Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide.

Reduction of the risk of asthma attacks is a major goal of current asthma management. We propose to derive a risk scale predicting asthma attacks based on the blood eosinophil count and exhaled nitric oxide (FeNO). Biomarker-stratified trial-level attack rates were extracted and pooled from the control arms of the Novel START, CAPTAIN, QUEST, Benralizumab Phase 2b, PATHWAY, STRATOS 1-2 and DREAM trials (n=3051). These were used to derive rate ratios and the predicted asthma attack rate for different patient groups. The resultant prototype risk scale shows potential to predict asthma attacks, which may be prevented by anti-inflammatory treatment.

Pneumomediastinum in COVID-19: a phenotype of severe COVID-19 pneumonitis? The results of the United Kingdom (POETIC) survey.

BACKGROUND: There is an emerging understanding that coronavirus disease 2019 (COVID-19) is associated with increased incidence of pneumomediastinum. We aimed to determine its incidence among patients hospitalised with COVID-19 in the United Kingdom and describe factors associated with outcome. METHODS: A structured survey of pneumomediastinum and its incidence was conducted from September 2020 to February 2021. United Kingdom-wide participation was solicited via respiratory research networks. Identified patients had SARS-CoV-2 infection and radiologically proven pneumomediastinum. The primary outcomes were to determine incidence of pneumomediastinum in COVID-19 and to investigate risk factors associated with patient mortality. RESULTS: 377 cases of pneumomediastinum in COVID-19 were identified from 58 484 inpatients with COVID-19 at 53 hospitals during the study period, giving an incidence of 0.64%. Overall 120-day mortality in COVID-19 pneumomediastinum was 195/377 (51.7%). Pneumomediastinum in COVID-19 was associated with high rates of mechanical ventilation. 172/377 patients (45.6%) were mechanically ventilated at the point of diagnosis. Mechanical ventilation was the most important predictor of mortality in COVID-19 pneumomediastinum at the time of diagnosis and thereafter (p<0.001) along with increasing age (p<0.01) and diabetes mellitus (p=0.08). Switching patients from continuous positive airways pressure support to oxygen or high flow nasal oxygen after the diagnosis of pneumomediastinum was not associated with difference in mortality. CONCLUSIONS: Pneumomediastinum appears to be a marker of severe COVID-19 pneumonitis. The majority of patients in whom pneumomediastinum was identified had not been mechanically ventilated at the point of diagnosis.

Should we apply a treatable traits approach to asthma care?

OBJECTIVE: To explore the evidence for adopting a "treatable traits" approach to asthma management. DATA SOURCES: PubMed, Medline, and Google Scholar. STUDY SELECTIONS: The above-mentioned databases were searched for randomized, controlled phase III or IV trials of adults containing the word "asthma" in the title published in the previous 10 years and for all articles containing the title words "treatable AND trait(s)," "asthma AND biomarker(s) OR smoking OR obesity OR laryngeal OR management" published within the previous 5 years. Articles were excluded if they were not published in English. Our search identified 257 articles for consideration. We also manually searched the reference lists of studies identified and searched the websites of the British Thoracic Society, European Respiratory Society, National Institute for Health and Care Excellence, and Global Initiative for Asthma for specific guidance related to asthma management. RESULTS: The "treatable traits" are described within 3 domains of pulmonary, extrapulmonary, or behavioral and lifestyle traits. We consider whether treatment should be targeted toward these traits where they are present in asthma patients, based on currently available evidence, rather than increasing treatment in response to symptoms in line with current step-up, step-down asthma management guidelines. CONCLUSION: We advocate that a treatable traits approach should be applied more broadly to the assessment and management of inadequately controlled asthma, rather than a step-up, step-down approach based on patient symptoms. This approach should be focused on the 2 treatable pulmonary traits of TH2 inflammation and airflow obstruction along with smoking cessation, in the first instance.

COVID-19 and pneumothorax: a multicentre retrospective case series.

INTRODUCTION: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). METHODS: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. RESULTS: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). CONCLUSION: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.

Take a Deep Breath - Time to Plunge into Inducible Laryngeal Obstruction.

Inducible laryngeal obstruction (ILO)/vocal cord dysfunction is frequently encountered in the specialist asthma clinic, where it is often misdiagnosed as asthma or is coexistent with asthma. It causes recurrent distressing episodes of acute dyspnea that can lead to hospital admissions, endotracheal intubation, and fruitless asthma treatment escalation, often including oral glucocorticoids.1-4 Early diagnosis and treatment of ILO offers the prospect of connecting patients with an effective speech- and language-based intervention earlier and avoiding these unnecessary and potentially harmful interventions.

Recovery of Breakthrough Asthma Attacks Treated With Oral Steroids While on Monoclonal Antibody Therapy: Protocol for a Prospective Observational Study (BOOST).

BACKGROUND: Asthma attacks are a common and important problem. Someone experiences an asthma attack in the United Kingdom every 10 seconds. Asthma attacks cause coughing, wheezing, breathlessness, and chest tightness and are highly stressful for patients. They result in reduced quality of life, with days lost from work or school. Asthma attacks are treated with oral corticosteroids (OCSs), but these have many short- and long-term side effects. Asthma monoclonal antibodies (mAbs) have revolutionized the treatment of severe asthma by reducing asthma attacks and OCS burden by over 50%, but some people still experience attacks while on mAbs. The MEX study showed that residual asthma attacks are broadly eosinophilic (high fractional exhaled nitric oxide [FeNO]) or noneosinophilic (low FeNO), but it did not measure response to OCS treatment. There is an evidence gap in understanding the clinical and inflammatory responses that occur when using OCSs to treat residual asthma attacks in patients taking asthma mAbs. OBJECTIVE: The primary objective is to compare the clinical recovery between high-FeNO and low-FeNO attacks after acute treatment with oral prednisolone among people established on long-term asthma mAb treatment. The exploratory objective is to compare the inflammatory response to acute treatment with oral prednisolone between high-FeNO and low-FeNO attacks. METHODS: BOOST (Breakthrough Asthma Attacks Treated With Oral Steroids) is a single-center, prospective observational study of 60 adults established on long-term asthma mAb treatment who receive acute treatment with oral prednisolone (usual care) for an asthma attack. The primary outcome will be the proportion of treatment failure (the need to start oral prednisolone or antibiotics or an unscheduled health care visit for asthma, following an attack) at day 28. The secondary outcomes will be the change in forced expiratory volume in 1 second and the change in visual analogue scale symptom score between the stable state, attack, day 7, and day 28 visits. The exploratory outcomes include the changes in sputum, nasal, and blood inflammometry between the stable state, attack, day 7, and day 28 visits. RESULTS: The last asthma attack visit is anticipated to occur in December 2023. Data analysis and publication will take place in 2024. CONCLUSIONS: We will test the hypothesis that there is a difference in the rate of recovery of clinical and inflammatory measures between high-FeNO and low-FeNO asthma attacks that occur in patients on mAb therapy. The study data will help power a future randomized placebo-controlled trial of prednisolone treatment for nonsevere attacks in patients treated with asthma mAbs and will provide important information on whether corticosteroid treatment should be FeNO-directed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46741.

Persistence of inflammatory and vascular mediators 5 months after hospitalization with COVID-19 infection.

Background and aim: In acute severe COVID-19, patients present with lung inflammation and vascular injury, accompanied by an exaggerated cytokine response. In this study, our aim was to describe the inflammatory and vascular mediator profiles in patients who were previously hospitalized with COVID-19 pneumonitis, months after their recovery, and compare them with those in patients recovering from severe sepsis and in healthy controls. Methods: A total of 27 different cytokine, chemokine, vascular endothelial injury and angiogenic mediators were measured in the plasma of forty-nine patients 5.0 ± 1.9 (mean ± SD) months after they were hospitalized with COVID-19 pneumonia, eleven patients 5.4 ± 2.9 months after hospitalization with acute severe sepsis, and 18 healthy controls. Results: Compared with healthy controls, IL-6, TNFα, SAA, CRP, Tie-2, Flt1, and PIGF were significantly increased in the post-COVID group, and IL-7 and bFGF were significantly reduced. While IL-6, PIGF, and CRP were also significantly elevated in post-Sepsis patients compared to controls, the observed differences in TNFα, Tie-2, Flt-1, IL-7 and bFGF were unique to the post-COVID group. TNFα levels significantly correlated with the severity of acute COVID-19 illness (spearman's r = 0.30, p < 0.05). Furthermore, in post-COVID patients, IL-6 and CRP were each strongly negatively correlated with gas transfer factor %predicted (spearman's r = -0.51 and r = -0.57, respectively, p < 0.002) and positively correlated with computed tomography (CT) abnormality scores at recovery (r = 0.28 and r = 0.46, p < 0.05, respectively). Conclusion: A unique inflammatory and vascular endothelial damage mediator signature is found in plasma months following acute COVID-19 infection. Further research is required to determine its pathophysiological and clinical significance.

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial.

BACKGROUND: The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19. METHODS: This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed. FINDINGS: 298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). No serious adverse events were reported. INTERPRETATION: In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford and Pfizer.

A multi-centre open-label two-arm randomised superiority clinical trial of azithromycin versus usual care in ambulatory COVID-19: study protocol for the ATOMIC2 trial.

