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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.

Background: Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods: In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results: All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion: Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab. [ABSTRACT FROM AUTHOR]

The article discusses the use of mesenchymal stromal cells (MSCs) in limiting house dust mite extract-induced mixed granulocytic lung inflammation in an experimental asthma model. The study found that intranasal administration of adipose tissue-derived MSCs reduced lung leukocyte infiltration, eosinophil and neutrophil counts, and altered gene expression related to inflammation. Additionally, MSCs were effective in reducing subepithelial collagen deposition and changing T effector cell responses. Further research is needed to fully understand the long-term effects of MSC transplantation in non-T2-driven asthmatic inflammation. [Extracted from the article]

Objectives: We aimed to characterize and investigate the safety and efficacy of Plonmarlimab, a novel anti‐granulocyte‐macrophage colony‐stimulating factor (anti‐GM‐CSF) neutralizing antibody, on the treatment of macrophage activation syndrome (MAS), a life‐threatening systemic inflammatory disease, in pre‐clinical models. Methods: The binding affinity was evaluated using Biacore. The neutralizing activity was measured through the blockade of ligand–receptor interaction, inhibition of STAT5 phosphorylation and suppression of TF‐1 cell proliferation. The efficacy of Plonmarlimab was evaluated in a humanized MAS model, which was established by engrafting human umbilical cord blood (UCB) cells into NOG‐EXL mice. Additionally, the safety profile of Plonmarlimab was investigated in cynomolgus monkeys. Results: At the molecular level, Plonmarlimab showed sub‐nanomolar binding affinity with human GM‐CSF and effectively blocked the binding of GM‐CSF to its receptor. At the cellular level, Plonmarlimab dose‐dependently inhibited intracellular STAT5 phosphorylation and suppressed GM‐CSF‐induced TF‐1 proliferation. In the UCB‐engrafted NOG‐EXL MAS mouse model, Plonmarlimab treatment significantly ameliorated disease progression, demonstrated by the improvements in body weight loss, anaemia and some histopathological features. Furthermore, Plonmarlimab was well tolerated up to 150 mg/kg weekly in monkeys with no reported adverse effects. Conclusions: Plonmarlimab is a highly potent GM‐CSF blocking antibody and has demonstrated promising efficacy in a pre‐clinical MAS model with a favourable safety profile, supporting its clinical development. [ABSTRACT FROM AUTHOR]

Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis, are not well understood. Herein, we report an ex vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant proinflammatory (IL-13) or profibrotic (TGF-β) cytokines. Compared with untreated cocultures, IL-13 increased expression of CD69 on eosinophils, whereas TGF-β increased expression of CD81, CD62L, and CD25. Eosinophils from IL-13–treated cocultures demonstrated increased secretion of GRO-α, IL-8, and macrophage colony-stimulating factor and also generated increased extracellular peroxidase activity following activation. Eosinophils from TGF-β–treated cocultures secreted increased IL-6 and exhibited increased chemotactic response to CCL11 compared with eosinophils from untreated or IL-13–treated coculture conditions. When eosinophils from TGF-β–treated cocultures were cultured with fibroblasts, they upregulated SERPINE1 expression and fibronectin secretion by fibroblasts compared with eosinophils that were cultured with granulocyte macrophage colony-stimulating factor alone. Translational studies revealed that CD62L was heterogeneously expressed by eosinophils in patient biopsy specimens. Our results demonstrate that disease-relevant proinflammatory and profibrotic signals present in the esophagus of patients with eosinophilic esophagitis cause distinct profiles of eosinophil activation and gene expression. [ABSTRACT FROM AUTHOR]

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine, able to promote both myelopoiesis and activation of immune cells. Particularly in the lung, GM-CSF plays an important homeostatic role in the development and maintenance of alveolar macrophages, and is therefore considered to play a role in respiratory virus infections such as influenza and SARS-CoV-2, although the benefits of GM-CSF treatment in clinical studies remain inconclusive. To address this, we tested inhaled GM-CSF treatment in the Pneumonia Virus of Mice (PVM) mouse model. Our findings show that local GM-CSF therapy during PVM disease increased local neutrophilia and monocytederived cell influx, but diminished CD8+ T cells responses. Despite this, the observed effects on T cells and myeloid cells did not result in an altered clinical outcome during PVM infection. We conclude that inhaled GM-CSF therapy cannot be considered as a universal protective therapy in respiratory virus infections. [ABSTRACT FROM AUTHOR]

The article discusses the challenges posed by the COVID-19 pandemic in lung transplantation, focusing on the virological assessment of donors and recipients. It presents two detailed cases of lung transplantation involving a SARS-CoV-2 RNA-positive donor and a recipient, highlighting the complexities of decision-making in such scenarios. The study emphasizes the importance of comprehensive virological analyses in determining the risk of postoperative infection and the successful outcomes of lung transplantation despite SARS-CoV-2 RNA detection in donors or recipients. The research contributes valuable insights for future donor selection and transplantation protocols in the context of the pandemic. [Extracted from the article]

A 31-year-old Japanese man presented with cerebral and pulmonary cryptococcosis. Cryptococcus gattii (C. gattii) genotype VGIIb was detected in the patient's sputum and cerebrospinal fluid specimens. The serum levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies were elevated in this patient, which has been associated with pulmonary alveolar proteinosis and is considered a risk factor for C. gattii infection. After undergoing >12 months of antifungal treatments, the patient showed improvements in symptoms and findings on brain and lung imaging. Several Japanese patients who develop C. gattii infection have also been reported; however, most of these patients have been infected outside Japan, as C. gattii infection is rare in Japan. Only one patient with C. gattii genotype VGIIb infection has been reported in Japan, and it is believed that this patient contracted the infection in China. In the present case, our patient has never been outside Japan, indicating that the infection originated in Japan. Our findings suggest that C. gattii might be spreading in Japan. Therefore, patients with positive serum anti-GM-CSF antibodies should be thoroughly monitored for C. gattii infection, even those living in Japan. [ABSTRACT FROM AUTHOR]

The article in MedComm discusses the impact of the androgen-type 2 innate lymphoid cells-dendritic cell axis on sex-associated differences in skin immune responses. The study by Chi et al. reveals that sex hormones and the microbiota influence tissue immune set points and dendritic cell network strength, leading to disparities in susceptibility to diseases between males and females. The research highlights the role of androgen signaling in regulating immune responses and emphasizes the potential for gender-tailored therapeutic approaches in various diseases. The findings underscore the complex interplay between sex hormones, microbiota, and immune cells in shaping tissue immune responses and DC network resilience, offering insights into sex differences in disease susceptibility. [Extracted from the article]

This letter to the editor discusses a rare case of a patient with primary myelofibrosis (PMF) who developed pulmonary alveolar proteinosis (PAP). The patient was successfully treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a tailored approach combining low-dose ruxolitinib and radiotherapy. The article highlights the potential of allo-HSCT as a treatment option for PAP and emphasizes the importance of proper management and monitoring of lung conditions before and after transplantation. The successful resolution of both diseases in this case demonstrates the effectiveness of allo-HSCT. [Extracted from the article]

With the increasing incidence of lung cancer, the coexistence of pulmonary alveolar proteinosis (PAP) and lung cancer is becoming more common. However, the standard treatment protocols for patients with both conditions are still being explored. The conflict between the rapidly evolving therapeutic approaches for tumors and the limited treatment options for PAP presents a significant challenge for clinicians. Determining the optimal timing of treatment for both conditions to maximize patient benefit is a clinical conundrum. Here, we report a rare case of PAP complicated by lung adenocarcinoma, where interstitial lung changes worsened after neoadjuvant therapy but improved significantly following surgical resection of the lung adenocarcinoma. This case highlights the importance of prioritizing tumor treatment in patients with lung cancer complicated by PAP and examines the interplay between the two conditions, as well as potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Homozygous or compound heterozygous mutations in JAGN1 cause severe congenital neutropenia. JAGN1-mutant patients present with severe early-onset bacterial infections and most have been described as low-responders to recombinant granulocyte colony-stimulating factor (G-CSF) therapy. In a murine, hematopoietic JAGN1 knockout model, which displays susceptibility to Candida albicans infection in the absence of neutropenia, treatment with granulocyte-macrophage-CSF (GM-CSF) was able to restore the functional defect of neutrophils. Patients: We present two unrelated patients with biallelic JAGN1 mutations, who were both treated with subcutaneous GM-CSF (sargramostim) after treatment failure to G-CSF. The first patient was an 18-year-old pregnant woman who received GM-CSF at 12 weeks of gestation up to a dose of 10 µg/kg/d for 7 days. The second patient was a 5-month-old girl who received GM-CSF for a total of 9 days at a dose of up to 20 µg/kg/d. GM-CSF did not increase neutrophil counts in our patients. Treatment was stopped when neutrophil numbers declined further, no beneficial effect was noticed, and patients presented with infections. No adverse effects were observed in either patient and the fetus. Both patients ultimately underwent successful hematopoietic stem cell transplantation. Discussion: Both patients showed a high recurrence rate of severe infections on G-CSF treatment. GM-CSF therapy did not ameliorate the clinical phenotype, in contrast to the improvement of neutrophil function observed in the JAGN1 mouse model. No major additional extra-hematopoietic manifestations were evident in our patients. Conclusion: In two unrelated patients, GM-CSF did not have any beneficial effect on neutrophil counts. Patients with JAGN1-mutant SCN with reduced G-CSF responsiveness and elevated infection rate should be evaluated early for stem cell transplantation. [ABSTRACT FROM AUTHOR]

