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.

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.)

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.

Fit-Tested N95 Masks Combined With Portable High-Efficiency Particulate Air Filtration Can Protect Against High Aerosolized Viral Loads Over Prolonged Periods at Close Range.

BACKGROUND: Healthcare workers (HCWs) are at risk from aerosol transmission of severe acute respiratory syndrome coronavirus 2. The aims of this study were to (1) quantify the protection provided by masks (surgical, fit-testFAILED N95, fit-testPASSED N95) and personal protective equipment (PPE), and (2) determine if a portable high-efficiency particulate air (HEPA) filter can enhance the benefit of PPE. METHODS: Virus aerosol exposure experiments using bacteriophage PhiX174 were performed. An HCW wearing PPE (mask, gloves, gown, face shield) was exposed to nebulized viruses (108 copies/mL) for 40 minutes in a sealed clinical room. Virus exposure was quantified via skin swabs applied to the face, nostrils, forearms, neck, and forehead. Experiments were repeated with a HEPA filter (13.4 volume-filtrations/hour). RESULTS: Significant virus counts were detected on the face while the participants were wearing either surgical or N95 masks. Only the fit-testPASSED N95 resulted in lower virus counts compared to control (P = .007). Nasal swabs demonstrated high virus exposure, which was not mitigated by the surgical/fit-testFAILED N95 masks, although there was a trend for the fit-testPASSED N95 mask to reduce virus counts (P = .058). HEPA filtration reduced virus to near-zero levels when combined with fit-testPASSED N95 mask, gloves, gown, and face shield. CONCLUSIONS: N95 masks that have passed a quantitative fit-test combined with HEPA filtration protects against high virus aerosol loads at close range and for prolonged periods of time.

Pulmonary actinomycosis and polymicrobial empyema in a patient with ABPA and bronchocoele.

We present a 43-year-old woman, with a history of allergic bronchopulmonary aspergillosis and a chronic bronchocoele, who was admitted to hospital with an infection of the bronchocoele, progressing to a pulmonary abscess and polymicrobial empyema, following dental extraction and regular Lactobacillus probiotic ingestion. Interval chest imaging following this procedure demonstrated worsening right upper lobe opacities and a right-sided pleural effusion. Bronchoscopies identified copious mucoid secretions and an infected bronchocoele with a right upper lobe airways impaction. Oral cavity organisms including Actinomyces odontolyticus were cultured on bronchial washings. Streptococcus mitis and Lactobacillus rhamnosus were cultured in pleural fluid. Treatment with endoscopic mucoid secretion suctioning; intercostal catheter insertion and therapeutic drainage; and antibiotic, glucocorticoid and anti-IgE therapy resulted in clinical and radiological improvement. Our case illustrates the potential pulmonary complications from oral cavity organisms following tooth extraction and probiotic use in patients with chronic lung disease associated with mucoid lesions and airways obstruction.

Right ventricular end-diastolic volume and outcomes in exacerbations of COPD.

BACKGROUND AND OBJECTIVE: Right ventricular (RV) volumes are crucial outcome determinants in pulmonary diseases. Little is known about the associations of RV volumes during hospitalized acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to ascertain associations of RV end-diastolic volume indexed to body surface area (RVEDVI) during hospitalized AECOPD and its relationship with mortality in long-term follow-up. METHODS: This is a prospective observational cohort study (December 2013-November 2019, ACTRN12617001562369) using dynamic retrospective ECG-gated computed tomography during hospitalized AECOPD. RVEDVI was defined as normal or high using Framingham Offspring Cohort values. Cox regression determined the prognostic relevance of RVEDVI for death. RESULTS: A total of 148 participants (70 ± 10 years [mean ± SD], 88 [59%] men) were included, of whom 75 (51%) had high RVEDVI. This was associated with more frequent hospital admissions in the 12 months before admission (52/75 [69%] vs. 38/73 [52%], p = 0.04) and higher breathlessness (modified Medical Research Council score, 2.9 ± 1.3 vs. 2.4 ± 1.2, p = 0.007). During follow-up, high RVEDVI was associated with greater mortality (log-rank p = 0.001). In univariable Cox regression, increasing RVEDVI was associated with higher mortality (hazard ratio [HR]: 1.02 per ml/m2 ; 95% CI: 1.01, 1.03; p = 0.001). In multivariable Cox regression, RVEDVI was independently associated with mortality (HR: 1.01 per ml/m2 ; 95% CI: 1.00, 1.03; p = 0.050) at a borderline significance level. Adding RVEDVI to three COPD mortality prediction systems improved model fit (pooled chi-square test [BODE: p = 0.05, ADO: p = 0.04, DOSE: p = 0.02]). CONCLUSION: In patients with hospitalized AECOPD, higher RV end-diastolic volume was associated with worse acute clinical parameters and greater mortality.

