Dataset Information

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

ABSTRACT:

Background

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.

Methods

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.

Results

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.

Discussion

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.

Conclusion

WLL lavage is possible in small PAP patients but should performed in close interdisciplinary cooperation and with age appropriate protocols.

SUBMITTER: Nickel K

PROVIDER: S-EPMC10883753 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Nickel Katja K Schütz Katharina K Carlens Julia J Grewendorf Simon S Wetzke Martin M Keil Oliver O Dennhardt Nils N Rigterink Vanessa V Köditz Harald H Sasse Michael M Happle Christine C Beck Christiane E CE Schwerk Nicolaus N

Klinische Padiatrie 20240123 2

<h4>Background</h4>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.<h4>Methods</h4>Here, we present data from more than ten y ...[more]

PMID: 38262422

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Project description:RationaleWhole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP.Methods18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled "rescue" WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group.ResultsThe primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported.ConclusionsThis long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.

Project description: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.

Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Dataset Information

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

Background

Methods

Results

Discussion

Conclusion

Publications

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

Similar Datasets

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