BACKGROUND: Azithromycin is an orally active synthetic macrolide antibiotic with a wide range of anti-bacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide and manufactured to scale and is a potential candidate therapy for pandemic coronavirus disease 2019 (COVID-19). Azithromycin was widely used to treat severe SARS-CoV and MERS-CoV, but to date, no randomised data are available in any coronavirus infections. Other ongoing trials are exploring short courses of azithromycin either in early disease, within the first 7 days of symptoms, when azithromycin's antiviral properties may be important, or late in disease when anti-bacterial properties may reduce the risk of secondary bacterial infection. However, the molecule's anti-inflammatory properties, including suppression of pulmonary macrophage-derived pro-inflammatory cytokines such as interleukins-1ß, -6, -8, and -18 and cytokines G-CSF and GM-CSF may provide a distinct therapeutic benefit if given in as a prolonged course during the period of progression from moderate to severe disease. METHODS: ATOMIC2 is a phase II/III, multi-centre, prospective, open-label, two-arm randomised superiority clinical trial of azithromycin versus standard care for adults presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation. We will enrol adults, ≥ 18 years of age assessed in acute hospitals in the UK with clinical diagnosis of COVID-19 infection where management on an ambulatory care pathway is deemed appropriate. Participants will be randomised in a 1:1 ratio to usual care or to azithromycin 500 mg orally daily for 14 days with telephone follow-up at days 14 and 28. The primary objective is to compare the proportion with either death or respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation. Secondary objectives include mortality/respiratory failure in those with a PCR-confirmed diagnosis; all-cause mortality; progression to pneumonia; progression to severe pneumonia; peak severity of illness and mechanistic analysis of blood and nasal biomarkers. DISCUSSION: This trial will determine the clinical utility of azithromycin in patients with moderately severe, clinically diagnosed COVID-19 and could be rapidly applicable worldwide. TRIAL REGISTRATION: ClinicalTrials.gov NCT04381962 . Registered on 11 May 2020. EudraCT identifier 2020-001740-26 . Opened for accrual on 29 May 2020.

Effects of syntactic expectations on speech segmentation.

Although the effect of acoustic cues on speech segmentation has been extensively investigated, the role of higher order information (e.g., syntax) has received less attention. Here, the authors examined whether syntactic expectations based on subject-verb agreement have an effect on segmentation and whether they do so despite conflicting acoustic cues. Although participants detected target words faster in phrases containing adequate acoustic cues ("spins" in take spins and "pins" in takes pins), this acoustic effect was suppressed when the phrases were appended to a plural context (those women take spins/*takes pins [with the asterisk indicating a syntactically unacceptable parse]). The syntactically congruent target ("spins") was detected faster regardless of the acoustics. However, a singular context (that woman *take spins/takes pins) had no effect on segmentation, and the results resembled those of the neutral phrases. Subsequent experiments showed that the discrepancy was due to the relative time course of syntactic expectations and acoustics cues. Taken together, the data suggest that syntactic knowledge can facilitate segmentation but that its effect is substantially attenuated if conflicting acoustic cues are encountered before full realization of the syntactic constraint.

Sentential, lexical, and acoustic effects on the perception of word boundaries.

This study investigates the effects of sentential context, lexical knowledge, and acoustic cues on the segmentation of connected speech. Listeners heard near-homophonous phrases (e.g., plmpaI for "plum pie" versus "plump eye") in isolation, in a sentential context, or in a lexically biasing context. The sentential context and the acoustic cues were piloted to provide strong versus mild support for one segmentation alternative (plum pie) or the other (plump eye). The lexically biasing context favored one segmentation or the other (e.g., skmpaI for "scum pie" versus *"scump eye," and lmpaI, for "lump eye" versus *"lum pie," with the asterisk denoting a lexically unacceptable parse). A forced-choice task, in which listeners indicated which of two words they thought they heard (e.g., "pie" or "eye"), revealed compensatory mechanisms between the sources of information. The effect of both sentential and lexical contexts on segmentation responses was larger when the acoustic cues were mild than when they were strong. Moreover, lexical effects were accompanied with a reduction in sensitivity to the acoustic cues. Sentential context only affected the listeners' response criterion. The results highlight the graded, interactive, and flexible nature of multicue segmentation, as well as functional differences between sentential and lexical contributions to this process.

Integration of multiple speech segmentation cues: a hierarchical framework.

A central question in psycholinguistic research is how listeners isolate words from connected speech despite the paucity of clear word-boundary cues in the signal. A large body of empirical evidence indicates that word segmentation is promoted by both lexical (knowledge-derived) and sublexical (signal-derived) cues. However, an account of how these cues operate in combination or in conflict is lacking. The present study fills this gap by assessing speech segmentation when cues are systematically pitted against each other. The results demonstrate that listeners do not assign the same power to all segmentation cues; rather, cues are hierarchically integrated, with descending weights allocated to lexical, segmental, and prosodic cues. