereafter, FVC remained relatively stable for 2 years, whereas DLCO declined during follow-up. APAP-associated fibrosing lung disease may present with a progressive fibrosing phenotype, but its diagnosis and management remain challenging. This case highlights the importance of distinguishing fibrotic progression from recurrence of intra-alveolar proteinosis.
2026-02-19 | Significant but Temporary Efficacy of Statin for a Patient With Severe Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is a rare autoimmune lung disorder characterised by the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Whole-lung lavage (WLL) therapy remains the standard treatment for severe cases. Recently, inhaled GM-CSF therapy has been approved in Japan; however, the cost of the treatment remains a limiting factor. Several reports have suggested that oral statin therapy may be a promising therapeutic option for APAP. Herein, we report a case of severe APAP that underwent WLL therapy twice and achieved an excellent response and remarkable clinical resolution of respiratory failure after the initiation of oral statin therapy. Remarkable improvements in oxygen saturation, blood gas analysis, serum biomarker levels and pulmonary function test results were observed after statin administration. However, the efficacy was temporary, and respiratory failure relapsed 2 years after the initiation of statin therapy. Statin therapy for APAP was deemed effective but potentially temporary.
2025-07-02 | Secondary Pulmonary Alveolar Proteinosis Complicated by Hemophagocytic Syndrome in a Patient with Adult-onset Still's disease: A Case-based Review
Treatment of secondary pulmonary alveolar proteinosis (SPAP) focuses on managing the underlying disease, typically myelodysplastic syndrome. However, immunosuppressive therapy may worsen the condition in autoimmune disease-associated SPAP. We report the case of a 74-year-old woman with hemophagocytic syndrome and adult-onset Still's disease, who developed ground-glass opacities and consolidations during immunosuppressive treatment. SPAP was confirmed by a biopsy and negative for anti-GM-CSF antibodies. Although whole-lung lavage was considered if SPAP worsened significantly, no further deterioration was observed with tapering of prednisolone. A literature review and details of this case highlight the importance of attenuating immunosuppressive therapy, rather than its intensification, for SPAP in autoimmune diseases.
2024-06-07 | A case of autoimmune pulmonary alveolar proteinosis responding to oral statin therapy.
There is no approved drug treatment for autoimmune pulmonary alveolar proteinosis (APAP), although traditionally requires complex treatments such as whole lung lavage (WLL). We herein report on a 67-year-old man diagnosed with APAP. Treatment with atorvastatin (5 mg daily) resulted in significant improvement in symptoms, lung function, and computed tomography findings, with enhanced oxygenation, although serum anti-GM-CSF antibody levels remained elevated. This case suggests that the remission observed in this case could potentially be attributed to a direct effect of atorvastatin within the pulmonary alveoli. Statins may be considered as one of the treatment options for APAP.
2024-01-05 | A Comprehensive Case Report on the Anaesthetic Management of Whole Lung Lavage in Severe Autoimmune Pulmonary Alveolar Proteinosis
This case report presents a comprehensive analysis of the anaesthetic management employed in the whole lung lavage (WLL) procedure for a 45 -year -old female diagnosed with severe autoimmune pulmonary alveolar proteinosis (PAP). Characterized by aberrant surfactant accumulation, PAP poses challenges to respiratory function, necessitating therapeutic interventions such as WLL. The anaesthetic strategy involved meticulous planning, lung isolation techniques, and the utilization of total intravenous anaesthesia (TIVA) to enhance procedural safety. Unique to this case was the strategic use of patient positioning during WLL, capitalizing on hypoxic pulmonary vasoconstriction (HPV) to optimize perfusion dynamics. Continuous monitoring, endobronchial suctioning, and judicious positive end -expiratory pressure (PEEP) application further ensured effective lung isolation. The postprocedural course, encompassing 16 -18 hours of mechanical ventilation, a successful spontaneous breathing trial, and subsequent extubation, underscored the efficacy of the anaesthetic approach. This report contributes valuable insights into refining WLLtechniques, emphasizing the integration of HPV and TIVA for optimal patient outcomes in severe autoimmune PAP cases.
antibodies
2026-02-20 | A Case of Autoimmune Pulmonary Alveolar Proteinosis.
Chemotherapeutic agents or regular doses of Rituximab may represent a potential therapeutic option for refractory cases of autoimmune pulmonary alveolar proteinosis.
2025-06-19 | The Novel Use of Daratumumab in the Treatment of Refractory Autoimmune Pulmonary Alveolar Proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by circulating anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies that impair alveolar macrophage and neutrophil function. Macrophage dysfunction leads to accumulation of protein- and lipid-rich surfactant within alveoli, impairing gas exchange and leading to respiratory failure. Standard treatments include whole lung lavage (WLL) as first-line therapy, nebulised replacement of GM-CSF, and in refractory cases, lymphocyte depletion, immunosuppression, or lung transplantation. We present a case of a 51-year-old patient with severe, treatment-refractory aPAP failing all standard PAP therapies. A compassionate access program enabled commencement of Daratumumab, a CD38-directed monoclonal antibody (mAb), targeting long-lived plasma cells and providing a novel approach to treatment-resistant autoimmune conditions. One year post completion of Daratumumab, the patient remained in remission with clinical and radiological improvement. There was a corresponding reduction in anti-GM-CSF antibody levels and improvement in gas exchange on pulmonary function testing.
2025-05-01 | Autoimmune Pulmonary Alveolar Proteinosis Treated With Whole Lung Lavage and Rituximab: A Case Report
Abstract A 39-year-old female non-smoker who enjoyed good past health, was hospitalized for persistent dyspnoea. She denied significant exposure to humidifiers, disinfectants, crops nor any animal contact. Physical examination showed bilateral lower zone crepitations. Serial chest X-ray showed progressive bilateral lung lower lobe opacities. There was no clinical evidence of rheumatological disease. Baseline blood tests for complete blood count, liver and renal function tests were unremarkable. Autoimmune markers, myositis panel and aspergillus antibody were negative. Eosinophil count, C-reactive protein and erythrocyte sedimentation rate were not elevated. Computed Tomography (CT) Thorax revealed patchy ground glass opacities in both lungs associated with intralobular septal thickening. Serial CT scan showed increasing patchy ground glass opacities with peripheral and basal predominance. Bronchoscopy with targeted transbronchial biopsy showed proteinaceous material in a few alveolar spaces with neutrophilic infiltrates at the alveolar wall, but there was insufficient tissue for further testing. Microbiological workups including bacterial culture, fungal culture and Acid-fast bacillus culture were negative. The patient was referred to cardiothoracic surgeon for surgical lung biopsy, which showed focal chronic inflammation and fibrosis without evidence of interstitial lung disease. The patient suffered from further reduction in exercise tolerance. Follow-up CT showed further worsening of ground glass opacities in bilateral lower lobes with crazy paving pattern. Repeated bronchoscopy with transbronchial biopsy showed distended alveoli cells with granular eosinophilic matter. Contents of the alveolar spaces are positive for Periodic acid-Schiff (PAS) stain. Blood for Anti-GM-CSF antibody was arranged, and came back positive with a high activity level seen on the neutralizing assay. A diagnosis of autoimmune pulmonary alveolar proteinosis (PAP) was made. Whole lung lavage and intravenous Rituximab infusion were arranged. There was both clinical and radiological improvement post treatment. Lung function test and 6-minute walk test were improved, and the patient remained asymptomatic and free from hospitalization. Pulmonary alveolar proteinosis is a rare disease, and a high level of clinical suspicion is needed in cases of dyspnoea with bilateral lower zone opacities on chest imaging. Typical CT findings include smooth thickening of interlobular and intralobular septal lines and ground glass opacities, also known as crazy paving pattern. PAS stain should be arranged during biopsy. The increasing availability of anti-GM-CSF blood testing can facilitate the diagnosis of autoimmune PAP. Treatment options include early referral to tertiary centers with expertise in whole lung lavage and Rituximab.
2024-12-18 | Rituximab Therapy in Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (PAP) is a rare lung condition characterized by the accumulation of surfactant proteins within the alveoli, leading to respiratory distress. We describe a 49-year-old female homemaker with a history of passive smoking and exposure to wood smoke and pigeon droppings. She presented with a dry cough and progressive dyspnea, experiencing significant deterioration in her condition over one year. Chest imaging revealed bilateral alveolar-interstitial syndrome with ground-glass opacities and alveolar condensations. Biopsy findings indicated type II pneumocytes and eosinophilic material, confirming a diagnosis of autoimmune PAP. After ruling out secondary causes of PAP, rituximab was administered successfully, leading to marked improvement in respiratory function and significant regression of radiological lesions within two months. This case highlights the importance of early diagnosis and treatment of autoimmune PAP, demonstrating the potential efficacy of rituximab in managing this challenging condition.
2024-05-27 | Role of rituximab as neoadjuvant therapy in a difficult case of relapsing pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is a rare disease which involves the accumulation of insoluble lipoproteinaceous material in the alveoli leading to impaired gas exchange and even respiratory failure. Autoimmune PAP is the most common type and is characterized by the presence of anti-granulocyte-monocyte colony stimulating factor (anti GM-CSF) antibody. Whole lung lavage has been traditionally used as first-line management of PAP but there is a lack of clarity especially in the treatment of relapsing cases of PAP. Rituximab is an anti Cluster of Differentiate 20 (CD 20) monoclonal antibody that has been tried as salvage therapy for relapsing cases of PAP. We present a case of 35 years old female patient who was diagnosed as a case of relapsing PAP who was managed initially with neoadjuvant rituximab. This is a retrospective observational report showing novel use of neoadjuvant rituximab in a difficult case of relapsing PAP.
cell therapies
2026-05-01 | A93-08 Human Bone Marrow-derived Mesenchymal Stem Cell Therapy For Autoimmune Pulmonary Alveolar Proteinosis: A First-in-human Phase Iia Clinical Trial
Abstract Rationale Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by impaired alveolar macrophage function and elevated anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. Previous studies demonstrated that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can remodel the alveolar immune microenvironment and enhance macrophage phagocytic function. We conducted the first clinical study of hBMMSC therapy for aPAP to evaluate its safety and preliminary efficacy. Methods This phase IIa, open-label, single-arm clinical trial enrolled 10 aPAP patients, assigned to three groups: low-dose (1 × 106 cells/kg, single infusion), high-dose (2 × 106 cells/kg, single infusion), and high-dose repeated (2 × 106 cells/kg, two infusions two weeks apart), all via intravenous infusion. The primary endpoint was change in alveolar-arterial oxygen gradient (A-aDO2) from baseline to 24 weeks. Safety and tolerability were assessed by incidence of serious adverse events (SAEs). Results Of 10 subjects enrolled, 3 withdrew and 7 completed 24-week evaluation. No treatment-related SAEs occurred. In 7 evaluable subjects, A-aDO2 and oxygenation index (P/F ratio) improved significantly at 24 weeks compared with baseline (both p < 0.05). Repeated high-dose infusion produced greater A-aDO2 improvement than single-dose groups. Conclusion This first clinical trial of hBMMSC therapy for aPAP demonstrates that the treatment is safe, well tolerated, and improves A-aDO2 and P/F ratio. Repeated dosing appears more effective than a single infusion, providing initial real-world clinical evidence supporting potential therapeutic application. This abstract is funded by: Jiuzhitang Maker(Beijing) Cell Technology Co.Ltd
2025-09-27 | Clinical Trial of Bone Marrow-Derived Mesenchymal Stem Cell Therapy for Autoimmune Pulmonary Alveolar Proteinosis
Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by dysfunctional alveolar macrophages due to elevated levels of autoantibodies against granulocyte-macrophage colony-stimulating factor. Our previous have shown that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can restore the alveolar immune microenvironment and enhance the phagocytic function of alveolar macrophages. Methods: This study is a Phase IIa, open-label, single-arm clinical trial designed to evaluate the safety and preliminary efficacy of allogenic hBMMSC for aPAP, with enrolling 10 subjects. The primary endpoint is the change in the alveolar-arterial oxygen gradient (A-aDO2) from baseline at 24 weeks post-treatment. Safety and tolerability are assessed with the number of serious adverse events (SAEs). Results: To date, all 10 subjects have been enrolled, with 2 subjects withdrawing and 3 subjects reaching the 24-week assessment. No SAEs related to the treatment have been reported. In the 3 subjects who have reached the 24-week assessment, there were improvements in the A-aDO2 (48.07±0.81 vs. 36.17±9.85 mmHg, p=0.150) and blood oxygen partial pressure (PaO2) (55.4±8.42 vs. 70.37±16.89 mmHg, p=0.111). Chest CT scans showed improvement in 2 subjects and stability in 1 subject. The remaining 5 subjects have not yet reached the 24-week assessment. Conclusion: The hBMMSC therapy for aPAP is safe. Data from the 3 subjects who have completed the efficacy evaluation suggest that MSCs may improve the A-aDO2, PaO2, and chest CT findings. The comprehensive safety and efficacy evaluation will be conducted after all subjects reach the 24-week assessment.
