Lung immune incompetency after mild peritoneal sepsis and its partial restoration by type 1 interferon: a mouse model study.

Background: Sepsis is commonly associated with acute respiratory distress syndrome (ARDS). Although the exaggerated inflammation may damage intact lung tissues, a percentage of patients with ARDS are reportedly immunocompromised, with worse outcomes. Herein, using a murine sepsis model, time-course immune reprogramming after sepsis was evaluated to explore whether the host is immunocompromised.

MRI and Blood-based Biomarkers Are Associated With Surgery in Children and Adults With Ileal Crohn's Disease.

Background: Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management.

Methods: This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy.

Protocol to develop human alveolar macrophage-like cells from mononuclear cells or purified monocytes for use in respiratory biology research.

Human alveolar macrophages are a unique myeloid subset critical for understanding pulmonary diseases and are difficult to access. Here, we present a protocol to generate human alveolar macrophage-like (AML) cells from fresh peripheral blood mononuclear cells or purified monocytes. We describe steps for cell isolation, incubation in a defined cocktail of pulmonary surfactant and lung-associated cytokines, phenotype analysis, and validation with human alveolar macrophages.

Disseminated nocardiosis and anti-GM-CSF antibodies.

Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp.

Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients.

Rationale: Whole 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.

Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study.

Background: Recruitment into clinical trials is a challenging process, with as many as 40% of studies failing to meet their target sample sizes. The principles of direct-to-consumer (DTC) advertising rely upon novel marketing strategies. The ability to reach expansive audiences in the web-based realm presents a unique opportunity for researchers to overcome various barriers to enrollment in clinical trials.

A dried blood spot test for diagnosis of autoimmune pulmonary alveolar proteinosis.

Granulocyte/macrophage colony-stimulating factor autoantibodies (GMAbs) mediate the pathogenesis of autoimmune pulmonary alveolar proteinosis (autoimmune PAP) and their quantification in serum by enzyme-linked immunosorbent assay (ELISA) - the serum GMAb test - is the 'gold standard' for diagnosis of autoimmune PAP. Because GMAbs are high in autoimmune PAP and low or undetectable in healthy people, we hypothesized that the ELISA could be adapted for evaluation of blood obtained from the fingertip using a dried blood spot card (DBSC) for specimen collection. Here, we report development of such a method - the DBSC GMAb test - and evaluate its ability to measure GMAb concentration in blood and to diagnose autoimmune PAP.

An exploratory study investigating biomarkers associated with autoimmune pulmonary alveolar proteinosis (aPAP).

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disorder involving production of autoantibodies against endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF). This study aimed to identify biomarkers that could be used to monitor for aPAP, particularly in patients treated with anti-GM-CSF antibodies. This was an exploratory, prospective, observational, single-center study.

Two-year follow-up of exposure, engineering controls, respiratory protection and respiratory health among workers at an indium-tin oxide (ITO) production and reclamation facility.

Objectives: To determine whether engineering controls and respiratory protection had measurable short-term impact on indium exposure and respiratory health among current indium-tin oxide production and reclamation facility workers.

Methods: We documented engineering controls implemented following our 2012 evaluation and recorded respirator use in 2012 and 2014. We measured respirable indium (In) and plasma indium (In) in 2012 and 2014, and calculated change in In (∆In) and In (∆In) by the 13 departments.

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.

Objectives: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission.

Methods: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia).

Autoimmune Pulmonary Alveolar Proteinosis.

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency. It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome. The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years.

Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis.

Objective: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD.

A murine model of hereditary pulmonary alveolar proteinosis caused by homozygous gene disruption.

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder caused by recessive mutations in GM-CSF receptor subunit α/β genes (/, respectively) characterized by impaired GM-CSF-dependent surfactant clearance by alveolar macrophages (AMs) resulting in alveolar surfactant accumulation and hypoxemic respiratory failure. Because hPAP is caused by mutations in most patients, we created an animal model of hPAP caused by gene disruption ( mice) and evaluated the effects on AMs and lungs. Macrophages from mice were unable to bind and clear GM-CSF, did not exhibit GM-CSF signaling, and had functional defects in phagocytosis, cholesterol clearance, and surfactant clearance.

Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial.

Background: In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation.

Methods: This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA.

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.

GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study.

Background: Mortality in patients with COVID-19 pneumonia and systemic hyperinflammation is high. We aimed to examine whether mavrilimumab, an anti-granulocyte-macrophage colony-stimulating factor receptor-α monoclonal antibody, added to standard management, improves clinical outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation.

Methods: This single-centre prospective cohort study included patients aged 18 years or older who were admitted to San Raffaele Hospital (Milan, Italy) with severe COVID-19 pneumonia, hypoxia, and systemic hyperinflammation.

A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment.

Background: Participant recruitment for clinical research studies remains a significant challenge for researchers. Novel approaches to recruitment are necessary to ensure that populations are easier to reach. In the context of rare diseases, social media provides a unique opportunity for connecting with patient groups that have representatively lower diagnosis rates when compared with more common diseases or illness.

Neutrophil extracellular traps activate IL-8 and IL-1 expression in human bronchial epithelia.

Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro.