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Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George's Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks. A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was -11.5 points (95% CI, -15.0 to -8.0) and -4.9 points (95% CI, -8.3 to -1.5), respectively (P = 0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups. Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP. (Funded by Savara; IMPALA-2 ClinicalTrials.gov number, NCT04544293; European Union Clinical Trials Information System number, 2024-511052-41-00.).

In patients with autoimmune pulmonary alveolar proteinosis, the use of inhaled recombinant granulocyte–macrophage colony-stimulating factor resulted in a significantly better alveolar–arterial oxygen gradient at 25 weeks than the use of placebo. The beneficial effect was not observed in smokers.

Patients with autoimmune pulmonary alveolar proteinosis received inhaled molgramostim or matching placebo for 24 weeks. Patients receiving molgramostim had greater improvement in pulmonary gas transfer and alleviation of symptoms than those receiving placebo.

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis. PAP can be classified into different types on the basis of the pathogenetic mechanism: primary PAP is characterized by the disruption of granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB , encoding GM-CSF receptor subunits); secondary PAP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production. In most patients, pathogenesis is driven by reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. PAP has a prevalence of at least 7 cases per million individuals in large population studies and affects men, women and children of all ages, ethnicities and geographical locations irrespective of socioeconomic status, although it is more-prevalent in smokers. Autoimmune PAP accounts for >90% of all cases. Management aims at improving symptoms and quality of life; whole-lung lavage effectively removes excessive surfactant. Novel pathogenesis-based therapies are in development, targeting GM-CSF signalling, immune modulation and cholesterol homeostasis. Pulmonary alveolar proteinosis comprises a group of diseases with different pathogenetic mechanisms but a common outcome — the progressive accumulation of alveolar surfactant in the lungs and dysfunction of alveolar macrophages, which result in respiratory failure and increased risk of secondary infections.

Abstract Tissue-resident macrophages are of vital importance as they preserve tissue homeostasis in all mammalian organs. Nevertheless, appropriate cell culture models are still limited. Here, we propose a novel culture model to study and expand murine primary alveolar macrophages (AMs), the tissue-resident macrophages of the lung, in vitro over several months. By providing a combination of granulocyte-macrophage colony-stimulating factor, TGFβ, and the PPARγ activator rosiglitazone, we maintain and expand mouse ex vivo cultured AMs (mexAMs) over several months. MexAMs maintain typical morphologic features and stably express primary AM surface markers throughout in vitro culture. They respond to microbial ligands and exhibit an AM-like transcriptional profile, including the expression of AM-specific transcription factors. Furthermore, when transferred into AM-deficient mice, mexAMs efficiently engraft in the lung and fulfill key macrophage functions, leading to a significantly reduced surfactant load in those mice. Altogether, mexAMs provide a novel, simple, and versatile tool to study AM behavior in homeostasis and disease settings.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Background: New therapies have emerged in the treatment of pulmonary alveolar proteinosis (PAP) and, therefore, there is a real need to evaluate the efficacy of whole-lung lavage (WLL) in this rare disease. Objectives: The aim of this study was to assess the efficacy of WLL in patients with PAP. Methods: We included 33 patients from 12 centers, which are members of the French-Speaking Thoracic Endoscopy Group, for analysis. Data collection concerned patients and disease characteristics, pulmonary function tests (PFTs) and technical information on the procedure. Results: The median age of the patients was 44 years (range 13-77). There were 23 (71.9%) patients with respiratory insufficiency at presentation. All patients underwent WLL by general anesthesia and selective lung ventilation, except 1 who underwent awake flexible bronchoscopy. We noted differences in the technique, as 12 (36.36%) patients had percussion during the procedure and only 4 (12.1%) patients underwent 2-lung lavage during 1 anesthesia. A median of 12 L was used to perform WLL (1.0-40 L). Complications occurred in 11 (33.3%) patients, and 18 (56.25%) of them relapsed in a median period of 16.9 months. No significant changes were found in any PFT parameters studied, except for PaO 2 , which was significantly improved by 6.375 mm Hg (p = 0.0213) after the procedure compared to before. Conclusions: Although the application of the WLL technique was variable, overall, it significantly improved patients' short-term respiratory condition by improving PaO 2 . However, a long-term effect needs to be confirmed, as many of our patients relapsed.

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-DPβ1 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 (β = 0.32; P  = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production. Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease. Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.

Pulmonary alveolar proteinosis (PAP) is a rare syndrome of alveolar surfactant accumulation, resulting hypoxemic respiratory failure, and increased infection risk. Despite advances in our understanding of disease pathogenesis and the availability of improved diagnostics, the epidemiology and healthcare burden of PAP remain poorly defined. To determine the prevalence, and healthcare utilization and costs associated with PAP, we interrogated a large health insurance claims database containing comprehensive data for approximately 15 million patients in the United States. We also evaluated data from a referral-based diagnostic testing program collected over a 15-year period. The prevalence of PAP was determined to be 6.87 ± 0.33 per million in the general population, similar in males and females, and increased with age, however considering difficulties and delays in diagnosing this is likely a minimum estimate of true prevalence. PAP patients had significantly more comorbidities, health care utilization and associated costs compared to control patients precisely matched for age and gender. Between 2004 and 2018, 249 patients confirmed to have PAP were evaluated to identify the PAP-causing disease; 91.5% had autoimmune PAP, 3% had hereditary PAP caused by GM-CSF receptor mutations, 4% had secondary PAP, and 1.5% had congenital PAP. Considering the high diagnostic accuracy of serum GM-CSF autoantibody testing and predominance of autoimmune PAP, these results emphasize the importance of utilizing blood-based testing in PAP syndrome to identify the PAP-causing disease rather than invasive lung biopsies, resulting in earlier diagnosis, reduced morbidity and lower healthcare costs.