The given text is a list of references to various scientific articles related to the topic of airway pressure release ventilation (APRV) and its effects on lung injury and respiratory mechanics. The articles discuss the preventive and therapeutic potential of APRV in conditions such as acute respiratory distress syndrome (ARDS), traumatic hemorrhagic shock, ventilator-induced lung injury, and extrapulmonary lung injury. The studies explore the physiological mechanisms and benefits of APRV, including its ability to prevent lung injury, reduce alveolar strain, improve respiratory mechanics, and minimize ventilator-associated lung injury. The articles also highlight the importance of personalized ventilation strategies and the role of dynamic alveolar physiology in minimizing lung injury. [Extracted from the article]

Pulmonary alveolar proteinosis is a rare diffuse lung disease; diagnosis and treatment of which is often delayed. We present the case study of a 43-year-old male with a six-month history of worsening breathlessness and non-productive cough referred for specialist respiratory input. Rapid investigations, including high-resolution computed tomography (HRCT) and bronchoalveolar lavage, confirmed the diagnosis of pulmonary alveolar proteinosis. Treatment with whole lung lavage significantly improved pulmonary function and quality of life. We discuss the diagnosis and management of this condition and highlight the importance of early recognition and multidisciplinary teamwork in managing pulmonary alveolar proteinosis. [ABSTRACT FROM AUTHOR]

This case report delves into pediatric lung isolation challenges and innovations in managing patients with pulmonary alveolar proteinosis undergoing whole lung lavage. The central focus is on a 5-year-old girl who initially encountered intraoperative complications, including bilateral pneumothorax and pulmonary edema. However, a subsequent attempt employing a Foley’s catheter for lung isolation proved successful, with the patient displaying marked postoperative improvements. The case offers valuable insights into the intricate balance of anesthesia, ventilatory parameters, and the novel use of common medical equipment, like the Foley’s catheter, for specialized procedures in pediatric pulmonology.

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.

Purpose: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are implicated in the pathogenesis of Cryptococcus gattii (C. gattii) infection and pulmonary alveolar proteinosis (PAP). Their presence has also been noted in nocardiosis cases, particularly those with disseminated disease. This study delineates a case series characterizing clinical features and specificity of anti-GM-CSF Abs in nocardiosis patients. Methods: In this study, eight patients were recruited to determine the presence or absence of anti-GM-CSF Abs. In addition to the detailed description of the clinical course, we thoroughly investigated the autoantibodies regarding the characteristics, isotypes, subclasses, titers, and neutralizing capacities by utilizing the plasma samples from patients. Results: Of eight patients, five tested positive for anti-GM-CSF Abs, all with central nervous system (CNS) involvement; patients negative for these antibodies did not develop CNS nocardiosis. Distinct from previously documented cases, none of our patients with anti-GM-CSF Abs exhibited PAP symptoms. The titer and neutralizing activity of anti-GM-CSF Abs in our cohort did not significantly deviate from those found in C. gattii cryptococcosis and PAP patients. Uniquely, one individual (Patient 3) showed a minimal titer and neutralizing action of anti-GM-CSF Abs, with no relation to disease severity. Moreover, IgM autoantibodies were notably present in all CNS nocardiosis cases investigated. Conclusion: The presence of anti-GM-CSF Abs suggests an intrinsic immunodeficiency predisposing individuals toward CNS nocardiosis. The presence of anti-GM-CSF Abs helps to elucidate vulnerability to CNS nocardiosis, even with low titer of autoantibodies. Consequently, systematic screening for anti-GM-CSF Abs should be considered a crucial diagnostic step for nocardiosis patients. [ABSTRACT FROM AUTHOR]

Abstract Background Pulmonary alveolar proteinosis (PAP) is a special clinical presentation mostly associated with autoimmune disorders. Here we report a rare case of PAP secondary to infection of Bacillus megaterium. Case presentation A 58-year-old woman presented with intermittent cough and dyspnea for half a year. Chest CT scan showed “crazy paving” pattern. B. megaterium was identified by percutaneous CT-guided needle biopsy. She continuously received antimicrobial treatment since the diagnosis and follow-up examination suggested great improvement. Conclusions To our knowledge, this is the first case of B. megaterium infection presented with PAP pattern in healthy individuals. Attention should be paid on the secondary causes including rare pathogen infection when patients presented with PAP syndrome.

ABSTRACT Introduction Lysinuric protein intolerance (LPI) is a rare genetic disorder caused by mutations in the solute carrier family 7A member 7 (SLC7A7) gene. Case presentation We presented two siblings with LPI, carrying novel mutations of c.776delT (p.L259Rfs*18) and c.155G>T (p.G52V) in SLC7A7. The younger sibling, preferring protein‐rich foods, showed severe symptoms, including alveolar proteinosis, macrophage activation syndrome, severe diarrhea, and disturbance of consciousness with involuntary movements. In contrast, the elder sibling only had mild symptoms, likely due to aversion to protein‐rich food since toddler age. Conclusion LPI is a congenital genetic metabolic disease with multi‐system involvement. Initiating appropriate protein‐restricted diet therapy as soon as possible could help prevent the progression of LPI.

