Pulmonary Alveolar Proteinosis Patients Research Articles

Pulmonary Alveolar Proteinosis and new therapeutic concepts.

Pulmonary alveolar proteinosis (PAP) is an umbrella term used to refer to a pulmonary syndrome which is characterized by excessive accumulation of surfactant in the lungs of affected individuals. In general, PAP is a rare lung disease affecting children and adults, although its prevalence and incidence is variable among different countries. Even though PAP is a rare disease, it is a prime example on how modern medicine can lead to new therapeutic concepts, changing ways and techniques of (genetic) diagnosis which ultimately led into personalized treatments, all dedicated to improve the function of the impaired lung and thus life expectancy and quality of life in PAP patients. In fact, new technologies, such as new sequencing technologies, gene therapy approaches, new kind and sources of stem cells and completely new insights into the ontogeny of immune cells such as macrophages have increased our understanding in the onset and progression of PAP, which have paved the way for novel therapeutic concepts for PAP and beyond. As of today, classical monocyte-derived macrophages are known as important immune mediator and immune sentinels within the innate immunity. Furthermore, macrophages (known as tissue resident macrophages (TRMs)) can also be found in various tissues, introducing e. g. alveolar macrophages in the broncho-alveolar space as crucial cellular determinants in the onset of PAP and other lung disorders. Given recent insights into the onset of alveolar macrophages and knowledge about factors which impede their function, has led to the development of new therapies, which are applied in the context of PAP, with promising implications also for other diseases in which macrophages play an important role. Thus, we here summarize the latest insights into the various forms of PAP and introduce new pre-clinical work which is currently conducted in the framework of PAP, introducing new therapies for children and adults who still suffer from this severe, potentially life-threatening disease.

Ten-year experience of whole lung lavage in pediatric Pulmonary Alveolar Proteinosis.

Pulmonary Alveolar Proteinosis (PAP) is extremely rare and can be caused by hereditary dysfunction of the granulocyte macrophage colony-stimulating factor receptor (GM-CSF) receptor, autoantibodies against GM-CSF, or other diseases leading to alveolar macrophage (AM) dysfunction. This leads to protein accumulation in the lung and severe dyspnea and hypoxemia. Whole lung lavage (WLL) is the first line treatment strategy. Here, we present data from more than ten years of WLL practice in pediatric PAP. WLL performed by the use of a single lumen or double lumen tube (SLT vs. DLT) were compared for technical features, procedure time, and adverse events. A total of n=57 procedures in six PAP patients between 3.5 and 14.3 years of age were performed. SLT based WLL in smaller children was associated with comparable rates of adverse events but with longer intervention times and postprocedural intensive care treatment when compared to DLT based procedures. Our data shows that WLL is feasible even in small children. DLT based WLL seems to be more effective, and our data supports the notion that it should be considered as early as possible in pediatric PAP. WLL lavage is possible in small PAP patients but should performed in close interdisciplinary cooperation and with age appropriate protocols.

Alveolar macrophage lipid burden correlates with clinical improvement in patients with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a life-threatening, rare lung syndrome for which there is no cure and no approved therapies. PAP is a disease of lipid accumulation characterized by alveolar macrophage foam cell formation. While much is known about the clinical presentation, there is a paucity of information regarding temporal changes in lipids throughout the course of disease. Our objectives were to define the detailed lipid composition of alveolar macrophages in PAP patients at the time of diagnosis and during treatment. We performed comprehensive mass spectrometry to profile the lipid signature of alveolar macrophages obtained from three independent mouse models of PAP and from PAP and non-PAP patients. Additionally, we quantified changes in macrophage-associated lipids during clinical treatment of PAP patients. We found remarkable variations in lipid composition in PAP patients, which were consistent with data from three independent mouse models. Detailed lipidomic analysis revealed that the overall alveolar macrophage lipid burden inversely correlated with clinical improvement and response to therapy in PAP patients. Specifically, as PAP patients experienced clinical improvement, there was a notable decrease in the total lipid content of alveolar macrophages. This crucial observation suggests that the levels of these macrophage-associated lipids can be utilized to assess the efficacy of treatment. These findings provide valuable insights into the dysregulated lipid metabolism associated with PAP, offering the potential for lipid profiling to serve as a means of monitoring therapeutic interventions in PAP patients.