Swallow patterns associated with aspiration in COPD: a prospective analysis.

Few studies have examined swallow of large liquid volumes representative of everyday drinking in COPD. Swallow by cup-drinking was evaluated in COPD using videofluoroscopy. Slower swallow was linked to aspiration indicating altered swallow habits in COPD. https://bit.ly/3wpdnO3.

MULTI-PHACET: multidimensional clinical phenotyping of hospitalised acute COPD exacerbations.

BACKGROUND: The generic term "exacerbation" does not reflect the heterogeneity of acute exacerbations of COPD (AECOPD). We utilised a novel algorithmic strategy to profile exacerbation phenotypes based on underlying aetiologies. METHODS: Patients hospitalised for AECOPD (n=146) were investigated for aetiological contributors summarised in a mnemonic acronym ABCDEFGX (A: airway virus; B: bacterial; C: co-infection; D: depression/anxiety; E: eosinophils; F: failure (cardiac); G: general environment; X: unknown). Results from clinical investigations were combined to construct AECOPD phenotypes. Relationships to clinical outcomes were examined for both composite phenotypes and their specific aetiological components. Aetiologies identified at exacerbation were reassessed at outpatient follow-up. RESULTS: Hospitalised AECOPDs were remarkably diverse, with 26 distinct phenotypes identified. Multiple aetiologies were common (70%) and unidentifiable aetiology rare (4.1%). If viruses were detected (29.5%), patients had longer hospitalisation (7.7±5.6 versus 6.0±3.9 days, p=0.03) despite fewer "frequent exacerbators" (9.3% versus 37%, p=0.001) and lower mortality at 1 year (p=0.03). If bacterial infection was found (40.4%), patients were commonly "frequent exacerbators" (44% versus 18.4%, p=0.001). Eosinophilic exacerbations (28%) were associated with lower pH (7.32±0.06 versus 7.36±0.09, p=0.04), higher venous carbon dioxide tension (P vCO2 ) (53.7±10.5 versus 48.8±12.8, p=0.04), greater noninvasive ventilation (NIV) usage (34.1% versus 18.1%) but shorter hospitalisation (4 (3-5) versus 6 (4-9) days, p<0.001) and lower infection rates (41.4% versus 80.9%, p<0.0001). Cardiac dysfunction and severe anxiety/depression were common in both infective and non-infective exacerbations. Characteristics identified at exacerbation often persisted after recovery. CONCLUSIONS: Hospitalised AECOPDs have numerous causes, often in combination, that converge in complex, multi-faceted phenotypes. Clinically important differences in outcomes suggest that a phenotyping strategy based on aetiologies can enhance AECOPD management.

Treatable cardiac disease in hospitalised COPD exacerbations.

INTRODUCTION: Acute exacerbations of COPD (AECOPD) are accompanied by escalations in cardiac risk superimposed upon elevated baseline risk. Appropriate treatment for coronary artery disease (CAD) and heart failure with reduced ejection fraction (HFrEF) could improve outcomes. However, securing these diagnoses during AECOPD is difficult, so their true prevalence remains unknown, as does the magnitude of this treatment opportunity. We aimed to determine the prevalence of severe CAD and severe HFrEF during hospitalised AECOPD using dynamic computed tomography (CT). METHODS: A cross-sectional study of 148 patients with hospitalised AECOPD was conducted. Dynamic CT was used to identify severe CAD (Agatston score ≥400) and HFrEF (left ventricular ejection fraction ≤40% and/or right ventricular ejection fraction ≤35%). RESULTS: Severe CAD was detected in 51 of 148 patients (35%), left ventricular systolic dysfunction was identified in 12 cases (8%) and right ventricular systolic dysfunction was present in 18 (12%). Clinical history and examination did not identify severe CAD in approximately one-third of cases and missed HFrEF in two-thirds of cases. Elevated troponin and brain natriuretic peptide did not differentiate subjects with severe CAD from nonsevere CAD, nor distinguish HFrEF from normal ejection fraction. Undertreatment was common. Of those with severe CAD, only 39% were prescribed an antiplatelet agent, and 53% received a statin. Of individuals with HFrEF, 50% or less received angiotensin blockers, beta blockers or antimineralocorticoids. CONCLUSION: Dynamic CT detects clinically covert CAD and HFrEF during AECOPD, identifying opportunities to improve outcomes via well-established cardiac treatments.

Prevalence of reduced carbon monoxide transfer factor in smokers with normal spirometry.

We report the prevalence of reduced levels of carbon monoxide transfer factor (TLCO) in middle-aged current or ex-smokers with normal spirometry. Spirometry and TLCO measurements were performed and we identified 391 subjects aged 40-60 years, with a significant smoking history and normal spirometry. In this group, 96 subjects (24%) had TLCO measuremements below the lower limit of normal when using the newly established Global Lung Initiative (GLI) reference equations. The measurement of TLCO should be considered as part of the standard assessment of smokers.

Aspiration and severe exacerbations in COPD: a prospective study.

RATIONALE: Swallow may be compromised in COPD leading to aspiration and adverse respiratory consequences. However, prevalence and consequences of detectable aspiration in stable COPD are not known. OBJECTIVES: We tested the hypothesis that a significant number of patients with stable COPD will have detectable aspiration during swallow (prandial aspiration) and that they would experience more frequent severe acute exacerbations of COPD (AECOPD) over the subsequent 12 months. METHODS: Patients (n=151) with verified and stable COPD of all severities were recruited at a tertiary care hospital. Videofluoroscopy was conducted to evaluate aspiration using Rosenbek's scale for penetration-aspiration during 100-mL cup drinking. AECOPD was documented as moderate (antibiotics and/or corticosteroid treatment) or severe (emergency department admission or hospitalisation) over the ensuing 12 months. MEASUREMENTS AND MAIN RESULTS: Aspiration was observed in 30 out of 151 patients (19.9%, 18 males, 12 females; mean age 72.4 years). Patients with aspiration had more overall AECOPD events (3.03 versus 2 per patient; p=0.022) and severe AECOPD episodes (0.87 versus 0.39; p=0.032). Severe AECOPD occurred in more patients with aspiration (50% of patients versus 18.2%; OR 4.5, CI 1.9-10.5; p=0.001) and with silent aspiration (36.7% versus 18.2%; OR 2.6, CI 1.1-6.2; p=0.045). Aspiration was related to a shorter exacerbation-free period during the 12-month follow-up period (p=0.038). CONCLUSIONS: Prandial aspiration is detectable in a subset of patients with COPD and was predictive of subsequent severe AECOPD. Studies to examine if the association is causal are essential to direct strategies aimed at prevention of aspiration and AECOPD.

Viable virus aerosol propagation by positive airway pressure circuit leak and mitigation with a ventilated patient hood.

INTRODUCTION: Nosocomial transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a major feature of the COVID-19 pandemic. Evidence suggests patients can auto-emit aerosols containing viable viruses; these aerosols could be further propagated when patients undergo certain treatments, including continuous positive airway pressure (PAP) therapy. Our aim was to assess 1) the degree of viable virus propagated from PAP circuit mask leak and 2) the efficacy of a ventilated plastic canopy to mitigate virus propagation. METHODS: Bacteriophage phiX174 (108 copies·mL-1) was nebulised into a custom PAP circuit. Mask leak was systematically varied at the mask interface. Plates containing Escherichia coli host quantified viable virus (via plaque forming unit) settling on surfaces around the room. The efficacy of a low-cost ventilated headboard created from a tarpaulin hood and a high-efficiency particulate air (HEPA) filter was tested. RESULTS: Mask leak was associated with virus contamination in a dose-dependent manner (χ2=58.24, df=4, p<0.001). Moderate mask leak (≥21 L·min-1) was associated with virus counts equivalent to using PAP with a vented mask. The highest frequency of viruses was detected on surfaces <1 m away; however, viable viruses were recorded up to 3.86 m from the source. A plastic hood with HEPA filtration significantly reduced viable viruses on all plates. HEPA exchange rates ≥170 m3·h-1 eradicated all evidence of virus contamination. CONCLUSIONS: Mask leak from PAP may be a major source of environmental contamination and nosocomial spread of infectious respiratory diseases. Subclinical mask leak levels should be treated as an infectious risk. Low-cost patient hoods with HEPA filtration are an effective countermeasure.