2022-07-14 | Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report
Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus- disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP.
2022-07-01 | [Lung transplantation for pulmonary alveolar proteinosis: a case report and literature review].
Objective: To observe the efficacy of lung transplantation for pulmonary alveolar proteinosis (PAP) patients and to improve the understanding of the therapy. Methods: The clinical data of a patient with autoimmune PAP treated with sequential homogenous bilateral lung transplantation were described and the literatures were reviewed. Results: This 55-year-old female patient was diagnosed with autoimmune PAP and had been treated with whole lung lavage for 19 times, but only achieved short-term symptomatic relief after each operation. Inhalation of granulocyte macrophage colony stimulating factor occurred allergic reactions. Lung transplantation was performed on February 15, 2022, and a significant improvement in oxygenation and clinical symptoms were observed. The patient remained stable during follow-up. Conclusion: Treatment with lung transplantation is safe and effective for end-stage patients with PAP in the early phase, but the long-term effect remains to be observed. 目的： 探讨肺移植治疗终末期肺泡蛋白沉积症的疗效。 方法： 患者女，55岁，因“胸闷、气喘伴咳嗽6年，加重1年”入院，经反复多次全肺灌洗治疗，效果欠佳，遂行同种异体序贯式双肺移植治疗，观察其临床资料并进行相关文献复习。以“肺移植”和“肺泡蛋白沉积症”为检索词检索中国知网及万方医学网中文文献数据库，以“lung transplantation”及“pulmonary alveolar proteinosis”为检索词检索PubMed数据库，检索时间截止到2022年2月。 结果： 该患者既往行全肺灌洗19次，前期效果尚可，后期症状进行性加重，粒细胞-巨噬细胞集落刺激因子雾化吸入治疗后，出现过敏反应，胸部CT提示肺部病变逐渐加重。2022年2月15日行肺移植术，PaO2从47 mmHg（1 mmHg=0.133 kPa）上升到85 mmHg，可脱离吸氧活动，2022年3月2日出院，随访病情稳定。文献检索获得相关英文文献13篇，其中论著2篇，病例报告11篇；肺移植后继发肺泡蛋白沉积症9篇；肺移植治疗肺泡蛋白沉积症4篇，报道了3个病例；国内未见肺移植治疗肺泡蛋白沉积症的报道。 结论： 肺移植治疗终末期肺泡蛋白沉积症，早期安全有效，长期效果有待进一步观察。.
2022-05-16 | Pulmonary Alveolar Proteinosis due to Familial Myelodysplastic Syndrome with resolution after stem cell transplant
Pulmonary alveolar proteinosis (PAP) is a rare lung disease with an incidence of 0.2 cases per million. PAP has multiple causes, including autoimmune, hereditary, congenital, or secondary. The latter includes hematologic conditions and exposure to different kinds of dust. Most patients present fever, dyspnea, and cough. The chest computed tomography (CT) may reveal the crazy-paving polygonal shapes with superimposed ground glass opacities delimited by thickened interlobular septa; however, this finding is more prevalent in patients with autoimmune PAP. Bronchoalveolar lavage (BAL) shows a milky-opaque appearance with PAS-positive debris on cytology. Treatment is focused on the underlying disease; however, some patients may require whole lung lavage for symptomatic management. We report a case of a 30-year-old female with a history of familial myelodysplastic syndrome (MDS) with GATA 2 mutation who presented to the outpatient clinic with several months of progressive dyspnea and nonproductive cough. The chest CT revealed bilateral ground-glass opacities prominently in the upper lobes. She underwent a bronchoscopy with lavage and biopsy, which revealed fragments of lung parenchyma with intra-alveolar coarse granular eosinophilic material strongly positive for PAS and d-PAS. The overall clinical presentation and histologic findings were diagnostic of PAP. Her GM-CSF was negative, and due to her history of MDS, secondary PAP (S-PAP) was strongly suspected. She underwent a successful allogeneic bone marrow pluripotent stem cell transplant to treat the myelodysplastic syndrome, with a follow-up chest CT showing clear lung parenchyma. The patient had resolution of symptoms about four months after the bone marrow transplant, confirming the diagnosis of S-PAP.
proteins
2026-02-01 | Extracellular DNA in bronchoalveolar lavage fluid as a candidate biomarker of disease severity in autoimmune pulmonary alveolar proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) results from the neutralization of autoantibodies against granulocyte-macrophage colony-stimulating factor, which leads to alveolar macrophage (AM) dysfunction and surfactant accumulation. However, disease progression cannot be solely explained by surfactant overload. This study aimed to investigate whether defective efferocytosis in aPAP contributes to persistent apoptotic debris and accumulation of extracellular double-stranded DNA (dsDNA), which is a candidate biomarker of disease severity. We analyzed bronchoalveolar lavage fluid (BALF) samples obtained from 13 patients with aPAP and 13 patients with other interstitial lung diseases (controls). Apoptotic debris was assessed cytologically, extracellular dsDNA was quantified fluorometrically with urea correction, and efferocytosis was evaluated using flow cytometry. Additionally, we analyzed correlations between BALF dsDNA levels and clinical indices. BALF samples from patients with aPAP contained abundant apoptotic debris and significantly higher dsDNA levels than those from controls. Further, AMs from patients with aPAP showed s markedly reduced uptake apoptotic cells, indicating altered efferocytosis-related processes. Corrected BALF dsDNA levels were negatively correlated with the arterial oxygen pressure to inspired oxygen fraction ratio and percent predicted diffusing capacity of the lung for carbon monoxide. Altered efferocytosis-related processes in patients with aPAP may promote the accumulation of apoptotic debris and extracellular DNA in the alveolar space. Further, dsDNA levels in BALF strongly reflect impaired gas exchange and provide a biomarker of disease severity. These findings further elucidate the pathogenesis of aPAP and establish extracellular DNA as a promising tool for disease monitoring and therapeutic evaluation.
2025-06-23 | Dyspnea and Deception: Overcoming Diagnostic Hurdles in Pulmonary Alveolar Proteinosis.
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by abnormal surfactant accumulation due to defective alveolar macrophage clearance. It often presents with exertional dyspnea and nonspecific imaging findings, commonly leading to diagnostic delays. We present the case of a 56-year-old woman with progressive hypoxia initially misattributed to acute respiratory distress syndrome, noncardiogenic pulmonary edema, and hypersensitivity pneumonitis. Corticosteroids were initiated based on early differential considerations. Further evaluation revealed concurrent methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and bronchoalveolar lavage findings suggestive of PAP. Following stabilization and treatment of the infection, transbronchial biopsy confirmed PAP. The patient required prolonged intensive care and was ultimately transferred for whole-lung lavage. This case highlights the critical importance of early recognition of PAP in patients with characteristic imaging findings and progressive respiratory failure. Misdiagnosis can lead to inappropriate therapies and increased risk of infectious complications.