Identified the pathogenic effects of GM-CSF autoantibodies in different diseases

Abstract Pathogenic GM-CSF autoantibodies are found in over 90% of people with pulmonary alveolar proteinosis (PAP), a rare pulmonary autoimmune disease with surfactant lipoprotein accumulating in alveoli spaces. However, more and more people with GM-CSF autoantibodies have also been identified without PAP phenotype but underlying severe central nervous system (CNS)-involved Cryptococcus gattii or Nocardia spp. infection since 2013, highlighting the pathogenic mechanisms that might differ between individual diseases. We developed single B cell cloning to isolate GM-CSF monoclonal antibodies from cryptococcosis patients aiming to investigate the pathogenic effects. GM-CSF autoantibodies in cryptococcosis bound GM-CSF through three non-overlapping epitopes, and formed a high-molecular-weight immune complex similar to the research of GM-CSF mAbs in PAP patients. Surprisingly, GM-CSF mAbs isolated from cryptococcosis revealed potentially binding to GM-CSF when the V gene reversed to the germline. GM-CSF autoantibodies underwent somatic hypermutation to enhance their binding ability and neutralizing activities. We analyzed whether the mAbs binding sites interfere with cytokine-specific receptor interaction, and only one epitope showed the receptor blockade. The GM-CSF mAbs from the other two epitopes remained inhibition effects, indicating another neutralizing mechanism independent of interfering receptor binding. The neutralizing pathway and biological impact of GM-CSF autoantibodies from cryptococcosis is still worthy of further investigation. These works might help know the anti-GM-CSF autoantibodies cause different clinical manifestations and find a novel pave for better diagnosis and treatments.

Association between one-session bilateral whole-lung lavage and periprocedural complications in patients with pulmonary alveolar proteinosis: a retrospective cohort study

BackgroundWhole lung lavage (WLL) has been recognized as the most effective therapy of severe pulmonary alveolar proteinosis (PAP). Most centers perform the lavage of each lung in two sessions under general anesthesia at an interval of several days to weeks. Compared with two-session WLL, one-session bilateral sequential WLL only requires general anesthesia once. However, the safety of one-session WLL in PAP patients has not been assessed by large cohort studies. In this study, we aimed to investigate the association between the mode of WLL procedure (one-session or two-session) and the risk of periprocedural complications in PAP patients.MethodsIn this single-center retrospective cohort study, we included adult patients who were diagnosed as PAP and had undergone WLL procedures under general anesthesia from 2000 to 2022. Patients requiring extra-corporeal oxygenation during WLL were excluded. Since some patients received multiple WLL procedures, we considered each procedure in one-session or two-session group as a unique unit in our analysis. The primary outcome was the occurrence of any complications during hospitalization, including termination of WLL procedure due to fluid leakage or refractory hypoxemia, bronchospasm, delayed endotracheal extubation, cardiovascular event, pneumothorax, and fever.ResultsWe included a total of 175 WLL procedures (118 patients), with 48 in the two-session group and 127 in the one-session group. Periprocedural complications occurred in 17 (35.4%) and 39 (30.7%) procedures in the two-session and the one-session groups, respectively. The risk of periprocedural complications did not differ significantly between groups, after adjusting the unbalanced confounders in a multivariable model (odds ratio 0.95, 95% confidence interval 0.34 to 2.69, P 0.929) or by inverse probability of treatment weighting (odds ratio 0.70, 95% confidence interval 0.30 to 1.54, P 0.379). Compared with the two-session WLL group, the one-session WLL group had a shorter postprocedural length of hospitalization and comparable decrease in alveolar-arterial oxygen tension gradient from baseline.ConclusionsOne-session bilateral WLL was not associated with an increased risk of periprocedural complications compared with two-session WLL in PAP patients. Experienced physicians may consider performing one-session WLL in view of the comparable safety and efficacy and potential advantages of saving time.

Quantitative chest CT assessment of pulmonary alveolar proteinosis with deep learning: a real-world longitudinal study

