Livedoid Vasculopathy with Severe Debilitating Neuropathy in a Prior Professional Athlete.

Livedoid vasculopathy (LV) can be a challenging diagnosis with an interesting pathophysiology. LV is an uncommon diagnosis that can be easily mistaken for more common skin conditions, especially in a person of color who may be underrepresented in pathology images used in medical education. LV has an average of five years from initial presentation to diagnosis, possibly due to providers not having it on their differential for lower extremity ulcerations. Prolonged time to diagnosis can potentially lead to life-changing complications. We present a case of a former professional sprinter who became debilitated by neuropathy secondary to complications from LV. He was seen multiple times and had an extensive work-up exploring a broad differential including autoimmune etiologies, hypercoagulable disorders, neuropathies, and other vascular disorders before reaching the diagnosis. This case emphasizes the importance of early diagnosis and treatment with a multidisciplinary team to help prevent the progression of these symptoms. We break down an extensive work-up that involves a multidisciplinary team including dermatology, hematology, neurology, rheumatology, and vascular surgery. This case will also highlight examples of LV in a patient with a dark skin complexion, which can be challenging to find in current literature. We additionally show images that demonstrate many of the classic pathologic findings associated with LV and how those can help lead to the diagnosis along with detailed descriptions of those findings. Classic physical exam findings including atrophic blanche and lower extremity ulcerations are highlighted. We also review LV's history, diagnosis, and treatment to help readers achieve a better understanding of the disease.

Coordinated nasal mucosa-mediated immunity accelerates recovery from COVID-19.

Introduction: Understanding the interplay of immune mediators in relation to clinical outcomes during acute infection has the potential to highlight immune networks critical to symptom recovery. The objective of the present study was to elucidate the immune networks critical to early symptom resolution following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: In a community-based randomised clinical trial comparing inhaled budesonide against usual care in 139 participants with early onset SARS-CoV-2 (the STOIC study; clinicaltrials.gov identifier NCT04416399), significant clinical deterioration (reported need for urgent care, emergency department visit, hospitalisation: the primary outcome), self-reported symptom severity (Influenza Patient-Reported Outcome questionnaire) and immune mediator networks were assessed. Immune mediator networks were determined using pre-defined mathematical modelling of immune mediators, determined by the Meso Scale Discovery U-Plex platform, within the first 7 days of SARS-CoV-2 infection compared to 22 healthy controls. Results: Interferon- and chemokine-dominant networks were associated with high viral burden. Elevated levels of the mucosal network (chemokine (C-C motif) ligand (CCL)13, CCL17, interleukin (IL)-33, IL-5, IL-4, CCL26, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor) was associated with a mean 3.7-day quicker recovery time, with no primary outcome events, irrespective of treatment arm. This mucosal network was associated with initial nasal and throat symptoms at day 0. Conclusion: A nasal immune network is critical to accelerated recovery and improved patient outcomes in community-acquired viral infections. Overall, early prognostication and treatments aimed at inducing epithelial responses may prove clinically beneficial in enhancing early host response to virus.

Identifying priority sites for whale shark ship collision management globally.

The expansion of the world's merchant fleet poses a great threat to the ocean's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark (Rhincodon typus) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation" sites are of significant ecological, socio-economic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world (>50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.

Paradoxical eosinophilic and cytokine responses to oral corticosteroid treatment in patients with asthma exacerbations.

Background: Thymic stromal lymphopoietin (TSLP) orchestrates eosinophilic inflammation, which may increase during asthma exacerbations. In contrast, microRNA-1 (miR-1) inhibits TSLP-mediated eosinophil trafficking in lung endothelium. Whether the balance of TSLP and miR-1 levels determines the response to oral corticosteroids (OCSs) during the treatment of asthma exacerbations remains unknown. Objective: Our aim was to investigate the involvement of TSLP/miR-1 axis in inflammatory response to OCS treatment for asthma exacerbations. Methods: We measured the concentrations of TSLP and other inflammatory cytokines and miR-1 expression during acute asthma exacerbations treated with standard OCSs in a real-life setting. A total of 28 consecutive patients with acute asthma exacerbations treated with OCS (prednisolone 30 mg/d) for 1 week at the emergency department were studied prospectively. Steroid responders were identified by a significant reduction in blood eosinophil counts, whereas paradoxical responders (PRs) showed no markedly decreased or even increased absolute blood eosinophil counts after OCS treatment. Differential white blood cell counts, blood cytokine levels, and miR-1 expression within and between groups were compared before and after OCS treatment. The baseline cytokine concentrations in both groups were compared with those of patients with stable asthma. Results: OCS treatment significantly reduced TSLP levels in steroid responders, whereas this effect did not occur in PRs (P = .006 and P = .742, respectively). In contrast, miR-1 expression was unchanged in steroid responders in response to OCS, whereas it was markedly reduced in the PRs, despite higher expression at baseline than in patients with stable asthma, which may account for slower resolution of the exacerbation. Conclusions: In some asthmatic patients with acute exacerbations who do not suppress eosinophils after a course of OCS, there is a paradoxical decrease in plasma miR-1 level and increase in TSLP level versus in steroid responders, which may result in slower clinical recovery.

Cefepime-Induced Generalized Fixed Drug Eruption With Morbilliform Rash.

Fixed drug eruption (FDE) is a cutaneous reaction that characteristically recurs in the same locations upon re-exposure to the offending drug(s). The typical presentation of FDEs is single or multiple violaceous plaques with hyperpigmentation due to inflammation. The causative agents for FDEs include antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, barbiturates, and anticonvulsants. We present an interesting case of a generalized fixed drug eruption secondary to cefepime that resolved with the cessation of the offending drug and the institution of antihistamines and topical steroids.

Small airway fibroblasts from patients with chronic obstructive pulmonary disease exhibit cellular senescence.

Small airway disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodeling. Parenchymal-derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAFs) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD. To investigate the senescent and fibrotic phenotype of SAF in COPD, SAFs were isolated from nonsmoker, smoker, and COPD lung resection tissue (n = 9-17 donors). Senescence and fibrotic marker expressions were determined using iCELLigence (proliferation), qPCR, Seahorse assay, and ELISAs. COPD SAFs were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent vs. 10% smallest/nonautofluorescent). The phenotype of the senescence-enriched population was investigated using RNA sequencing and pathway analysis. Markers of senescence were observed in COPD SAFs, including senescence-associated ß-galactosidase, SASP release, and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell sorting to enrich senescent COPD SAFs. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis, and mitochondrial dysfunction pathways. These data suggest COPD SAFs are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding of cellular senescence in SAFs may lead to potential therapies to limit SAD progression.NEW & NOTEWORTHY Fibroblasts and senescence are thought to play key roles in the pathogenesis of small airway disease and COPD; however, the characteristics of small airway-derived fibroblasts are not well explored. In this study we isolate and enrich the senescent small airway-derived fibroblast (SAF) population from COPD lungs and explore the pathways driving this phenotype using bulk RNA-seq.

Rational use of inhaled corticosteroids for the treatment of COPD: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Inhaled corticosteroids (ICS) are a type of medication delivered via an inhaler device that are commonly used in the treatment of asthma. ICS can also be used to treat chronic obstructive pulmonary disease (COPD), a progressive respiratory condition in which the lungs become worse over time. However, unlike in asthma, ICS are only effective in a small proportion of people with COPD. ICS can cause significant side effects in people with COPD, including pneumonia. Because of this, guidelines written by COPD experts recommend that ICS should largely be prescribed to people with COPD whose symptoms flare up frequently and become difficult to manage (episodes known as exacerbations). Despite this guidance, records collected from routine clinical practice suggest that many healthcare professionals prescribe ICS to people with COPD who do not have frequent exacerbations, putting them at unnecessary risk of side effects. The over-prescription of ICS in COPD may partly be due to the recent introduction of single-inhaler combination therapies, which combine ICS with other medicines (bronchodilators). This 'one inhaler for all' approach is a concerning trend as it goes against global COPD treatment guidelines, which recommend ICS use in only a small proportion of people. This is a plain language summary of a review article originally published in the journal NPJ Primary Care Respiratory Medicine. In this review, we investigate the benefits and risks of ICS use in COPD. Using data from both randomized controlled trials (RCTs) and observational studies, we explain which people benefit from ICS use, and why health regulatory bodies have concluded that ICS do not help people with COPD to live longer. Lastly, we provide practical guidance for doctors and people with COPD regarding when ICS should be prescribed and when they should be withdrawn.

Endogenous inhibitory mechanisms in asthma.

Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E2, prostaglandin I2, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma.

DEL-1, as an anti-neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma.

BACKGROUND: Neutrophil migration into the airways is a key process in neutrophilic asthma. Developmental endothelial locus-1 (DEL-1), an extracellular matrix protein, is a neutrophil adhesion inhibitor that attenuates neutrophilic inflammation. METHODS: Levels of DEL-1 were measured in exhaled breath condensate (EBC) and serum in asthma patients by ELISA. DEL-1 modulation of neutrophil adhesion and transepithelial migration was examined in a co-culture model in vitro. The effects of DEL-1-adenoviral vector-mediated overexpression on ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma were studied in mice in vivo. RESULTS: DEL-1 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients. Serum DEL-1 concentrations were reduced in patients with severe asthma compared with normal subjects (567.1 ± 75.3 vs. 276.8 ± 29.36 pg/mL, p < .001) and were negatively correlated to blood neutrophils (r = -0.2881, p = .0384) and neutrophil-to-lymphocyte ratio (NLR) (r = -0.5469, p < .0001). DEL-1 concentrations in the EBC of severe asthmatic patients (113.2 ± 8.09 pg/mL) were also lower than normal subjects (193.0 ± 7.61 pg/mL, p < .001) and were positively correlated with the asthma control test (ACT) score (r = 0.3678, p = .0035) and negatively related to EBC IL-17 (r = -0.3756, p = .0131), myeloperoxidase (MPO) (r = -0.5967, p = .0055), and neutrophil elastase (NE) (r = -0.5488, p = .0009) expression in asthma patients. Neutrophil adhesion and transepithelial migration in asthma patients were associated with LFA-1 binding to ICAM-1 and inhibited by DEL-1. DEL-1 mRNA and protein expression in human bronchial epithelial cells were regulated by IL-17. Exogenous DEL-1 inhibited IL-17-enhanced neutrophil adhesion and migration. DEL-1 expression was decreased while neutrophil infiltration was increased in the airway of a murine model of neutrophilic asthma. This was prevented by DEL-1 overexpression. CONCLUSIONS: DEL-1 down-regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma.

Senotherapy for lung diseases.

Increasing evidence suggests that there is acceleration of lung ageing in chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), with the accumulation of senescent cells in the lung. Senescent cells fail to repair tissue damage and release an array of inflammatory proteins, known as the senescence-associated secretory phenotype, which drive further senescence and disease progression. This suggests that targeting cellular senescence with senotherapies may treat the underlying disease process in COPD and IPF and thus reduce disease progression and mortality. Several existing or future drugs may inhibit the development of cellular senescence which is driven by chronic oxidative stress (senostatics), including inhibitors of PI3K-mTOR signalling pathways, antagomirs of critical microRNAs and novel antioxidants. Other drugs (senolytics) selectively remove senescent cells by promoting apoptosis. Clinical studies with senotherapies are already underway in chronic lung diseases.

Rational use of inhaled corticosteroids for the treatment of COPD.

Inhaled corticosteroids (ICS) are the mainstay of treatment for asthma, but their role in chronic obstructive pulmonary disease (COPD) is debated. Recent randomised controlled trials (RCTs) conducted in patients with COPD and frequent or severe exacerbations demonstrated a significant reduction (~25%) in exacerbations with ICS in combination with dual bronchodilator therapy (triple therapy). However, the suggestion of a mortality benefit associated with ICS in these trials has since been rejected by the European Medicines Agency and US Food and Drug Administration. Observational evidence from routine clinical practice demonstrates that dual bronchodilation is associated with better clinical outcomes than triple therapy in a broad population of patients with COPD and infrequent exacerbations. This reinforces guideline recommendations that ICS-containing maintenance therapy should be reserved for patients with frequent or severe exacerbations and high blood eosinophils (~10% of the COPD population), or those with concomitant asthma. However, data from routine clinical practice indicate ICS overuse, with up to 50-80% of patients prescribed ICS. Prescription of ICS in patients not fulfilling guideline criteria puts patients at unnecessary risk of pneumonia and other long-term adverse events and also has cost implications, without any clear benefit in disease control. In this article, we review the benefits and risks of ICS use in COPD, drawing on evidence from RCTs and observational studies conducted in primary care. We also provide a practical guide to prescribing ICS, based on the latest global treatment guidelines, to help primary care providers identify patients for whom the benefits of ICS outweigh the risks.

An Update on Outcomes for COPD Pharmacological Trials: A COPD Investigators Report - Reassessment of the 2008 American Thoracic Society/European Respiratory Society Statement on Outcomes for COPD Pharmacological Trials.

Background: In 2008, a dedicated American Thoracic Society/European Respiratory Society task force published a paper on the possible use and limitations of clinical outcomes and biomarkers to evaluate the impact of pharmacological therapy in patients with chronic obstructive pulmonary disease. Since then, our scientific understanding of chronic obstructive pulmonary disease has increased considerably; there has been a progressive shift from a one-size-fits-all diagnostic and therapeutic approach to a personalized approach; and many new treatments currently in development will require new endpoints to evaluate their efficacy adequately. Objectives: The emergence of several new relevant outcome measures motivated the authors to review advances in the field and highlight the need to update the content of the original report. Methods: The authors separately created search strategies for the literature, primarily based on their opinions and assessments supported by carefully chosen references. No centralized examination of the literature or uniform criteria for including or excluding evidence were used. Measurements and Main Results: Endpoints, outcomes, and biomarkers have been revisited. The limitations of some of those reported in the American Thoracic Society/European Respiratory Society task force document have been highlighted. In addition, new tools that may be useful, especially in evaluating personalized therapy, have been described. Conclusions: Because the "label-free" treatable traits approach is becoming an important step toward precision medicine, future clinical trials should focus on highly prevalent treatable traits, and this will influence the choice of outcomes and markers to be considered. The use of the new tools, particularly combination endpoints, could help better identify the right patients to be treated with the new drugs.

Single cell quantification of microRNA from small numbers of non-invasively sampled primary human cells.

Expression levels of microRNAs (miRNAs) in single cells are low and conventional miRNA detection methods require amplification that can be complex, time-consuming, costly and may bias results. Single cell microfluidic platforms have been developed; however, current approaches are unable to absolutely quantify single miRNA molecules expressed in single cells. Herein, we present an amplification-free sandwich hybridisation assay to detect single miRNA molecules in single cells using a microfluidic platform that optically traps and lyses individual cells. Absolute quantification of miR-21 and miR-34a molecules was achieved at a single cell level in human cell lines and validated using real-time qPCR. The sensitivity of the assay was demonstrated by quantifying single miRNA molecules in nasal epithelial cells and CD3+ T-cells, as well as nasal fluid collected non-invasively from healthy individuals. This platform requires ~50 cells or ~30 µL biofluid and can be extended for other miRNA targets therefore it could monitor miRNA levels in disease progression or clinical studies.

Air pollution and COPD: GOLD 2023 committee report.

Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world.