2024-12-01 | Severity and prognosis of COVID-19 complicated by autoimmune pulmonary alveolar proteinosis.
The prognosis of patients with coronavirus disease 2019 (COVID-19) was poor although its survival rate has been improved after the occurrence of the Omicron strain. Autoimmune pulmonary alveolar proteinosis (APAP), a lung disease caused by macrophage dysfunction induced by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)-neutralizing autoantibodies, is characterized by the deposition of proteinaceous material in the alveolar spaces. The clinical course of COVID-19 in patients with APAP remains unclear and this study aimed to clarify it. The data of 23 patients with APAP, who were diagnosed with COVID-19 between January 2020 and May 2023 and collected through a nationwide questionnaire surveillance system, were retrospectively reviewed. Based on the epidemiological frequency at disease onset, suspected strains of severe acute respiratory syndrome coronavirus 2 were Omicron (n = 18) and non-Omicron (n = 5). Fifteen patients were vaccinated. Six and three patients received anti-viral drugs and corticosteroids, respectively. One patient in the third trimester of pregnancy died despite treatment in the intensive care unit. Six patients were complicated by pneumonia and/or required supplemental oxygen. These patients were suspected to have non-Omicron strains (p = 0.087). Vaccination status showed a significant association with suspected Omicron strains. The radiological findings in four patients and shortness of breath improved in two of the four patients after COVID-19. The severity and prognosis of the patients were not worse than those predicted based on the results of a previous study. The transition from a non-Omicron strain to an Omicron strain and the vaccination status may have affected these results.
2024-10-09 | Autoimmune pulmonary alveolar proteinosis presenting as localized multifocal GGOs: A case report.
Pulmonary alveolar proteinosis (PAP) is a rare disease, which is characterized by the alveolar accumulation of surfactant. A crazy-paving appearance on chest thin-section computed tomography (TSCT) is a characteristic feature of this disease. We report an unusual case of PAP, which presented as multiple localized ground glass opacites (GGOs) on TSCT in an 80-year-old female. As one of these lesions at the apex of the right lung increased in size, it was suspected to be a pulmonary adenocarcinoma. However, the others became smaller during the follow-up period. Right upper lobectomy was performed, and PAP was histologically diagnosed. In cases exhibiting multiple localized GGOs, PAP should be considered, even if GGOs with a crazy-paving-like appearance are distributed in a lobular rather than diffuse manner.
2024-09-04 | Inhaled molgramostim therapy for the treatment of autoimmune pulmonary alveolar proteinosis (aPAP): a plain language summary of the IMPALA trial.
What is this summary about? This is a plain language summary of a late-stage clinical trial called IMPALA, originally reported in The New England Journal of Medicine. The IMPALA trial studied a drug called molgramostim nebulizer solution (molgramostim) to see how well it worked and how safe it was in patients with autoimmune pulmonary alveolar proteinosis (aPAP). Normally, tiny air sacs (alveoli) in the lungs are covered by a thin layer of an oily substance called surfactant that helps to keep them open. In aPAP, surfactant builds up and clogs alveoli making it difficult to breathe. Inhaled molgramostim helps to reduce the amount of surfactant clogging the alveoli.What were the results of the trial? After 24 weeks of treatment, patients who received molgramostim every day had better oxygen transfer into blood than patients who received an inactive substance (placebo). Patients’ sense of well-being and quality of life was improved more with daily molgramostim than placebo. The amount of surfactant in the lungs measured using scans and the number of whole-lung lavages (lung washes) patients required were lower with daily molgramostim than placebo. The number of medical problems (adverse events) was similar in patients who received molgramostim and placebo except for chest pain, which was more common with molgramostim.What do the results of the trial mean? The IMPALA trial demonstrated that molgramostim is a promising treatment option for people with aPAP.
other
2022-04-01 | Targeted therapy for pulmonary alveolar proteinosis: the time is now
Pulmonary alveolar proteinosis (PAP) is a rare syndrome with a complex pathogenesis leading, at the end, to accumulation of surfactant phospholipids and lipoproteins in the alveoli, and causing progressive respiratory insufficiency [1]. Alongside the most common autoimmune form, affecting more than 90% of patients and characterised by the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, there are severe forms associated with genetic mutations, which are usually diagnosed in children. The landscape of genetic mutations underlying PAP is rapidly evolving and advances in this field from the past decade are impressive [2, 3]. In terms of frequency, the most common mutations, associated with primary hereditary PAP, affect genes coding for the a- and b-subunit of GM-CSF receptor (CSF2RA and CSF2RB), followed by surfactant (SFTPB, SFTPC, SFTPA1 and SFTPA2), ABCA3 and NKX2.1 gene mutations; PAP syndrome occurs sporadically in the latter two. Further, GATA-2 mutations, associated with a genetic immunodeficiency syndrome (MonoMAC) [4–6], SLC7A7, MARS, FARSB and NPC 2 gene mutations (causing lysinuric protein intolerance, methionine deficit, phenylalanine-tRNA synthetase deficit and Niemann–Pick disease, respectively) [2], and telomerase reverse transcriptase (TERT) mutations [7, 8] can also be revealed by PAP. Gene therapy and impaired pathway correction are promising treatments for selected patients with pulmonary alveolar proteinosis syndrome
small molecules
2026-08-02 | Progressive Fibrosing Lung Disease Treated With Nintedanib in a Patient With Long-Standing Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is caused by impaired surfactant clearance due to neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor. Although whole-lung lavage and inhaled granulocyte-macrophage colony-stimulating factor therapy are established treatment options, pulmonary fibrosis is increasingly recognized as a clinically relevant complication in a subset of patients with APAP. However, the clinical behavior of APAP-associated fibrosing lung disease and the role of antifibrotic therapy remain unclear. A 54-year-old man with a 15-year history of APAP was referred to our institution. High-resolution computed tomography images obtained before referral showed slow progression of reticulation and traction bronchiectasis, suggesting fibrotic progression rather than recurrence of APAP. At presentation, forced vital capacity (FVC) was 3.31 L (80.0% predicted), and diffusion capacity for carbon monoxide (DLCO) was preserved. During 6 months of observation, FVC declined to 3.03 L (73.5% predicted), accompanied by worsening dry cough and exertional dyspnea. Nintedanib was initiated for a progressive fibrosing phenotype in the context of APAP. Thereafter, FVC remained relatively stable for 2 years, whereas DLCO declined during follow-up. APAP-associated fibrosing lung disease may present with a progressive fibrosing phenotype, but its diagnosis and management remain challenging. This case highlights the importance of distinguishing fibrotic progression from recurrence of intra-alveolar proteinosis.
2026-02-19 | Significant but Temporary Efficacy of Statin for a Patient With Severe Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is a rare autoimmune lung disorder characterised by the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Whole-lung lavage (WLL) therapy remains the standard treatment for severe cases. Recently, inhaled GM-CSF therapy has been approved in Japan; however, the cost of the treatment remains a limiting factor. Several reports have suggested that oral statin therapy may be a promising therapeutic option for APAP. Herein, we report a case of severe APAP that underwent WLL therapy twice and achieved an excellent response and remarkable clinical resolution of respiratory failure after the initiation of oral statin therapy. Remarkable improvements in oxygen saturation, blood gas analysis, serum biomarker levels and pulmonary function test results were observed after statin administration. However, the efficacy was temporary, and respiratory failure relapsed 2 years after the initiation of statin therapy. Statin therapy for APAP was deemed effective but potentially temporary.
2025-07-02 | Secondary Pulmonary Alveolar Proteinosis Complicated by Hemophagocytic Syndrome in a Patient with Adult-onset Still's disease: A Case-based Review
Treatment of secondary pulmonary alveolar proteinosis (SPAP) focuses on managing the underlying disease, typically myelodysplastic syndrome. However, immunosuppressive therapy may worsen the condition in autoimmune disease-associated SPAP. We report the case of a 74-year-old woman with hemophagocytic syndrome and adult-onset Still's disease, who developed ground-glass opacities and consolidations during immunosuppressive treatment. SPAP was confirmed by a biopsy and negative for anti-GM-CSF antibodies. Although whole-lung lavage was considered if SPAP worsened significantly, no further deterioration was observed with tapering of prednisolone. A literature review and details of this case highlight the importance of attenuating immunosuppressive therapy, rather than its intensification, for SPAP in autoimmune diseases.
2024-06-07 | A case of autoimmune pulmonary alveolar proteinosis responding to oral statin therapy.
There is no approved drug treatment for autoimmune pulmonary alveolar proteinosis (APAP), although traditionally requires complex treatments such as whole lung lavage (WLL). We herein report on a 67-year-old man diagnosed with APAP. Treatment with atorvastatin (5 mg daily) resulted in significant improvement in symptoms, lung function, and computed tomography findings, with enhanced oxygenation, although serum anti-GM-CSF antibody levels remained elevated. This case suggests that the remission observed in this case could potentially be attributed to a direct effect of atorvastatin within the pulmonary alveoli. Statins may be considered as one of the treatment options for APAP.
2024-01-05 | A Comprehensive Case Report on the Anaesthetic Management of Whole Lung Lavage in Severe Autoimmune Pulmonary Alveolar Proteinosis
This case report presents a comprehensive analysis of the anaesthetic management employed in the whole lung lavage (WLL) procedure for a 45 -year -old female diagnosed with severe autoimmune pulmonary alveolar proteinosis (PAP). Characterized by aberrant surfactant accumulation, PAP poses challenges to respiratory function, necessitating therapeutic interventions such as WLL. The anaesthetic strategy involved meticulous planning, lung isolation techniques, and the utilization of total intravenous anaesthesia (TIVA) to enhance procedural safety. Unique to this case was the strategic use of patient positioning during WLL, capitalizing on hypoxic pulmonary vasoconstriction (HPV) to optimize perfusion dynamics. Continuous monitoring, endobronchial suctioning, and judicious positive end -expiratory pressure (PEEP) application further ensured effective lung isolation. The postprocedural course, encompassing 16 -18 hours of mechanical ventilation, a successful spontaneous breathing trial, and subsequent extubation, underscored the efficacy of the anaesthetic approach. This report contributes valuable insights into refining WLLtechniques, emphasizing the integration of HPV and TIVA for optimal patient outcomes in severe autoimmune PAP cases.
antibodies
2026-02-20 | A Case of Autoimmune Pulmonary Alveolar Proteinosis.
Chemotherapeutic agents or regular doses of Rituximab may represent a potential therapeutic option for refractory cases of autoimmune pulmonary alveolar proteinosis.
2025-06-19 | The Novel Use of Daratumumab in the Treatment of Refractory Autoimmune Pulmonary Alveolar Proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by circulating anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies that impair alveolar macrophage and neutrophil function. Macrophage dysfunction leads to accumulation of protein- and lipid-rich surfactant within alveoli, impairing gas exchange and leading to respiratory failure. Standard treatments include whole lung lavage (WLL) as first-line therapy, nebulised replacement of GM-CSF, and in refractory cases, lymphocyte depletion, immunosuppression, or lung transplantation. We present a case of a 51-year-old patient with severe, treatment-refractory aPAP failing all standard PAP therapies. A compassionate access program enabled commencement of Daratumumab, a CD38-directed monoclonal antibody (mAb), targeting long-lived plasma cells and providing a novel approach to treatment-resistant autoimmune conditions. One year post completion of Daratumumab, the patient remained in remission with clinical and radiological improvement. There was a corresponding reduction in anti-GM-CSF antibody levels and improvement in gas exchange on pulmonary function testing.
