Diagnostic and therapeutic practices of cardiac sarcoidosis in the United States: a nationwide questionnaire based study.

BACKGROUND AND AIM: Cardiac sarcoidosis (CS) is the second most common cause of death in patients with sarcoidosis and data pertaining to its diagnosis and management is limited. We sought to describe diagnostic modalities and management of patients with CS in the United States, based on a national registry questionnaire. METHODS: We conducted a retrospective study based on a national registry investigating 3,835 respondents to the Foundation for Sarcoidosis Research Questionnaire. The registry includes patient surveys completed between June 2014 and August 2019. Summary and univariate analyses were performed. RESULTS: A total of 394 patients (10.3%) with CS were identified; 57% (n=223) were women and 81% (n=317) were white. The mean (±SD) age at diagnosis was 45 years (±13). CS was the initial presentation of sarcoidosis in 30%. Multiorgan involvement (≥3 organs) was present in 68%. Two-thirds of patients were admitted at least once to the hospital. Cardiac magnetic resonance imaging (74.4%) was the most common diagnostic modality used followed by positron emission tomography (PET) scan (59.3%) and cardiac biopsy (n=52, 13%).  Most patients received corticosteroids (86%) and steroid-sparing medications (61%) including methotrexate (26%) and tumor necrosis factor (TNF) inhibitors (19%). A combined cardioverter defibrillator and pacemaker (39%) was the most common cardiac device implanted. CONCLUSIONS: The prevalence of CS in this cohort was higher than previously described. CS was a common initial presentation of sarcoidosis. The diagnosis was most likely made using cMRI. Steroids, methotrexate and infliximab are the most common medications used. Conduction abnormalities and arrhythmias often occurred.

Sirolimus suppresses circulating fibrocytes in idiopathic pulmonary fibrosis in a randomized controlled crossover trial.

BACKGROUNDFibrocytes are BM-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).METHODSWe conducted a short-term randomized double-blind placebo-controlled crossover pilot trial to assess the safety and tolerability of sirolimus in IPF. Participants were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4-week washout, they were assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment.RESULTSIn the 28 study participants, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing α-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment, with the exception of a small decline in gas transfer during treatment with placebo.CONCLUSIONAs compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in participants with IPF, with an acceptable safety profile.TRIAL REGISTRATIONClinicalTrials.gov, accession no. NCT01462006.FUNDINGNIH R01HL098329 and American Heart Association 18TPA34170486.

Role of Transbronchial Lung Cryobiopsy in the Diagnosis of Interstitial Lung Disease: A Meta-analysis of 68 Studies and 6300 Patients.

BACKGROUND: Diagnosis of interstitial lung disease (ILD) is based on multidisciplinary team discussion (MDD) with the incorporation of clinical, radiographical, and histopathologic information if available. We aim to evaluate the diagnostic yield and safety outcomes of transbronchial lung cryobiopsy (TBLC) in the diagnosis of ILD. METHODS: We conducted a meta-analysis by comprehensive literature search to include all studies that evaluated the diagnostic yields and/or adverse events with TBLC in patients with ILD. We calculated the pooled event rates and their 95% confidence intervals (CIs) for the diagnostic yield by MDD, histopathologic diagnostic yield, and various clinical adverse events. RESULTS: We included 68 articles (44 full texts and 24 abstracts) totaling 6386 patients with a mean age of 60.7±14.1 years and 56% men. The overall diagnostic yield of TBLC to achieve a definite or high-confidence diagnosis based on MDD was 82.3% (95% CI: 78.9%-85.2%) and histopathologic diagnosis of 72.5% (95% CI: 67.7%-76.9%). The overall rate of pneumothorax was 9.6% (95% CI: 7.9%-11%), while the rate of pneumothorax requiring drainage by a thoracostomy tube was 5.3% (95% CI: 4.1%-6.9%). The rate of moderate bleeding was 11.7% (95% CI: 9.1%-14.9%), while the rate of severe bleeding was 1.9% (95% CI: 1.4%-2.6%). The risk of mortality attributed to the procedure was 0.9% (95% CI: 0.7%-1.3%). CONCLUSION: Among patients with undiagnosed or unclassified ILD requiring tissue biopsy for diagnosis, transbronchial cryobiopsy represents a reliable alternative to surgical lung biopsy with decreased incidence of various clinical adverse events.

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis.

Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments and an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme. Nephritic mice had an attenuated expression of SLC7A11, a cystine importer, an impaired glutathione synthesis pathway, and low expression of glutathione peroxidase 4, a ferroptosis inhibitor. Lipidomics of nephritic kidneys confirmed ferroptosis. Using nephrotoxic serum, we induced immune complex glomerulonephritis in congenic mice and demonstrate that impaired iron sequestration within the proximal tubules exacerbates ferroptosis. Lupus nephritis patient serum rendered human proximal tubular cells susceptibility to ferroptosis which was inhibited by Liproxstatin-2, a novel ferroptosis inhibitor. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in human and murine lupus nephritis.

