Contemporary Concise Review 2023: Asthma.

Asthma research and management needs to meet the priorities of the end user-patients, carers and clinicians. A better understanding of the natural history of asthma and the progression of disease has highlighted the importance of early identification of patients with asthma and the potential role of early intervention. Management of mild asthma requires a consistent approach with the same detail and consideration used when managing severe disease. Evidence around treatable traits approaches continues to evolve, supporting the role of a personalized medicine in asthma. Oral corticosteroid (OCS) stewardship continues to be an urgent issue in asthma management. Strategies to taper OCS doses and the implementation of biologic therapies for their steroid sparing benefits will be important steps to address this problem. The concept of remission in asthma provides an ambitious target and treatment outcome.

Vocal cord dysfunction/inducible laryngeal obstruction cannot be diagnosed from symptoms.

Vocal cord dysfunction/inducible laryngeal obstruction is highly variable. Standard clinical symptoms and questionnaires cannot predict laryngoscopic diagnosis in a "lung disease" population. https://bit.ly/3QUtsbB.

Elevated blood lactate in COPD exacerbations associates with adverse clinical outcomes and signals excessive treatment with ß2 -agonists.

BACKGROUND AND OBJECTIVE: Raised blood lactate secondary to high dose ß2 -agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and ß2 -agonist treatments during AECOPD. METHODS: Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, ß2 -agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with ß2 -agonist dosages. RESULTS: Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV1 (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative ß2 -agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01). CONCLUSION: Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of ß2 -agonists. Raised lactate may indicate excessive ß2 -agonist treatment and should now be investigated as a possible biomarker.

Diagnosis of vocal cord dysfunction/inducible laryngeal obstruction: An International Delphi Consensus Study.

BACKGROUND: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research. OBJECTIVES: We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO. METHODS: We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement. RESULTS: Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO. CONCLUSIONS: This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research.

Vocal cord dysfunction/inducible laryngeal obstruction-2022 Melbourne Roundtable Report.

Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO), is a common condition characterized by breathlessness associated with inappropriate laryngeal narrowing. Important questions remain unresolved, and to improve collaboration and harmonization in the field, we convened an international Roundtable conference on VCD/ILO in Melbourne, Australia. The aims were to delineate a consistent approach to VCD/ILO diagnosis, appraise disease pathogenesis, outline current management and model(s) of care and identify key research questions. This report summarizes discussions, frames key questions and details recommendations. Participants discussed clinical, research and conceptual advances in the context of recent evidence. The condition presents in a heterogenous manner, and diagnosis is often delayed. Definitive diagnosis of VCD/ILO conventionally utilizes laryngoscopy demonstrating inspiratory vocal fold narrowing >50%. Computed tomography of the larynx is a new technology with potential for swift diagnosis that requires validation in clinical pathways. Disease pathogenesis and multimorbidity interactions are complex reflecting a multi-factorial, complex condition, with no single overarching disease mechanism. Currently there is no evidence-based standard of care since randomized trials for treatment are non-existent. Recent multidisciplinary models of care need to be clearly articulated and prospectively investigated. Patient impact and healthcare utilization can be formidable but have largely escaped inquiry and patient perspectives have not been explored. Roundtable participants expressed optimism as collective understanding of this complex condition evolves. The Melbourne VCD/ILO Roundtable 2022 identified clear priorities and future directions for this impactful condition.

Vocal cord dysfunction/inducible laryngeal obstruction: novel diagnostics and therapeutics.

INTRODUCTION: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is an important medical condition but understanding of the condition is imperfect. It occurs in healthy people but often co-exists with asthma. Models of VCD/ILO pathophysiology highlight predisposing factors rather than specific mechanisms and disease expression varies between people, which is seldom appreciated. Diagnosis is often delayed, and the treatment is not evidence based. AREAS COVERED: A unified pathophysiological model and disease phenotypes have been proposed. Diagnosis is conventionally made by laryngoscopy during inspiration with vocal cord narrowing >50% Recently, dynamic CT larynx was shown to have high specificity (>80%) with potential as a noninvasive, swift, and quantifiable diagnostic modality. Treatment entails laryngeal retraining with speech pathology intervention and experimental therapies such as botulinum toxin injection. Multidisciplinary team (MDT) clinics are a novel innovation with demonstrated benefits including accurate diagnosis, selection of appropriate treatment, and reductions in oral corticosteroid exposure. EXPERT OPINION: Delayed diagnosis of VCD/ILO is pervasive, often leading to detrimental treatments. Phenotypes require validation and CT larynx can reduce the necessity for laryngoscopy, thereby fast-tracking diagnosis. MDT clinics can optimize management. Randomized controlled trials are essential to validate speech pathology intervention and other treatment modalities and to establish international standards of care.