2025-05-01 | Autoimmune Pulmonary Alveolar Proteinosis Treated With Whole Lung Lavage and Rituximab: A Case Report
Abstract A 39-year-old female non-smoker who enjoyed good past health, was hospitalized for persistent dyspnoea. She denied significant exposure to humidifiers, disinfectants, crops nor any animal contact. Physical examination showed bilateral lower zone crepitations. Serial chest X-ray showed progressive bilateral lung lower lobe opacities. There was no clinical evidence of rheumatological disease. Baseline blood tests for complete blood count, liver and renal function tests were unremarkable. Autoimmune markers, myositis panel and aspergillus antibody were negative. Eosinophil count, C-reactive protein and erythrocyte sedimentation rate were not elevated. Computed Tomography (CT) Thorax revealed patchy ground glass opacities in both lungs associated with intralobular septal thickening. Serial CT scan showed increasing patchy ground glass opacities with peripheral and basal predominance. Bronchoscopy with targeted transbronchial biopsy showed proteinaceous material in a few alveolar spaces with neutrophilic infiltrates at the alveolar wall, but there was insufficient tissue for further testing. Microbiological workups including bacterial culture, fungal culture and Acid-fast bacillus culture were negative. The patient was referred to cardiothoracic surgeon for surgical lung biopsy, which showed focal chronic inflammation and fibrosis without evidence of interstitial lung disease. The patient suffered from further reduction in exercise tolerance. Follow-up CT showed further worsening of ground glass opacities in bilateral lower lobes with crazy paving pattern. Repeated bronchoscopy with transbronchial biopsy showed distended alveoli cells with granular eosinophilic matter. Contents of the alveolar spaces are positive for Periodic acid-Schiff (PAS) stain. Blood for Anti-GM-CSF antibody was arranged, and came back positive with a high activity level seen on the neutralizing assay. A diagnosis of autoimmune pulmonary alveolar proteinosis (PAP) was made. Whole lung lavage and intravenous Rituximab infusion were arranged. There was both clinical and radiological improvement post treatment. Lung function test and 6-minute walk test were improved, and the patient remained asymptomatic and free from hospitalization. Pulmonary alveolar proteinosis is a rare disease, and a high level of clinical suspicion is needed in cases of dyspnoea with bilateral lower zone opacities on chest imaging. Typical CT findings include smooth thickening of interlobular and intralobular septal lines and ground glass opacities, also known as crazy paving pattern. PAS stain should be arranged during biopsy. The increasing availability of anti-GM-CSF blood testing can facilitate the diagnosis of autoimmune PAP. Treatment options include early referral to tertiary centers with expertise in whole lung lavage and Rituximab.
2024-12-18 | Rituximab Therapy in Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (PAP) is a rare lung condition characterized by the accumulation of surfactant proteins within the alveoli, leading to respiratory distress. We describe a 49-year-old female homemaker with a history of passive smoking and exposure to wood smoke and pigeon droppings. She presented with a dry cough and progressive dyspnea, experiencing significant deterioration in her condition over one year. Chest imaging revealed bilateral alveolar-interstitial syndrome with ground-glass opacities and alveolar condensations. Biopsy findings indicated type II pneumocytes and eosinophilic material, confirming a diagnosis of autoimmune PAP. After ruling out secondary causes of PAP, rituximab was administered successfully, leading to marked improvement in respiratory function and significant regression of radiological lesions within two months. This case highlights the importance of early diagnosis and treatment of autoimmune PAP, demonstrating the potential efficacy of rituximab in managing this challenging condition.
2024-05-27 | Role of rituximab as neoadjuvant therapy in a difficult case of relapsing pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is a rare disease which involves the accumulation of insoluble lipoproteinaceous material in the alveoli leading to impaired gas exchange and even respiratory failure. Autoimmune PAP is the most common type and is characterized by the presence of anti-granulocyte-monocyte colony stimulating factor (anti GM-CSF) antibody. Whole lung lavage has been traditionally used as first-line management of PAP but there is a lack of clarity especially in the treatment of relapsing cases of PAP. Rituximab is an anti Cluster of Differentiate 20 (CD 20) monoclonal antibody that has been tried as salvage therapy for relapsing cases of PAP. We present a case of 35 years old female patient who was diagnosed as a case of relapsing PAP who was managed initially with neoadjuvant rituximab. This is a retrospective observational report showing novel use of neoadjuvant rituximab in a difficult case of relapsing PAP.
cell therapies
2026-05-01 | A93-08 Human Bone Marrow-derived Mesenchymal Stem Cell Therapy For Autoimmune Pulmonary Alveolar Proteinosis: A First-in-human Phase Iia Clinical Trial
Abstract Rationale Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by impaired alveolar macrophage function and elevated anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. Previous studies demonstrated that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can remodel the alveolar immune microenvironment and enhance macrophage phagocytic function. We conducted the first clinical study of hBMMSC therapy for aPAP to evaluate its safety and preliminary efficacy. Methods This phase IIa, open-label, single-arm clinical trial enrolled 10 aPAP patients, assigned to three groups: low-dose (1 × 106 cells/kg, single infusion), high-dose (2 × 106 cells/kg, single infusion), and high-dose repeated (2 × 106 cells/kg, two infusions two weeks apart), all via intravenous infusion. The primary endpoint was change in alveolar-arterial oxygen gradient (A-aDO2) from baseline to 24 weeks. Safety and tolerability were assessed by incidence of serious adverse events (SAEs). Results Of 10 subjects enrolled, 3 withdrew and 7 completed 24-week evaluation. No treatment-related SAEs occurred. In 7 evaluable subjects, A-aDO2 and oxygenation index (P/F ratio) improved significantly at 24 weeks compared with baseline (both p < 0.05). Repeated high-dose infusion produced greater A-aDO2 improvement than single-dose groups. Conclusion This first clinical trial of hBMMSC therapy for aPAP demonstrates that the treatment is safe, well tolerated, and improves A-aDO2 and P/F ratio. Repeated dosing appears more effective than a single infusion, providing initial real-world clinical evidence supporting potential therapeutic application. This abstract is funded by: Jiuzhitang Maker(Beijing) Cell Technology Co.Ltd
2025-09-27 | Clinical Trial of Bone Marrow-Derived Mesenchymal Stem Cell Therapy for Autoimmune Pulmonary Alveolar Proteinosis
Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by dysfunctional alveolar macrophages due to elevated levels of autoantibodies against granulocyte-macrophage colony-stimulating factor. Our previous have shown that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can restore the alveolar immune microenvironment and enhance the phagocytic function of alveolar macrophages. Methods: This study is a Phase IIa, open-label, single-arm clinical trial designed to evaluate the safety and preliminary efficacy of allogenic hBMMSC for aPAP, with enrolling 10 subjects. The primary endpoint is the change in the alveolar-arterial oxygen gradient (A-aDO2) from baseline at 24 weeks post-treatment. Safety and tolerability are assessed with the number of serious adverse events (SAEs). Results: To date, all 10 subjects have been enrolled, with 2 subjects withdrawing and 3 subjects reaching the 24-week assessment. No SAEs related to the treatment have been reported. In the 3 subjects who have reached the 24-week assessment, there were improvements in the A-aDO2 (48.07±0.81 vs. 36.17±9.85 mmHg, p=0.150) and blood oxygen partial pressure (PaO2) (55.4±8.42 vs. 70.37±16.89 mmHg, p=0.111). Chest CT scans showed improvement in 2 subjects and stability in 1 subject. The remaining 5 subjects have not yet reached the 24-week assessment. Conclusion: The hBMMSC therapy for aPAP is safe. Data from the 3 subjects who have completed the efficacy evaluation suggest that MSCs may improve the A-aDO2, PaO2, and chest CT findings. The comprehensive safety and efficacy evaluation will be conducted after all subjects reach the 24-week assessment.