3D Single-Breath Chemical Shift Imaging Hyperpolarized Xe-129 MRI of Healthy, CF, IPF, and COPD Subjects.

3D Single-breath Chemical Shift Imaging (3D-SBCSI) is a hybrid MR-spectroscopic imaging modality that uses hyperpolarized xenon-129 gas (Xe-129) to differentiate lung diseases by probing functional characteristics. This study tests the efficacy of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects-16 healthy, 11 idiopathic pulmonary fibrosis (IPF), 13 cystic fibrosis (CF), and 5 chronic obstructive pulmonary disease (COPD)-were given 1/3 forced vital capacity (FVC) of hyperpolarized Xe-129, inhaled for a ~7 s MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (R = -0.74). FEV1 predicted correlated well with RBC/Gas ratio (R = 0.67). COPD and IPF had significantly higher Tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated Tissue/RBC ratio, shorter Tissue T2* relaxation, and greater RBC chemical shift. 3D-SBCSI may be helpful in the detection and characterization of pulmonary disease, following treatment efficacy, and predicting disease outcomes.

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. METHODS: Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is "cross talk" between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. RESULTS: AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. CONCLUSIONS: The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.

Computational Modeling of Macrophage Iron Sequestration during Host Defense against Aspergillus.

Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in aspergillosis, we generated a transcriptomic time series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2 to 4 h after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of transferrin receptor-1 (TfR1) after fungal recognition, independent of the iron regulatory protein-labile iron pool (IRP-LIP) system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis. IMPORTANCE Invasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.

Labile iron accumulation augments T follicular helper cell differentiation.

T follicular helper (Tfh) cells are a subset of CD4+ T cells that are essential in the pathogenesis of systemic lupus erythematosus (SLE). Notably, iron is required for activated CD4+ T lymphocytes to sustain high proliferation and metabolism. In this issue of the JCI, Gao et al. showed that CD4+ T cells from patients with SLE accumulated iron, augmenting their differentiation into Tfh cells and correlating with disease activity. Using human cells and murine models, the authors demonstrated that miR-21 was overexpressed in lupus T cells and inhibited 3-hydroxybutyrate dehydrogenase-2 (BDH2). The subsequent loss of BDH2 drove labile iron to accumulate in the cytoplasm and promoted TET enzyme activity, BCL6 gene demethylation, and Tfh cell differentiation. This work identifies a role for iron in CD4+ T cell biology and the development of pathogenic effectors in SLE. We await future investigations that could determine whether modulating iron levels could regulate Tfh cells in human health and disease.

Multi-scale mechanistic modelling of the host defence in invasive aspergillosis reveals leucocyte activation and iron acquisition as drivers of infection outcome.

Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address it, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate seems to be an essential prerequisite for the establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition and leucocyte activation as critical determinants of the fate of the infection.

Aspergillus Utilizes Extracellular Heme as an Iron Source During Invasive Pneumonia, Driving Infection Severity.

BACKGROUND: Depriving microbes of iron is critical to host defense. Hemeproteins, the largest source of iron within vertebrates, are abundant in infected tissues in aspergillosis due to hemorrhage, but Aspergillus species have been thought to lack heme import mechanisms. We hypothesized that heme provides iron to Aspergillus during invasive pneumonia, thereby worsening the outcomes of the infection. METHODS: We assessed the effect of heme on fungal phenotype in various in vitro conditions and in a neutropenic mouse model of invasive pulmonary aspergillosis. RESULTS: In mice with neutropenic invasive aspergillosis, we found a progressive and compartmentalized increase in lung heme iron. Fungal cells cultured under low iron conditions took up heme, resulting in increased fungal iron content, resolution of iron starvation, increased conidiation, and enhanced resistance to oxidative stress. Intrapulmonary administration of heme to mice with neutropenic invasive aspergillosis resulted in markedly increased lung fungal burden, lung injury, and mortality, whereas administration of heme analogs or heme with killed Aspergillus did not. Finally, infection caused by fungal germlings cultured in the presence of heme resulted in a more severe infection. CONCLUSIONS: Invasive aspergillosis induces local hemolysis in infected tissues, thereby supplying heme iron to the fungus, leading to lethal infection.

Clinical Characteristics of Sarcoidosis Patients with Self-Reported Lymphoma: A US Nationwide Registry Study.