Abstract Background Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine, ornithine and arginine. Infants with LPI typically present with recurrent vomiting, poor growth, interstitial lung disease or renal impairment. The early onset of pulmonary alveolar proteinosis (PAP) has been reported to be associated with a severe form of LPI. Treatment of PAP most commonly consists of whole-lung lavage (WLL) and in autoimmune PAP, granulocyte-macrophage colony stimulating factor (GM-CSF) administration. Nevertheless, GM-CSF therapy in LPI-associated PAP has not been scientifically justified. Case presentation We describe the case of an 8-month-old infant presenting with respiratory failure due to LPI associated with PAP, who was twice treated with WLL; firstly, while on veno-venous ECMO assistance and then by the use of a selective bronchial blocker. After the two treatments with WLL, she was weaned from daytime respiratory support while on initially subcutaneous, then on inhaled GM-CSF therapy. Conclusions This case supports the notion that GM-CSF therapy might be of benefit in patients with LPI-associated PAP. Further studies are needed to clarify the exact mechanism of GM-CSF in patients with LPI-associated PAP.

Background: Pulmonary alveolar proteinosis (PAP) is a special clinical presentation mostly associated with autoimmune disorders. Here we report a rare case of PAP secondary to infection of Bacillus megaterium. Case presentation: A 58-year-old woman presented with intermittent cough and dyspnea for half a year. Chest CT scan showed "crazy paving" pattern. B. megaterium was identified by percutaneous CT-guided needle biopsy. She continuously received antimicrobial treatment since the diagnosis and follow-up examination suggested great improvement. Conclusions: To our knowledge, this is the first case of B. megaterium infection presented with PAP pattern in healthy individuals. Attention should be paid on the secondary causes including rare pathogen infection when patients presented with PAP syndrome. [ABSTRACT FROM AUTHOR]

ObjectiveMethodResultsConclusionIn systemic lupus erythematosus (SLE), the non-classical monocyte compartment is expanded, but its phenotype and association with clinical disease manifestations have not been explored.Monocyte subsets from 39 SLE patients, 32 healthy age-matched controls, and 16 patients from a disease control (autoimmune connective tissue disease other than SLE) were determined based on CD14 and CD16 surface expression. Cell surface expression of the receptors for macrophage colony-stimulating factor (M-CSF) (CD115) and granulocyte–macrophage colony-stimulating factor (GM-CSF) (CD116), as well as 6-Sulpho LacNAc (slan), were analysed by flow cytometry. The association of monocyte populations with disease manifestations, disease activity markers, and current medication of each patient was analysed by chart review.Non-classical monocytes displayed a cell-type specific signature of high M-CSF receptor CD115 and low GM-CSF receptor CD116 expression that separated them from the other two monocyte subsets. In healthy individuals, the M-CSF receptor on non-classical monocytes was an age-dependent surface marker, with lower expression in young adults. However, SLE monocytes were characterized by a marked expansion of M-CSF receptor/CD115+ non-classical monocytes in patients of all ages. The expanded population of M-CSF receptor/CD115+ non-classical monocytes was associated with lupus nephritis but not with disease activity, and coexpressed slan.The non-classical monocyte subset in SLE is characterized by an expansion of M-CSF receptor/CD115+ cells that are associated with lupus nephritis and coexpress slan. [ABSTRACT FROM AUTHOR]