2022-07-14 | Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report
Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus- disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP.
2022-07-01 | [Lung transplantation for pulmonary alveolar proteinosis: a case report and literature review].
Objective: To observe the efficacy of lung transplantation for pulmonary alveolar proteinosis (PAP) patients and to improve the understanding of the therapy. Methods: The clinical data of a patient with autoimmune PAP treated with sequential homogenous bilateral lung transplantation were described and the literatures were reviewed. Results: This 55-year-old female patient was diagnosed with autoimmune PAP and had been treated with whole lung lavage for 19 times, but only achieved short-term symptomatic relief after each operation. Inhalation of granulocyte macrophage colony stimulating factor occurred allergic reactions. Lung transplantation was performed on February 15, 2022, and a significant improvement in oxygenation and clinical symptoms were observed. The patient remained stable during follow-up. Conclusion: Treatment with lung transplantation is safe and effective for end-stage patients with PAP in the early phase, but the long-term effect remains to be observed. 目的： 探讨肺移植治疗终末期肺泡蛋白沉积症的疗效。 方法： 患者女，55岁，因“胸闷、气喘伴咳嗽6年，加重1年”入院，经反复多次全肺灌洗治疗，效果欠佳，遂行同种异体序贯式双肺移植治疗，观察其临床资料并进行相关文献复习。以“肺移植”和“肺泡蛋白沉积症”为检索词检索中国知网及万方医学网中文文献数据库，以“lung transplantation”及“pulmonary alveolar proteinosis”为检索词检索PubMed数据库，检索时间截止到2022年2月。 结果： 该患者既往行全肺灌洗19次，前期效果尚可，后期症状进行性加重，粒细胞-巨噬细胞集落刺激因子雾化吸入治疗后，出现过敏反应，胸部CT提示肺部病变逐渐加重。2022年2月15日行肺移植术，PaO2从47 mmHg（1 mmHg=0.133 kPa）上升到85 mmHg，可脱离吸氧活动，2022年3月2日出院，随访病情稳定。文献检索获得相关英文文献13篇，其中论著2篇，病例报告11篇；肺移植后继发肺泡蛋白沉积症9篇；肺移植治疗肺泡蛋白沉积症4篇，报道了3个病例；国内未见肺移植治疗肺泡蛋白沉积症的报道。 结论： 肺移植治疗终末期肺泡蛋白沉积症，早期安全有效，长期效果有待进一步观察。.
2022-05-16 | Pulmonary Alveolar Proteinosis due to Familial Myelodysplastic Syndrome with resolution after stem cell transplant
Pulmonary alveolar proteinosis (PAP) is a rare lung disease with an incidence of 0.2 cases per million. PAP has multiple causes, including autoimmune, hereditary, congenital, or secondary. The latter includes hematologic conditions and exposure to different kinds of dust. Most patients present fever, dyspnea, and cough. The chest computed tomography (CT) may reveal the crazy-paving polygonal shapes with superimposed ground glass opacities delimited by thickened interlobular septa; however, this finding is more prevalent in patients with autoimmune PAP. Bronchoalveolar lavage (BAL) shows a milky-opaque appearance with PAS-positive debris on cytology. Treatment is focused on the underlying disease; however, some patients may require whole lung lavage for symptomatic management. We report a case of a 30-year-old female with a history of familial myelodysplastic syndrome (MDS) with GATA 2 mutation who presented to the outpatient clinic with several months of progressive dyspnea and nonproductive cough. The chest CT revealed bilateral ground-glass opacities prominently in the upper lobes. She underwent a bronchoscopy with lavage and biopsy, which revealed fragments of lung parenchyma with intra-alveolar coarse granular eosinophilic material strongly positive for PAS and d-PAS. The overall clinical presentation and histologic findings were diagnostic of PAP. Her GM-CSF was negative, and due to her history of MDS, secondary PAP (S-PAP) was strongly suspected. She underwent a successful allogeneic bone marrow pluripotent stem cell transplant to treat the myelodysplastic syndrome, with a follow-up chest CT showing clear lung parenchyma. The patient had resolution of symptoms about four months after the bone marrow transplant, confirming the diagnosis of S-PAP.
proteins
2026-02-01 | Extracellular DNA in bronchoalveolar lavage fluid as a candidate biomarker of disease severity in autoimmune pulmonary alveolar proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) results from the neutralization of autoantibodies against granulocyte-macrophage colony-stimulating factor, which leads to alveolar macrophage (AM) dysfunction and surfactant accumulation. However, disease progression cannot be solely explained by surfactant overload. This study aimed to investigate whether defective efferocytosis in aPAP contributes to persistent apoptotic debris and accumulation of extracellular double-stranded DNA (dsDNA), which is a candidate biomarker of disease severity. We analyzed bronchoalveolar lavage fluid (BALF) samples obtained from 13 patients with aPAP and 13 patients with other interstitial lung diseases (controls). Apoptotic debris was assessed cytologically, extracellular dsDNA was quantified fluorometrically with urea correction, and efferocytosis was evaluated using flow cytometry. Additionally, we analyzed correlations between BALF dsDNA levels and clinical indices. BALF samples from patients with aPAP contained abundant apoptotic debris and significantly higher dsDNA levels than those from controls. Further, AMs from patients with aPAP showed s markedly reduced uptake apoptotic cells, indicating altered efferocytosis-related processes. Corrected BALF dsDNA levels were negatively correlated with the arterial oxygen pressure to inspired oxygen fraction ratio and percent predicted diffusing capacity of the lung for carbon monoxide. Altered efferocytosis-related processes in patients with aPAP may promote the accumulation of apoptotic debris and extracellular DNA in the alveolar space. Further, dsDNA levels in BALF strongly reflect impaired gas exchange and provide a biomarker of disease severity. These findings further elucidate the pathogenesis of aPAP and establish extracellular DNA as a promising tool for disease monitoring and therapeutic evaluation.
2025-06-23 | Dyspnea and Deception: Overcoming Diagnostic Hurdles in Pulmonary Alveolar Proteinosis.