High-resolution computed tomography (HRCT) plays an important role in accessing the severity of pulmonary alveolar proteinosis (PAP). Visual evaluation of changes between two HRCT scans is subjective. This study was conducted to quantitatively evaluate lung burden changes in patients with PAP using HRCT-based automated deep-learning method following 12 months of statin therapy. In this prospective real-world observational study, patients with PAP who underwent chest HRCT were evaluated from November 28, 2018, to April 12, 2021. Oral statin administration was initiated as therapy for these PAP patients with 12 months of follow-up. HRCT-derived lung ground-glass opacification percentage of the whole lung and 5 lobes and the percentage of different densities of ground glass were automatically quantified with deep-learning software. Longitudinal changes of the HRCT quantitative parameter were also compared. The study enrolled 50 patients with PAP, including 25 mild-moderate PAP cases and 25 severe PAP cases. The percentage of lung ground-glass opacification of the whole lung and 5 lobes and the percentage of different densities of ground glass were significantly different among the 2 different clinical types at baseline (all P values <0.05). Overall, the percentage of whole-lung ground-glass opacification significantly decreased between the baseline HRCT and the HRCT results after 12 months of follow-up (P=0.023; 95% CI: 1.384-18.684). Changes in the total opacification of the whole lung were positively correlated with changes in partial pressure of arterial oxygen (PaO2; r=0.716; P<0.001) and percentage of predicted diffusion capacity for carbon monoxide (DLCO%pred; r=0.664; P<0.001). A quantitative image parameter automatically generated by a deep-learning tool from chest HRCT scans may be used to evaluate the severity of PAP and may help to evaluate and quantify the response to statin therapy.

Assessment of Statin Treatment for Pulmonary Alveolar Proteinosis without Hypercholesterolemia: A 12-Month Prospective, Longitudinal, and Observational Study

Pulmonary alveolar proteinosis (PAP) is a rare disorder which is characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy has been reported to be a novel therapy for PAP with hypercholesterolemia. We aimed to evaluate the safety and efficacy of oral statin therapy for PAP without hypercholesterolemia. In a prospective real-world observational study, 47 PAP patients without hypercholesterolemia were screened. Oral statin was initiated as therapy for these PAP patients with 12 months of follow-up. Forty PAP patients completed the study. 26 (65%) of 40 PAP patients responded to statin therapy according to the study criteria. Partial pressure of arterial oxygen (PaO2) and percentage of diffusion capacity predicted (DLCO%) significantly increased while disease severity score (DSS) and radiographic abnormalities decreased after 12 months of statin therapy (all p < 0.05). The factors associated with response were higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody and baseline total cholesterol/high-density lipoprotein cholesterol (TC/HDL) (p = 0.015 and p = 0.035, respectively). The area under the receiver operating characteristic curve (AUROC) of dose of atorvastatin for predicting the response to statin therapy for PAP was 0.859 (95% CI: 0.738-0.979, p < 0.001). The cutoff dose of atorvastatin was 67.5 mg daily with their corresponding specificity (64.3%) and sensitivity (96.2%). No severe side effects were observed during the study. In PAP patients without hypercholesterolemia, statin therapy resulted in improvements in arterial blood gas (ABG) measurement, pulmonary function, and radiographic assessment.

Genel Anestezi Altında Total Akciğer Lavajı Yapılan Hastalarda Anestezi Yönetimi ve Ultrasonografi Kullanımı: Retrospektif Analiz

Objective: Whole lung lavage (WLL) is a treatment procedure for pulmonary alveolar proteinosis (PAP), in which lung is washed with large amounts of saline in a controlled manner. Our aim is to analyze the anesthesia management and the ultrasonography use during WLL, retrospectively. Methods: Preoperative and perioperative anesthesia related data and data on the use of ultrasonography of 19 WLL precedures of 11 patients, with PAP, performed between January 2018 and December 2020 were evaluated. Results: A statistically significant difference was found in the partial oxygen pressure and peripheral oxygen saturation values of the patients after WLL when compared to the pre-procedure (p&lt;0.001). The number of patients who required O2 decresaed to 1 from 9 after WLL (p=0.008) Complications were recorded in only 4 of 19 procedures. While only hypoxia was observed during one procedure, hypoxemia and fluid leakage were detected during two procedures. Hypoxemia, fluid leakage and hypotension were detected in one procedure. Conclusion: Whole lung lavage procedure is safe when performed by an experienced and coordinated team in management of PAP patients. We think that ultrasonography may play an effective role in continuing the procedure safely and in early diagnosis of complications that may occur during WLL. Keywords: Pulmonary alveolar proteinosis, whole lung lavage, general anesthesia, lung ultrasound

