Transbronchial lung biopsy (TBLB) in diagnosing pulmonary alveolar proteinosis (PAP): forgotten role in Australia?
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ABSTRACT:
SUBMITTER: Tung AH
PROVIDER: S-EPMC4694603 | biostudies-other | 2015 Dec
REPOSITORIES: biostudies-other
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Project description:BackgroundThe purpose of this study was to investigate whether ultra-low-dose chest computed tomography (CT) can be used for visual assessment of CT features in patients with pulmonary alveolar proteinosis (PAP) and to evaluate the relationship between the quantitative analysis of the ultra-low-dose CT scans and the pulmonary function tests (PFTs).MethodsThirty-eight patients (mean [SD] age, 44.47 [12.28] years; 29 males, 9 females) with PAP were enrolled and subjected to two scans each with low-dose CT (reference parameters: 120 kV and 50 mAs) and ultra-low-dose CT (reference parameters, 80 kV, 25 mAs). Images were reconstructed via filtered back projection (FBP) for low-dose CT and iterative reconstruction (IR) for ultra-low-dose CT. All patients underwent PFT. The Visual analysis for ground glass opacity (GGO) is performed. The quantitative CT and PFT results were analyzed by canonical correlations.ResultsThe mean body mass index (BMI) was 25.37±3.26 kg/m2. The effective radiation doses were 2.30±0.46 and 0.24±0.05 mSv for low-dose and ultra-low-dose CT, respectively. The size-specific dose estimates were 5.81±0.81 and 0.62±0.09 mSv for low-dose and ultra-low-dose CT. GGOs and interlobular septal thickening were observed bilaterally in all patients. The average visual GGO score was lower in the upper field (2.67±1.24) but higher in the middle and lower fields (3.08±1.32 and 3.08±0.97, respectively). The average score for the whole lung was 2.94±1.19. There is a significant correlation between PFTs and quantitative of ultra-low-dose CT (canonical loading = 0.78).ConclusionsUltra-low-dose CT has the potential to quantify the lung parenchyma changes of PAP. This technique could provide a sensitive and objective assessment of PAP and has good relation with PFTs. In addition, the radiation dose of ultra-low-dose CT was very low.
| S-EPMC5354367 | biostudies-literature
Project description:BackgroundPulmonary 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.MethodsHere, 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.ResultsA 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.DiscussionOur 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.ConclusionWLL lavage is possible in small PAP patients but should performed in close interdisciplinary cooperation and with age appropriate protocols.
| S-EPMC10883753 | biostudies-literature
Project description:BACKGROUND:Radial endobronchial ultrasound (R-EBUS) transbronchial lung biopsy (TBLB) improves the diagnostic yield from peripheral pulmonary lesions (PPLs). However, the small specimens obtained using small forceps through a guide sheath (GS) may impede diagnosis and molecular analysis. Here, we investigated the diagnostic significance of additional conventional TBLB with standard forceps after R-EBUS-GS-guided TBLB. METHODS:We retrospectively reviewed data from 55 patients who underwent conventional TBLB after R-EBUS-GS-guided TBLB for PPL diagnosis. Procedures were performed on single PPLs with no visible lesions on bronchoscopy. In cases with inconclusive pathologic confirmation, final diagnoses were made based on pathologic specimens or clinical observations. RESULTS:The median size of the target lesions was 28?mm. The appearances on computed tomography images were solid (n = 45, 81.8%), part-solid (n = 7, 12.7%), and cavitary nodules (n = 3, 5.5%). A computed tomography bronchus sign was present in 35 (63.6%) cases, and a radial probe was positioned within target lesion in 32 (58.2%) cases. R-EBUS-GS-guided TBLB was diagnostic in 30 (54.5%) patients, and subsequent conventional TBLB yielded additional diagnostic information in 8 (14.5%) patients. Probe positioning within target lesions and the outer margin of PPLs more than 1 cm from pleura were significantly associated with enhanced diagnostic yield from the combined procedures. In conventional TBLB, probe positioning within target lesions (75.0% vs. 11.8%, P = 0.004) and characteristic of nonsolid nodules (83.3% vs. 15.8%, P = 0.006) were significantly associated with additional diagnostic utility. CONCLUSIONS:Conventional TBLB following R-EBUS-GS-guided TBLB could be a useful procedure for diagnosing PPLs, especially for nonsolid nodules. KEY POINTS:Significant findings of the study: Additional conventional TBLB with standard forceps after R-EBUS-GS-guided TBLB yielded an additional 14.5% diagnostic utility for peripheral pulmonary lesions. For conventional TBLB, probe positioning within target lesions and nonsolid nodules were significantly associated with additional diagnostic utility. WHAT THIS STUDY ADDS:Conventional TBLB with standard forceps after R-EBUS-GS-guided TBLB is an effective and economically accessible diagnostic tool for peripheral pulmonary lesions.
| S-EPMC7263016 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage- and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.
| S-EPMC2866141 | biostudies-literature
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.
| S-EPMC3432632 | biostudies-literature
Project description:This case report demonstrates 44-year old man, presenting with recurring clinical pneumonias during a period of over 1 year. The patient was clinically affected with, i.a., weight loss, finger clubbing and severely reduced diffusion capacity. Repetitive chest x-rays showed bilateral and consolidating infiltrates, and a high-resolution computed tomography of the thorax (HRCT) exposed ground glass opacities superimposed on a reticular pattern as the so-called 'crazy paving' pattern. A bronchoscopic alveolar lavage revealed alveolar proteinaceous material compatible with the diagnosis pulmonary alveolar proteinosis (PAP). PAP is a rare syndrome where surfactant is accumulated in the alveoli, causing respiratory disease in typically young to middle-aged patients with male predominance. Both symptoms and prognosis are variable, and range from spontaneous remission to terminal respiratory failure. The standard treatment is whole lung lavage, where surfactant is mechanically rinsed from the lungs. The lack of specific clinical symptoms makes it easy to overlook the diagnosis, as supported by this case report. It serves as a reminder, that the findings of a crazy paving pattern on HRCT in young adults should alert of this rare disease, and advises on the further examinations required to make the diagnosis.
| S-EPMC6282426 | biostudies-literature
Project description:Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Ralpha) and nonbinding affinity-enhancing (GM-CSF-Rbeta) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Ralpha-encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Ralpha, severely reducing GM-CSF binding, receptor signaling, and GM-CSF-dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
| S-EPMC2585845 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR]?=?5.2; P?=?2.4?×?10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR?=?4.8; P?=?4.8?×?10-12), followed by an additional independent risk allele at HLA-DP?1 amino acid position 8 (OR?=?0.28; P?=?3.4?×?10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (??=?0.32; P?=?0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
| S-EPMC7884840 | biostudies-literature
Project description: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.
| S-EPMC6081448 | biostudies-literature
Project description:RationaleWe identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF.ObjectivesIncreased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction.MethodsWe screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls.Measurement and main resultsEight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy.ConclusionsCSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.
| S-EPMC3001266 | biostudies-literature