Introduction: Postpartum endometritis is a prevalent reproductive disorder in bovines, leading to a prolonged open period, infertility, and other complications. While Lactobacillus strains can mitigate these conditions by reducing uterine inflammation, their effectiveness is limited due to a lack of direct anti microbial action and extended treatment duration. This study aimed to construct a recombinant Lactobacillus johnsonii strain expressing bovine Granulocytemacrophage colony-stimulating factor (GM-CSF) to evaluate its potential in reducing postpartum uterine inflammation. Methods: The recombinant Lactobacillus johnsonii strain was engineered to express bovine GM-CSF and administered to pregnant mice via vaginal perfusion. Postpartum endometritis was induced using E. coli infection, and the protective effects of the engineered strain were assessed. Inflammatory markers (IL-6, IL-1β, TNF-α), myeloperoxidase (MPO) activity, and nitric oxide (NO) concentration were measured. Histological examination was performed to evaluate uterine morphology and pathological damage. Results: The recombinant L. johnsonii strain expressing GM-CSF significantly reduced inflammation levels induced by E. coli infection in the uterus. This reduction was evidenced by decreased expression of IL-6, IL-1β, TNF-α, as well as reduced MPO activity and NO concentration. Histological examination revealed improved uterine morphology and reduced pathological damage in mice treated with the recombinant GM-CSF strain. Crucially, the recombinant strain also exerts beneficial effects on bovine endometritis by reducing levels of inflammatory cytokines, suggesting a beneficial effect on clinical bovine endometritis. Conclusion: The recombinant Lactobacillus johnsonii expressing GM-CSF demonstrated protective effects against postpartum endometritis in bovines by reducing inflammatory cytokines. The findings indicate the potential clinical application of this engineered strain in preventing postpartum uterine inflammation, offering a novel and effective protective option for related disorders and improving bovine reproductive efficiency. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Amyloidosis refers to an assortment of diseases characterized by the accumulation and deposition of misfolded proteins in the extracellular matrix of tissues and organs. It may present systemically, affecting multiple organs, or locally by affecting a single organ. When the lungs or mediastinal structures are involved, the term pulmonary amyloid is used. Sole pulmonary involvement with amyloid is extremely rare. There is no definitive treatment for this disease, but proposed treatment options include surgery, cytotoxic medications, and external beam radiation therapy (EBRT). Case Report: A 68-year-old man with a left apical lung mass presented with subacute shortness of breath. Comprehensive evaluation of the patient’s symptoms and findings, including infectious and oncologic evaluation, were performed. Infectious evaluation revealed positive acid-fast bacilli sputum cultures with Mycobacterium chimerea intracellulare. Biopsy of the mass revealed a Lambda restricted amyloidoma, which is usually seen in lymphoproliferative diseases and disorders. Bone marrow biopsy did not reveal any monoclonal cell lines or neoplasms. Abdominal fat pad biopsy was performed to rule out systemic amyloid and the results were negative. The diagnosis of isolated apical pulmonary amyloidoma was made. EBRT was performed over 12 fractions in 24 mGy, with improvement in the patient’s symptoms. Conclusions: The diagnosis of pulmonary amyloid necessitates comprehensive evaluation. There is no specific treatment for pulmonary amyloid; however, there has been success with surgical intervention, cytotoxic medications, and EBRT. Successful treatment of the amyloidoma is based on its anatomic location. We suggest EBRT in fractionated doses for optimal treatment of rare isolated apical pulmonary amyloidoma. [ABSTRACT FROM AUTHOR]

To explore serum KL-6 level and investigate its diagnostic value in interstitial lung diseases (ILDs). Methods: Serum KL-6 level was measured using the chemiluminescent enzyme immunoassay. Statistical analysis was performed for determining the KL-6 concentration of each group. Results: KL-6 level (U/mL) in the ILD group was 1388.321 ± 1943.116, which was higher than that in the control group, showing a significant statistical difference. ROC curve analysis based on the receiver operating characteristic curve showed the optimal cut-off value of 402.5U/mL, sensitivity of 77.4%, specificity of 93.4%, and accuracy of 89.4%; through Chi-square test with the two groups, the positive rate of KL-6 in patients with ILD was proved to be significantly higher than that in the control group. KL-6 level was 1063.00± 504.757 in the idiopathic pulmonary fibrosis (IPF) group, 1346.892 ± 1827.252 in the connective tissue disease-associated interstitial lung disease (CTD-ILD) group, 467.889± 288.859 in the organizing pneumonia (OP) group, 8252.333± 6050.625 in the pulmonary alveolar proteinosis (PAP) group, and 359.200± 392.707 in the sarcoidosis group. The rank sum test showed that the differences were statistically significant. KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group. Conclusion: Serum KL-6 level was confirmed to be highly sensitive, specific, and accurate in the diagnosis of ILD. Subgroup analysis showed that the KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group. [ABSTRACT FROM AUTHOR]

Asthma affects 25 million Americans, and recent advances in treatment are effective for only a portion of severe asthma patients. TREM-1, an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. It is unknown how TREM-1 contributes to allergic asthma pathology. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow–derived eosinophils by incubation with interleukin 33, lipopolysaccharide, or granulocyte-macrophage colony-stimulating factor. Compared to TREM-1− airway eosinophils, TREM-1+ eosinophils were enriched for proinflammatory gene sets, including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 exacerbated airway interleukin (IL) 5 production, airway MUC5AC production, and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis and superoxide generation–related gene sets were enriched in TREM-1+ eosinophils. Consistent with these findings, annexin V and caspase-3/7 staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1− eosinophils in the inflammatory airway. In vitro, Trem1/3−/− bone marrow–derived eosinophils consumed less oxygen than wild-type in response to phorbol myristate acetate, suggesting that TREM-1 promotes superoxide generation in eosinophils. These data reveal protein-level expression of TREM-1 by eosinophils, define a population of TREM-1+ inflammatory eosinophils, and demonstrate that eosinophil TREM-1 restricts key features of type 2 lung inflammation. [ABSTRACT FROM AUTHOR]

Background: Macrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here, we investigate the combination of a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal to induce macrophage phagocytosis of ES cells in vitro and inhibit tumor growth and metastasis in vivo. Methods: Macrophages were derived from human peripheral blood monocytes by granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Flow cytometry- and microscopy-based in-vitro phagocytosis assays were performed to evaluate macrophage phagocytosis of ES cells. Annexin-V assay was performed to evaluate apoptosis. CD47 was knocked out by CRISPR/Cas9 approach. ES cell-based and patient-derived-xenograft (PDX)-based mouse models were utilized to assess the effects of MAG and/or DOX on ES tumor development and animal survival. RNA-Seq combined with CIBERSORTx analysis was utilized to identify changes in tumor cell transcriptome and tumor infiltrating immune cell profiling in MAG and/or DOX treated xenograft tumors. Results: We found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (p < 0.01) and had significant effect on reducing tumor burden (p < 0.01) and increasing survival in NSG mouse model (p < 0.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (p < 0.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (p < 0.01) and significantly decreased tumor burden (p < 0.01) and lung metastasis (p < 0.0001) and extended animal survival in vivo in two different mouse models of ES (p < 0.0001). Furthermore, we identified CD38, CD209, CD163 and CD206 as potential markers for ES-phagocytic macrophages. Moreover, we found increased M2 macrophage infiltration and decreased expression of Cd209 in the tumor microenvironment of MAG and DOX combinatorial therapy treated tumors. Conclusions: By turning "two keys" simultaneously to reactivate macrophage phagocytic activity, our data demonstrated an effective and highly translatable alternative therapeutic approach utilizing innate (tumor associated macrophages) immunotherapy against high-risk metastatic ES. [ABSTRACT FROM AUTHOR]

Allergen-stimulated basophils secrete leukotriene C4 (LTC4), acting on the cysteinyl leukotriene receptor (CysLTR2) in neurons, activating neuronal signaling that mediates acute itch exacerbation in atopic dermatitis (AD). CXCR2+ basophils recruited to the kidney release interleukin (IL)-6, which recruits type 17 T helper (T H 17) cells, contributing to the pathogenesis of renal fibrosis. Targeting CXCR2+ basophils might be considered a therapeutic strategy in renal fibrosis. In mouse bone marrow granulocyte–monocyte progenitors, high expression of E-cadherin on myeloid progenitors marks an early population of pro-basophil and mast cell progenitors, which is committed to the basophil and mast cell fates. Lung-resident basophils establish a lung-specific function influenced by IL-33 and granulocyte–macrophage colony-stimulating factor (GM-CSF), which are crucial for maintaining alveolar macrophage development and function. Basophils serve as multifunctional regulators in either maintaining homeostasis or contributing to disease pathogenesis. Recent findings highlight their diverse lineage-priming stages and involvement in disorders across organs such as the skin, lung, kidney, and heart, suggesting systemic influence and potential heterogeneous subpopulations. However, the underlying mechanisms of basophil differentiation and heterogeneity remain unclear, meriting further investigation, particularly when developing possible therapeutic strategies for relevant disorders. Basophils, rare granulocytes, have long been acknowledged for their roles in type 2 immune responses. However, the mechanisms by which basophils adapt their functions to diverse mammalian microenvironments remain unclear. Recent advancements in specific research tools and single-cell-based technologies have greatly enhanced our understanding of basophils. Several studies have shown that basophils play a role in maintaining homeostasis but can also contribute to pathology in various tissues and organs, including skin, lung, and others. Here, we provide an overview of recent basophil research, including cell development, characteristics, and functions. Based on an increasing understanding of basophil biology, we suggest that the precise targeting of basophil features might be beneficial in alleviating certain pathologies such as asthma, atopic dermatitis (AD), and others. [ABSTRACT FROM AUTHOR]

Background: Bronchoalveolar lavage (BAL) is a widely used diagnostic procedure in pulmonology, yet its utility across diverse pulmonary conditions warrants further evaluation. Methods: This prospective study involved 47 patients suspected of having pulmonary diseases, where conventional diagnostics were inconclusive. BAL was performed to diagnose infections, interstitial lung diseases (ILDs), and malignancies, with subsequent analysis for sensitivity, specificity, and diagnostic yield. Results: BAL identified tuberculosis in 15 cases (31.9%), bacterial pneumonia in 10 (21.3%), fungal infections in 2 (4.3%), ILDs in 5 (10.6%), and malignancies in 6 (12.8%). The procedure demonstrated high diagnostic accuracy with sensitivity and specificity rates notably high across conditions: tuberculosis (88.2%, 97.0%; p<0.001), bacterial pneumonia (76.9%, 98.5%; p<0.001), fungal infections (66.7%, 99.0%; p=0.005), ILDs (83.3%, 96.7%; p=0.001), and malignancies (85.7%, 97.5%; p<0.001). Conclusion: The study highlights BAL's substantial diagnostic value in pulmonary diseases, reinforcing its role in enhancing diagnostic accuracy and informing therapeutic strategies. BAL emerges as an indispensable tool in the early detection and management of complex lung diseases. [ABSTRACT FROM AUTHOR]

Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte−macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies. [ABSTRACT FROM AUTHOR]

Background: Alkaptonuria is a rare congenital metabolic disorder characterized by homogentisic acid accumulation in body cartilage and connective tissues due to a deficient homogentisic acid dioxygenase enzyme. This disorder manifests in various clinical symptoms, including spondyloarthropathy, ocular and dermal pigmentation, genitourinary tract obstruction by ochronosis stones, and cardiovascular system involvement. Cardiac ochronosis is a rare manifestation of alkaptonuria that may present as aortic stenosis, sometimes accompanied by other cardiovascular complications. Case presentation: We report an unexpected case of ochronosis diagnosed during cardiac surgery. Due to the fragile, thin, and atheromatous nature of the ascending aorta in patients with ochronosis, we opted for a sutureless aortic valve replacement procedure. This approach appears to be more suitable for patients with ochronosis. Conclusions: Although cardiac ochronosis is rare, surgeons should remain vigilant and consider the possibility of this condition when examining patients with aortic valve stenosis, paying close attention to the clinical manifestations of alkaptonuria. [ABSTRACT FROM AUTHOR]

Pulmonary edema refers to the accumulation of excessive fluid in the alveolar walls and alveolar spaces of the lungs. It is a life-threatening condition with a high mortality rate and requires immediate assessment and management. Use of intravenous nitroglycerin has been advocated for such cases. The authors present a case series of 3 patients who presented to the emergency department with sympathetic crashing acute pulmonary edema (SCAPE) and were managed with high-dose intravenous nitroglycerin and bilevel positive airway pressure support using the SCAPE treatment protocol, leading to early correction of blood pressure, avoidance of endotracheal intubation, and no episodes of hypotension or rebound hypertension. The authors recommend emergency physicians utilize the SCAPE treatment protocol while managing patients with SCAPE. [ABSTRACT FROM AUTHOR]

We report a case of neurogenic pulmonary edema (NPE) caused by an intraparenchymal bleed following a fall. We review the literature regarding the pathophysiology, clinical presentation, and management of neurogenic pulmonary edema. Pulmonary edema is the accumulation of fluid within the alveolar and interstitial spaces; one of the lesserappreciated causes is neurogenic. NPE occurs following acute central nervous system (CNS) injury and is often rapidly developing in nature. Common insults include epileptic seizures, traumatic brain injury, intracranial hemorrhage, and pediatric encephalitis The low prevalence of NPE and the distracting primary disease often divert physicians' attention away from its prompt diagnosis, this is regrettable as up to 35% of patients with intracranial hemorrhage have NPE. NPE is a prevalent yet underdiagnosed disease. The underlying mechanisms are still debatable and much more research is required to diagnose and treat the condition effectively. Treatment is mainly supportive with judicious use of invasive ventilation and management of primary pathology. We aimed to refresh the knowledge of young clinicians regarding NPE. [ABSTRACT FROM AUTHOR]

Background Nocardiosis, a bacterial opportunistic infection caused by Nocardia spp, has recently been reported in patients with anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, but insufficient data are available about disease presentation, outcomes, and occurrence of autoimmune pulmonary alveolar proteinosis (aPAP) in this population. Methods We performed a prospective, multicenter, nationwide study in France and included patients with a Nocardia infection who had anti-GM-CSF autoantibodies. We describe their clinical, microbiological, and radiological characteristics, and their outcome at 1 year of follow-up. Results Twenty patients (18 [90%] male) were included, with a median age of 69 (interquartile range, 44–75) years. The organs most frequently involved were the brain (14/20 [70%]) and the lung (12/20 [60%]). Half of the infections were disseminated (10/20 [50%]). Nocardia identification was predominantly made in abscess fluid (17/20 [85%]), among which 10 (59%) were brain abscesses. The 1-year all-cause mortality was 5% (1/20), and only 1 case of aPAP (1/20 [5%]) occurred during the follow-up period. Conclusions Nocardiosis with anti-GM-CSF autoantibodies is associated with a low mortality rate despite a high incidence of brain involvement. Although the occurrence of aPAP was infrequent during the 1-year follow-up period, long-term clinical data are needed to fully understand the potential relationship between nocardiosis, anti-GM-CSF autoantibodies, and aPAP. [ABSTRACT FROM AUTHOR]

Background: Severe cases of COVID‐19 often lead to the development of acute respiratory syndrome, a critical condition believed to be caused by the harmful effects of SARS‐CoV‐2 on type II alveolar cells. These cells play a crucial role in producing pulmonary surfactants, which are essential for proper lung function. Specifically focusing on surfactant proteins, including Surfactant protein A (SP‐A), Surfactant protein B, Surfactant protein C, and Surfactant protein D (SP‐D), changes in the levels of pulmonary surfactants may be a significant factor in the pathological changes seen in COVID‐19 infection. Objective: This study aims to gain insights into surfactants, particularly their impacts and changes during COVID‐19 infection, through a comprehensive review of current literature. The study focuses on the function of surfactants as prognostic markers, diagnostic factors, and essential components in the management and treatment of COVID‐19. Finding: In general, pulmonary surfactants serve to reduce the surface tension at the gas–liquid interface, thereby significantly contributing to the regulation of respiratory mechanics. Additionally, these surfactants play a crucial role in the innate immune system within the pulmonary microenvironment. Within the spectrum of COVID‐19 infections, a compelling association is observed, characterized by elevated levels of SP‐D and SP‐A across a range of manifestations from mild to severe pneumonia. The sudden decline in respiratory function observed in COVID‐19 patients may be attributed to the decreased synthesis of surfactants by type II alveolar cells. Conclusion: Collectin proteins such as SP‐A and SP‐D show promise as biomarkers, offering potential avenues for predicting and monitoring pulmonary alveolar injury in the context of COVID‐19. This clarification enhances our understanding of the molecular complexities contributing to respiratory complications in severe COVID‐19 cases, providing a foundation for targeted therapeutic approaches using surfactants and refined clinical management strategies. Highlights: SARS‐CoV‐2 affects alveolar type II cells, which limits the synthesis and secretion of pulmonary surfactant into the alveolar space, ultimately leading to lung failure.Surfactant proteins A and D, as members of the lectin‐C family, play a prominent role in COVID‐19 infection. SP‐D exhibits a higher affinity for binding the spike protein of SARS‐CoV‐2 compared to SP‐A.In COVID‐19 infection, the levels of SP‐D and SP‐A were significantly higher in cases of mild to moderate pneumonia than in severe or critical cases. [ABSTRACT FROM AUTHOR]

A 46‐year‐old male was treated with corticosteroids for nonspecific interstitial pneumonia (NSIP). He was referred to our hospital and admitted for worsening dyspnea and diffuse ground‐glass opacity on chest computed tomography (CT) during corticosteroid treatment. Gottron's sign was observed, and the patient was diagnosed with clinically amyopathic dermatomyositis on skin biopsy. We increased the corticosteroid dose and added immunosuppressive agents; however, the opacity on the chest CT worsened. Based on periodic‐acid‐Schiff‐positive granular material in the bronchoalveolar lavage fluid and the presence of anti‐GM‐CSF antibodies, the patient was diagnosed with autoimmune pulmonary alveolar proteinosis (APAP). The concentration of anti‐GM‐CSF antibodies in preserved serum was also elevated when the patient was diagnosed with NSIP. Thus, we assumed that NSIP and APAP coexisted, and that APAP manifested during immunosuppressive therapy. When exacerbation is observed during the treatment of interstitial pneumonia with immunosuppressive agents, it is necessary to consider APAP. [ABSTRACT FROM AUTHOR]

Educational Aims Cystic fibrosis (CF) is a monogenic disorder cause by mutations in the CF Transmembrane Regulator (CFTR) gene. The prognosis of cystic fibrosis has been transformed by the discovery of highly effective modulator therapies (HEMT). Treatment has changed from reactive therapy dealing with complications of the disease to pro-active correction of the underlying molecular functional abnormality. This has come about by discovering the detailed biology of the different CF molecular sub-endotypes; the development of biomarkers to assess response even in mild disease or young children; the performance of definitive large randomised controlled trials in patients with a common mutation and the development of in vitro testing systems to test efficacy in those patients with rare CFTR mutations. As a result, CF is now an umbrella term, rather than a specific diagnostic label; we have moved from clinical phenotypes to molecular subendotypes. Children's Interstitial Lung Diseases (chILDs) comprise more than 200 entities, and are a diverse group of diseases, for an increasing number of which an underlying gene mutation has been discovered. Many of these entities are umbrella terms, such as pulmonary alveolar proteinosis or hypersensitivity pneumonitis, for each of which there are multiple and very different endotypes. Even those chILDs for which a specific gene mutation has been discovered comprise, as with CF, different molecular subendotypes likely mandating different therapies. For most chILDs, current treatment is non-specific (corticosteroids, azithromycin, hydroxychloroquine). The variability of the different entities means that there is little evidence for the efficacy of any treatment. This review considers how some of the lessons of the success story of CF are being applied to chILD, thus opening the opportunities for truly personalised medicine in these conditions. Advances in knowledge in the molecular biology of surfactant protein C and Adenosine triphosphate binding cassette subfamily A member 3 (ABCA3), and the possibilities of discovering novel therapies by in vitro studies will especially be highlighted. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colonystimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/ APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy. [ABSTRACT FROM AUTHOR]