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

BackgroundAnti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear. Therefore, we examined anti-GM-CSF autoantibodies to determine whether amount or neutralizing activity could distinguish between groups.MethodsPlasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n = 15), cryptococcal meningitis (n = 15), severe nocardiosis (n = 5) or overlapping phenotypes (n = 6) were compared. The relative amount of aAb was assessed using a particle-based approach, reported as a mouse monoclonal anti-human GM-CSF as standard curve and expressed in an arbitrary Mouse Monoclonal Antibody Unit (MMAU). The neutralizing activity of the plasma was assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes.ResultsAnti-GM-CSF aAb relative amounts were higher in PAP patients compared to those with cryptococcosis (mean 495 ± 464 MMAU vs 197 ± 159 MMAU, p = 0.02); there was no difference with patients with nocardiosis (430 ± 493 MMAU) nor between the two types of infections.The dilution of plasma resulting in 50% inhibition of GM-CSF-induced pSTAT5 (approximate IC50) did not vary appreciably across groups of patients (1.6 ± 3.1%, 3.9 ± 6% and 1.8 ± 2.2% in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in the presence of 10 MMAU of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti-GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels.ConclusionsDespite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

Efficacy of whole lung lavage in pulmonary alveolar proteinosis: a 20-year experience at a reference center in Thailand.

BackgroundPulmonary alveolar proteinosis (PAP) is a rare lung syndrome. The current standard treatment is whole lung lavage (WLL). We reviewed PAP cases treated with WLL during a 243-month period. The primary objective was to describe the efficacy of WLL. We compared chest imaging resolution and pulmonary function tests (PaO2 and DLCO) before the first and after the last WLL. The secondary objectives were to compare mMRC dyspnea scores, other lung function parameters, and complications of WLL.MethodsWe retrospectively reviewed PAP patients from 1 January 2000 to 31 March 2020. Demographic data, pulmonary function tests, and the efficacy of WLL were collected from the electronic medical database and analyzed by descriptive analysis. Differences in data used the student t-test to compare parameters pre- and post-WLL.ResultsA total of 19 PAP patients and 50 WLL procedures were included. Eleven patients (57.9%) were females and the mean age was 51.5±11.7 years. Dyspnea (100%) and cough (94.7%) were the two leading symptoms. The most common indication for WLL was progressive dyspnea. There were significant improvements in SpO2 from 86% to 94% (P<0.001), PaO2 from 49.3 to 66.1 (P<0.001), DLCO from 31.8% to 52.5% predicted (P=0.013), and the mMRC dyspnea score from 3 to 2 (P<0.001) without major complications.ConclusionsWLL is an effective standard treatment for PAP cases. It is safe and can be used as a primary treatment in case of inhaled anti GM-CSF is not available.

Expression profiles and potential functions of long noncoding RNAs and mRNAs in autoimmune pulmonary alveolar proteinosis patients.

Autoimmune pulmonary alveolar proteinosis (APAP) is a rare lung disease that may be associated with surfactant overaccumulation. To assess the function of long noncoding RNAs (lncRNAs) in APAP, we performed microarray analyses to identify differentially expressed (DE) lncRNAs and mRNAs between peripheral blood samples from five APAP patients and five healthy volunteers. In total, 12459 DE lncRNAs and 9331 DE mRNAs were identified in APAP patient samples. A qRT-PCR validation of 20 DE lncRNAs and 20 mRNAs indicated that 12 DE lncRNAs may be involved in the pathogenesis of APAP. Coding and noncoding co-expression (CNC) and competing endogenous RNA (ceRNA) regulatory networks were constructed with these 12 DE lncRNAs. Gene Ontology analysis of the downregulated mRNAs and the CNC network revealed that “ubiquitin-like protein transferase activity” was suppressed in APAP patient samples. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the “MAPK signaling pathway” was enriched in the ceRNA network. Gene Ontology analysis also indicated that mRNAs involved in many transmembrane ion transport processes were upregulated in APAP patients. The DE lncRNAs and mRNAs discovered in this study have elucidated the pathogenesis of APAP, and the CNC and ceRNA networks have provided novel insights for future functional research.

Correlation of Lipid Ratios With the Severity of Pulmonary Alveolar Proteinosis: A Cross-Sectional Study.

Background: Lipids are known to accumulate abnormally in the alveoli and circulate during pulmonary alveolar proteinosis (PAP). However, the relationship between lipid ratios and PAP is not clear. In this study, we investigated the lipid ratios in PAP patients and explored the relationships between lipid ratios and the severity of PAP.Methods: A total of 122 PAP patients were diagnosed and divided the mild- moderate PAP group (n = 61) and the severe PAP group (n = 61) according to the value of disease severity score (DSS). One hundred thirty healthy volunteers were classified as the control group. Routine blood examination and pulmonary function tests were performed and lipid profile were measured.Results: Compared with the control group, patients with PAP had significantly higher TG, TC/HDL-C, TG/HDL-C, and non-HDL-C, while lower HDL-C (all P < 0.05). Patients with the severe PAP had higher TC, TG, LDL-C, TC/HDL-C, and non-HDL-C, while lower HDL-C than patients with the mild- moderate PAP (all P < 0.05). Binary logistic regression analysis indicated that TC/HDL-C (OR = 2.322, 95% CI 1.621–3.713, P = 0.024) and non-HDL-C (OR = 1.797, 95% CI 1.239–3.109, P = 0.036) were all significantly correlated with the severity of PAP after adjustment for other risk factors. The AUC value of TC/HDL-C for predicting the severity of PAP was larger than that of non-HDL-C. The AUROC for TC/HDL-C was 0.741 (0.654–0.828), and the optimal cut-off point for TC/HDL-C was 5.05 (sensitivity: 73.6%, specificity: 68.1%).Conclusions: Lipid ratios, including TC-HDL-C and non-HDL-C, were independent risk factors for the severity of PAP. TC/HDL-C is a promising biomarker for the severity of PAP.

A5 GM-CSF AUTOANTIBODIES: PREDICTORS OF CROHN’S DISEASE DEVELOPMENT AND A NOVEL THERAPEUTIC APPROACH

Abstract Background Crohn’s disease (CD) is a heterogenous, chronic inflammatory disorder driven by a combination of genetic, environmental, and microbiota-dependent risk factors. Mononuclear phagocytes (MNP) are crucial cells that maintain intestinal homeostasis. An important cytokine for MNP survival and function is granulocyte-macrophage colony stimulating factor (GM-CSF). Interestingly, several studies reported CD-associated genetic risk variants within the GM-CSF receptor and its downstream signaling components. Furthermore, high titers of autoantibodies specific to GM-CSF can be detected in CD patients. Taken together, this data suggests an important role for GM-CSF in abrogation of CD development in a subgroup of patients. Aims This study sought to investigate the function of GM-CSF autoantibodies in CD. Methods We retrospectively quantified and characterized GM-CSF autoantibodies in sera of 220 CD, 200 ulcerative colitis (UC) patients, and 220 healthy controls (HC) sampled at 3 time points prior to disease diagnosis and one time point after diagnosis. ELISA was used to determine GM-CSF autoantibody titers and isotypes followed by in vitro multiplexed mass cytometry (CyTOF) neutralization assays on peripheral blood mononuclear cells. Flow cytometry and CyTOF were used to map the profile of immune cells isolated from inflamed and non-inflamed CD mucosa. Results Our data demonstrates that GM-CSF autoantibodies are specific to CD, significantly elevated up to 7 years prior to diagnosis of disease, and correlate with disease location, severity, and complications at the time of diagnosis. Moreover, in contrast to GM-CSF autoantibodies in pulmonary alveolar proteinosis patients, CD-associated autoantibodies neutralize GM-CSF via specific recognition of post-translational modifications (PTM), affecting MNP function. Removal of PTM enabled GM-CSF to escape autoantibody binding and restored MNP response to GM-CSF in the presence of neutralizing antibodies, indicating a potential therapeutic avenue. Furthermore, we identified group 3 innate lymphoid cells (ILC3) as a major source of GM-CSF in the healthy intestinal tract, suggesting intriguing crosstalk of MNP and ILC3 across the GM-CSF-GM-CSFR axis. Conclusions Our results identify GM-CSF autoantibodies as predictive serological biomarker for CD in a subgroup of patients presenting with severe and complicated form of disease at the time of diagnosis. The presence of GM-CSF autoantibodies precedes the onset of CD by several years and likely abrogates homeostatic immune cell crosstalk involving ILC3 and MNP, suggesting the development of a pre-diseased state in CD patients. Funding Agencies CIHRDr. Edward Ketchum Graduate Scholarship

Valuable Serum Markers in Pulmonary Alveolar Proteinosis.

Objective Several serum markers were reported to reflect the severity of pulmonary alveolar proteinosis (PAP). The aim of this study is to investigate a reliable and facile marker to access and monitor the clinical course of PAP in a large cohort. Methods PAP patients from January 2010 to June 2018 were enrolled. Hospital records were used as data sources. The levels of various serum indicators were detected. We evaluated the correlation between pulmonary function test results and clinical variables. Results Diffusion capacity for carbon monoxide (DLCO) level was positively correlated with the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05) in 122 patients of PAP at baseline. The levels of HDL-C and DLCO significantly increased while carcinoembryonic antigen (CEA), CYFRA21-1, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH) levels decreased six months after granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy between 14 patients with PAP. Nevertheless, the increased DLCO was significantly correlated with decreased CEA (r = ‐0.579, P = 0.031) and CYFRA 21-1 (r = ‐0.632, P = 0.015). In 10 PAP patients without GM-CSF inhalation therapy, HDL-C and DLCO significantly decreased while NSE and LDH levels increased after six months of follow-up. The decreased DLCO was significantly correlated with increased LDH (r = ‐0.694, P = 0.026). Conclusions Serum CEA, CYFRA21-1, and LDH are valuable serum markers for the evaluation of disease activity of PAP and may predict the response to treatment of PAP.

Memory B cell pool of autoimmune pulmonary alveolar proteinosis patients contains higher frequency of GM-CSF autoreactive B cells than healthy subjects

The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.

The influence of genetics on therapeutic developments in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients. Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance. WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.

Whole-lung Lavage and Pulmonary Alveolar Proteinosis: Review of Clinical and Patient-centered Outcomes

The objective of this retrospective review was to evaluate the perioperative and procedural management of patients with pulmonary alveolar proteinosis (PAP) who presented for whole-lung lavage (WLL). The records of all adult patients with PAP who underwent WLL between January 1, 1988 and August 20, 2017 were reviewed and pertinent demographic, preoperative, anesthetic, procedural, and postoperative data were recorded. Large academic tertiary referral center. Forty patients with PAP underwent 79 WLL procedures. Patients with PAP undergoing WLL. Successful WLL, defined by visual clearing of lavage fluid, was completed in 91% of cases. Whole-lung lavage was terminated prematurely in 9% of cases (refractory hypoxia most common), while 8% of cases were found to have 30-day complications. There were no cases of intraoperative death, hemodynamic collapse, pneumothorax or hydrothorax, or need for emergent reintubation. Postoperative clinical follow-up at the authors' institution within 6 months of WLL showed 68% of patients reported improvement in symptoms and/or functional status. The authors here present a retrospective study describing the perioperative and procedural management of PAP patients undergoing WLL to help familiarize providers with the management of this population (Fig 1). The findings of this study outline a successful and consistent approach to WLL using a multidisciplinary team experienced in this procedure. Even in experienced hands, procedural complications and 30-day postoperative complications emphasize the risk in this complex patient population.

Pulmonary alveolar proteinosis: An autoimmune disease lacking an HLA association

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant in alveolar macrophages and alveoli, resulting in respiratory impairment and an increased risk of opportunistic infections. Autoimmune PAP is an autoimmune lung disease that is caused by autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). A shared feature among many autoimmune diseases is a distinct genetic association to HLA alleles. In the present study, we HLA-typed patients with autoimmune PAP to determine if this disease had any HLA association. We analyzed amino acid and allele associations for HLA-A, B, C, DRB1, DQB1, DPB1, DRB3, DRB4 and DRB5 in 41 autoimmune PAP patients compared to 1000 ethnic-matched controls and did not find any HLA association with autoimmune PAP. Collectively, these data may suggest the absence of a genetic association to the HLA in the development of autoimmune PAP.

Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb−/− mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP.

An eleven-year retrospective cross-sectional study on pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare disease in the field of pulmonary medicine. The efficacy of whole-lung lavage (WLL) as the treatment of PAP had never been evaluated in the Iranian population. Therefore, there is a real need to investigate the characteristics of PAP and also to evaluate the efficacy of WLL in this rare disease. The study aimed to investigate demographic features, clinical presentation and treatment outcomes of the disease in Iranian PAP patients. Data of 45 patients with definite diagnosis of PAP, who had regular follow-ups from March 2004 to March 2015 at an Iranian referral respiratory hospital, were collected. Whole-lung lavages (WLL) efficacy was assessed by comparing spirometric, arterial blood gas parameters and six-minute walk test (6MWT) results before and after all lavages. Mean age at diagnosis of disease was 30.33 ± 14.56 years. Four patients (8.8%) reported non-massive hemoptysis and three subjects (6.6%) had concomitant pulmonary tuberculosis. In 71.1% of cases, transbronchial lung biopsy and bronchoalveolar lavage were sufficient for diagnosis. Spirometric results and arterial blood gas parameters and 6MWD improved significantly after all the lavages. Four patients (8.8%) died because of respiratory failure. The only variable capable of predicting treatment failure was the history of hemoptysis. The study revealed sufficiency of WLL as the PAP patients' treatment. Also hemoptysis was found to be the independent factor that can predict treatment failure.