PURPOSE: Little is known about the association between sarcoidosis and lymphoma. We aim to determine the prevalence of lymphoma in US sarcoidosis patients and compare the clinical characteristics of patients with and without lymphoma. METHODS: Using a national registry-based study investigating 3560 respondents to the Foundation for Sarcoidosis Research Sarcoidosis Advanced Registry for Cures Questionnaire (FSR-SARC) completed between June 2014 and August 2019, we identified patients who reported the diagnosis of lymphoma following sarcoidosis and randomly selected a computer-generated control sample of sarcoidosis patients with no reported lymphoma with a 2:1 ratio. RESULTS: Among 3560 patients with sarcoidosis, 43 (1.2%) reported developing lymphoma following their sarcoidosis diagnosis. Patients with lymphoma were more likely to be diagnosed with sarcoidosis at a younger age (median, IQR) 40 (27-50) vs 45 (34.8-56, p = 0.017) years, were more likely to be African-Americans OR 95% CI 3.9 (1.6-9.6, p = 0.002), and have low annual income (OR 2.7, 1.1-6.4 p = 0.026). The sarcoidosis-lymphoma group were more likely to have salivary gland (16% vs 5%, p = 0.026) (OR 4; 1.1-14.5) and cutaneous (46% vs 23%, p = 0.023) (OR 2.9; 1.1-7.3) sarcoidosis. They also reported more chronic fatigue (42% vs 23%, p = 0.029), chronic pain (37% vs 13%, p = 0.001), and depression (42% vs 22%, p = 0.019). CONCLUSION: The prevalence of lymphoma reported in sarcoidosis patients is higher than the general population which further supports the possible increased risk of lymphoma in sarcoidosis. Diagnosis of sarcoidosis at a younger age, African-American race, cutaneous, and salivary glands sarcoidosis were associated with lymphoma. Sarcoidosis patients who developed lymphoma reported higher disease burden and more non-organ-specific manifestations.

Evaluation of Regional Lung Function in Pulmonary Fibrosis with Xenon-129 MRI.

Idiopathic pulmonary fibrosis, a pattern of interstitial lung disease, is often clinically unpredictable in its progression. This paper presents hyperpolarized Xenon-129 chemical shift imaging as a noninvasive, nonradioactive method of probing lung physiology as well as anatomy to monitor subtle changes in subjects with IPF. Twenty subjects, nine healthy and eleven IPF, underwent HP Xe-129 ventilation MRI and 3D-SBCSI. Spirometry was performed on all subjects before imaging, and DLCO and hematocrit were measured in IPF subjects after imaging. Images were post-processed in MATLAB and segmented using ANTs. IPF subjects exhibited, on average, higher Tissue/Gas ratios and lower RBC/Gas ratios compared with healthy subjects, and quantitative maps were more heterogeneous in IPF subjects. The higher ratios are likely due to fibrosis and thickening of the pulmonary interstitium. T2* relaxation was longer in IPF subjects and corresponded with hematocrit scores, although the mechanism is not well understood. A lower chemical shift in the red blood cell spectroscopic peak correlated well with a higher Tissue/RBC ratio and may be explained by reduced blood oxygenation. Tissue/RBC also correlated well, spatially, with areas of fibrosis in HRCT images. These results may help us understand the underlying mechanism behind gas exchange impairment and disease progression.

Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis.

Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.

Neutrophil-Derived Tumor Necrosis Factor Drives Fungal Acute Lung Injury in Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) results from deficiency of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase and impaired reactive oxygen species (ROS) generation. This leads to impaired killing of Aspergillus and, independently, a pathologic hyperinflammatory response to the organism. We hypothesized that neutrophil-derived ROS inhibit the inflammatory response to Aspergillus and that acute lung injury in CGD is due to failure of this regulation. Mice with gp91phox deficiency, the most common CGD mutation, had more severe lung injury, increased neutrophilinfiltration, and increased lung tumor necrosis factor (TNF) after Aspergillus challenge compared with wild-types. Neutrophils were surprisingly the predominant source of TNF in gp91phox-deficient lungs. TNF neutralization inhibited neutrophil recruitment in gp91phox-deficient mice and protected from lung injury. We propose that, in normal hosts, Aspergillus stimulates TNF-dependent neutrophil recruitment to the lungs and neutrophil-derived ROS limit inflammation. In CGD, in contrast, recruited neutrophils are the dominant source of TNF, promoting further neutrophil recruitment in a pathologic positive-feedback cycle, resulting in progressive lung injury.

Circulating fibrocytes traffic to the lung in murine acute lung injury and predict outcomes in human acute respiratory distress syndrome: a pilot study.

BACKGROUND: Fibrosis is an integral component of the pathogenesis of acute lung injury and is associated with poor outcomes in patients with acute respiratory distress syndrome (ARDS). Fibrocytes are bone marrow-derived cells that traffic to injured tissues and contribute to fibrosis; hence their concentration in the peripheral blood has the potential to serve as a biomarker of lung fibrogenesis. We therefore sought to test the hypothesis that the concentration and phenotype of circulating fibrocytes in patients with ARDS predicts clinical outcomes. METHODS: For the animal studies, C57Bl/6 mice were infected with experimental Klebsiella pneumoniae in a model of acute lung injury; one-way ANOVA was used to compare multiple groups and two-way ANOVA was used to compare two groups over time. For the human study, 42 subjects with ARDS and 12 subjects with pneumonia (without ARDS) were compared to healthy controls. Chi-squared or Fisher's exact test were used to compare binary outcomes. Survival data was expressed using a Kaplan-Meier curve and compared by log-rank test. Univariable and multivariable logistic regression were used to predict death. RESULTS: In mice with acute lung injury caused by Klebsiella pneumonia, there was a time-dependent increase in lung soluble collagen that correlated with sequential expansion of fibrocytes in the bone marrow, blood, and then lung compartments. Correspondingly, when compared via cross-sectional analysis, the initial concentration of blood fibrocytes was elevated in human subjects with ARDS or pneumonia as compared to healthy controls. In addition, fibrocytes from subjects with ARDS displayed an activated phenotype and on serial measurements, exhibited intermittent episodes of markedly elevated concentration over a median of 1 week. A peak concentration of circulating fibrocytes above a threshold of > 4.8 × 106 cells/mL cells correlated with mortality that was independent of age, ratio of arterial oxygen concentration to the fraction of inspired oxygen, and vasopressor requirement. CONCLUSIONS: Circulating fibrocytes increase in a murine model of acute lung injury and elevation in the number of these cells above a certain threshold is correlated with mortality in human ARDS. Therefore, these cells may provide a useful and easily measured biomarker to predict outcomes in these patients.

Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia.

Pulmonary hypertension complicates the care of many patients with chronic lung diseases (defined as Group 3 pulmonary hypertension), yet the mechanisms that mediate the development of pulmonary vascular disease are not clearly defined. Despite being the most prevalent form of pulmonary hypertension, to date there is no approved treatment for patients with disease. Myeloid-derived suppressor cells (MDSCs) and endothelial cells in the lung express the chemokine receptor CXCR2, implicated in the evolution of both neoplastic and pulmonary vascular remodeling. However, precise cellular contribution to lung disease is unknown. Therefore, we used mice with tissue-specific deletion of CXCR2 to investigate the role of this receptor in Group 3 pulmonary hypertension. Deletion of CXCR2 in myeloid cells attenuated the recruitment of polymorphonuclear MDSCs to the lungs, inhibited vascular remodeling, and protected against pulmonary hypertension. Conversely, loss of CXCR2 in endothelial cells resulted in worsened vascular remodeling, associated with increased MDSC migratory capacity attributable to increased ligand availability, consistent with analyzed patient sample data. Taken together, these data suggest that CXCR2 regulates MDSC activation, informing potential therapeutic application of MDSC-targeted treatments.

Sporadic Obliterative Bronchiolitis: Case Series and Systematic Review of the Literature.

OBJECTIVE: To describe the clinical characteristics and outcomes of patients diagnosed with obliterative bronchiolitis (OB) not associated with transplantation or point-source exposures to inhaled toxins. PATIENTS AND METHODS: We compiled all confirmed diagnoses of OB at our institution and analyzed their demographic characteristics, treatments, and outcomes as defined by pulmonary function tests (PFTs) and transplant-free mortality. The study period ranged from July 2007 to August 2017. Histological diagnosis was confirmed by a pathologist, and high-resolution chest computed tomography (CT) scans were reviewed and scored by chest radiologists. We also performed a systematic literature review of sporadic OB series. RESULTS: We identified 19 confirmed cases at our institution and 9 publications in the literature containing 104 patients. In both our series and the literature, patients were disproportionately middle-aged Caucasian women. The disease was idiopathic in 42% and was associated with connective tissue diseases and inhalational exposures in 31% and 15%, respectively. Chest CT showed expiratory air trapping in all patients. Patients were treated with corticosteroids, steroid-sparing agents, and macrolides in 77%, 46%, and 22%, respectively. Over a median follow-up in our series of 1703 days (range, 11-3206 days), PFTs did not change significantly. In all series combined, mortality incidence from any cause was 82/1000 patient-years (95% CI, 65-102). Of 14 patients who died, 3 deaths were due to respiratory failure and 5 were potentially related to complications of immunosuppressive therapy. CONCLUSION: Sporadic OB is a rare disease that is uniformly associated with air trapping on high-resolution chest CT. The diagnosis should be established with surgical biopsy if possible. The illness is not typically progressive.

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension.

Myeloid⁻derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow⁻derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.