Effect of COVID-19 lockdown on body weight in chronic obstructive pulmonary disease.

A series of studies has reported weight gain in association with COVID-19 lockdowns; typically, this research has had short-term follow-up in populations that tended to gain weight. In this study, the effect of prolonged lockdowns on weight was assessed in a population of patients with chronic obstructive pulmonary disease. Before lockdown subjects gained an average of 0.022 kg per month; after lockdown this trend reversed with subjects losing weight at 0.032 kg per month, a trend that was highly significant (P < 0.001).

Computed Tomography Imaging of the Larynx for Diagnosis of Vocal Cord Dysfunction.

BACKGROUND: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathlessness and often mimics or accompanies severe asthma. The disorder occurs intermittently, and the diagnosis is established by using laryngoscopy. Dynamic computed tomography (CT) imaging of the larynx at low-radiation doses has the potential to provide an alternative method to make the diagnosis of VCD/ILO. METHODS: We report two case series: in series A, laryngoscopy (diagnostic standard) and CT imaging of the larynx were each performed within 1 hour of each other (n=31), and in series B, the procedures were performed on separate days 4 to 6 weeks apart (n=72). Diagnosis of VCD/ILO by laryngoscopy used conventional criteria, and diagnosis by CT imaging was based on vocal cord narrowing in excess of a validated normal threshold. In each series, we evaluated the accuracy of CT imaging of the larynx to establish a diagnosis of VCD/ILO compared with laryngoscopy. RESULTS: In series A, the sensitivity of CT imaging of the larynx was 53.8%, and specificity was 88.9%; in series B, the sensitivity of CT imaging of the larynx was 76.2%, and specificity was 93.3%. At a disease prevalence of 30% (which was known to be the case in our clinic), the positive predictive value was 67.5% in series A and 83% in series B. Negative predictive values were 81.8% and 90.1% in series A and B, respectively, and false-positive rates were 11.1% and 6.7%. CONCLUSIONS: When the population prevalence was assumed to be 30%, low-dose CT imaging of the larynx detected VCD/ILO with negative predictive values greater than 80% in both series settings and agreed with each other within 9 percentage points. Positive predictive values for laryngeal CT imaging varied substantially between the settings of the two case series. (Supported by Monash Lung and Sleep Institute and Grant APP ID 1198362 and others.)

Diagnosis of vocal cord dysfunction / inducible laryngeal obstruction-A Delphi study protocol.

INTRODUCTION: Currently there is no consistent and widely accepted approach to the diagnosis of vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO). Harmonised diagnostic methods are vital to enable optimal diagnosis, advance management and enable research. We aim to obtain consensus on how expert clinicians recognise and diagnose VCD/ILO. METHODS AND ANALYSIS: Two-round modified Delphi, with workshop validation. ETHICS AND DISSEMINATION: Institutional Board Review was obtained from the Monash Health Human Research Ethics Committee. The dissemination plan is for presentation and publication. REGISTRATION DETAILS: Registered at Australia and New Zealand Clinical Trials Registry ACTRN12621001520820p.

Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1ß axes bridge innate immunity and epithelial apoptosis to promote emphysema.

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1ß but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1ß and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.

Nuclear Transport of Respiratory Syncytial Virus Matrix Protein Is Regulated by Dual Phosphorylation Sites.

Respiratory syncytial virus (RSV) is a major cause of respiratory infections in infants and the elderly. Although the RSV matrix (M) protein has key roles in the nucleus early in infection, and in the cytoplasm later, the molecular basis of switching between the nuclear and cytoplasmic compartments is not known. Here, we show that protein kinase CK2 can regulate M nucleocytoplasmic distribution, whereby inhibition of CK2 using the specific inhibitor 4,5,6,7-tetrabromobenzo-triazole (TBB) increases M nuclear accumulation in infected cells as well as when ectopically expressed in transfected cells. We use truncation/mutagenic analysis for the first time to show that serine (S) 95 and threonine (T) 205 are key CK2 sites that regulate M nuclear localization. Dual alanine (A)-substitution to prevent phosphorylation abolished TBB- enhancement of nuclear accumulation, while aspartic acid (D) substitution to mimic phosphorylation at S95 increased nuclear accumulation. D95 also induced cytoplasmic aggregate formation, implying that a negative charge at S95 may modulate M oligomerization. A95/205 substitution in recombinant RSV resulted in reduced virus production compared with wild type, with D95/205 substitution resulting in an even greater level of attenuation. Our data support a model where unphosphorylated M is imported into the nucleus, followed by phosphorylation of T205 and S95 later in infection to facilitate nuclear export and cytoplasmic retention of M, respectively, as well as oligomerization/virus budding. In the absence of widely available, efficacious treatments to protect against RSV, the results raise the possibility of antiviral strategies targeted at CK2.