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by abnormal surfactant accumulation due to defective alveolar macrophage clearance. It often presents with exertional dyspnea and nonspecific imaging findings, commonly leading to diagnostic delays. We present the case of a 56-year-old woman with progressive hypoxia initially misattributed to acute respiratory distress syndrome, noncardiogenic pulmonary edema, and hypersensitivity pneumonitis. Corticosteroids were initiated based on early differential considerations. Further evaluation revealed concurrent methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and bronchoalveolar lavage findings suggestive of PAP. Following stabilization and treatment of the infection, transbronchial biopsy confirmed PAP. The patient required prolonged intensive care and was ultimately transferred for whole-lung lavage. This case highlights the critical importance of early recognition of PAP in patients with characteristic imaging findings and progressive respiratory failure. Misdiagnosis can lead to inappropriate therapies and increased risk of infectious complications.
2024-12-01 | Severity and prognosis of COVID-19 complicated by autoimmune pulmonary alveolar proteinosis.
The prognosis of patients with coronavirus disease 2019 (COVID-19) was poor although its survival rate has been improved after the occurrence of the Omicron strain. Autoimmune pulmonary alveolar proteinosis (APAP), a lung disease caused by macrophage dysfunction induced by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)-neutralizing autoantibodies, is characterized by the deposition of proteinaceous material in the alveolar spaces. The clinical course of COVID-19 in patients with APAP remains unclear and this study aimed to clarify it. The data of 23 patients with APAP, who were diagnosed with COVID-19 between January 2020 and May 2023 and collected through a nationwide questionnaire surveillance system, were retrospectively reviewed. Based on the epidemiological frequency at disease onset, suspected strains of severe acute respiratory syndrome coronavirus 2 were Omicron (n = 18) and non-Omicron (n = 5). Fifteen patients were vaccinated. Six and three patients received anti-viral drugs and corticosteroids, respectively. One patient in the third trimester of pregnancy died despite treatment in the intensive care unit. Six patients were complicated by pneumonia and/or required supplemental oxygen. These patients were suspected to have non-Omicron strains (p = 0.087). Vaccination status showed a significant association with suspected Omicron strains. The radiological findings in four patients and shortness of breath improved in two of the four patients after COVID-19. The severity and prognosis of the patients were not worse than those predicted based on the results of a previous study. The transition from a non-Omicron strain to an Omicron strain and the vaccination status may have affected these results.
2024-10-09 | Autoimmune pulmonary alveolar proteinosis presenting as localized multifocal GGOs: A case report.
Pulmonary alveolar proteinosis (PAP) is a rare disease, which is characterized by the alveolar accumulation of surfactant. A crazy-paving appearance on chest thin-section computed tomography (TSCT) is a characteristic feature of this disease. We report an unusual case of PAP, which presented as multiple localized ground glass opacites (GGOs) on TSCT in an 80-year-old female. As one of these lesions at the apex of the right lung increased in size, it was suspected to be a pulmonary adenocarcinoma. However, the others became smaller during the follow-up period. Right upper lobectomy was performed, and PAP was histologically diagnosed. In cases exhibiting multiple localized GGOs, PAP should be considered, even if GGOs with a crazy-paving-like appearance are distributed in a lobular rather than diffuse manner.
2024-09-04 | Inhaled molgramostim therapy for the treatment of autoimmune pulmonary alveolar proteinosis (aPAP): a plain language summary of the IMPALA trial.
What is this summary about? This is a plain language summary of a late-stage clinical trial called IMPALA, originally reported in The New England Journal of Medicine. The IMPALA trial studied a drug called molgramostim nebulizer solution (molgramostim) to see how well it worked and how safe it was in patients with autoimmune pulmonary alveolar proteinosis (aPAP). Normally, tiny air sacs (alveoli) in the lungs are covered by a thin layer of an oily substance called surfactant that helps to keep them open. In aPAP, surfactant builds up and clogs alveoli making it difficult to breathe. Inhaled molgramostim helps to reduce the amount of surfactant clogging the alveoli.What were the results of the trial? After 24 weeks of treatment, patients who received molgramostim every day had better oxygen transfer into blood than patients who received an inactive substance (placebo). Patients’ sense of well-being and quality of life was improved more with daily molgramostim than placebo. The amount of surfactant in the lungs measured using scans and the number of whole-lung lavages (lung washes) patients required were lower with daily molgramostim than placebo. The number of medical problems (adverse events) was similar in patients who received molgramostim and placebo except for chest pain, which was more common with molgramostim.What do the results of the trial mean? The IMPALA trial demonstrated that molgramostim is a promising treatment option for people with aPAP.
other
2022-04-01 | Targeted therapy for pulmonary alveolar proteinosis: the time is now
Pulmonary alveolar proteinosis (PAP) is a rare syndrome with a complex pathogenesis leading, at the end, to accumulation of surfactant phospholipids and lipoproteins in the alveoli, and causing progressive respiratory insufficiency [1]. Alongside the most common autoimmune form, affecting more than 90% of patients and characterised by the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, there are severe forms associated with genetic mutations, which are usually diagnosed in children. The landscape of genetic mutations underlying PAP is rapidly evolving and advances in this field from the past decade are impressive [2, 3]. In terms of frequency, the most common mutations, associated with primary hereditary PAP, affect genes coding for the a- and b-subunit of GM-CSF receptor (CSF2RA and CSF2RB), followed by surfactant (SFTPB, SFTPC, SFTPA1 and SFTPA2), ABCA3 and NKX2.1 gene mutations; PAP syndrome occurs sporadically in the latter two. Further, GATA-2 mutations, associated with a genetic immunodeficiency syndrome (MonoMAC) [4–6], SLC7A7, MARS, FARSB and NPC 2 gene mutations (causing lysinuric protein intolerance, methionine deficit, phenylalanine-tRNA synthetase deficit and Niemann–Pick disease, respectively) [2], and telomerase reverse transcriptase (TERT) mutations [7, 8] can also be revealed by PAP. Gene therapy and impaired pathway correction are promising treatments for selected patients with pulmonary alveolar proteinosis syndrome
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Drug Discovery Landscape
5 orphan drug designations for Autoimmune pulmonary alveolar proteinosis.
5 orphan drug designations for Autoimmune pulmonary alveolar proteinosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
L-methionine | other | EMA | 2024-06-28 | — | Imagine Institut Des Maladies Genetiques Necker Enfants Malades |
Sargramostim | proteins | EMA | 2024-06-28 | — | CATS Consultants GmbH |
sargramostim | proteins | FDA | 2018-10-22 | — | Partner Therapeutics, Inc. |
Granulocyte macrophage colony stimulating factor | proteins | EMA | 2013-07-17 | — | Savara ApS |
recombinant human GM-CSF, molgramostim | proteins | FDA | 2012-10-31 | — | Savara Inc. |
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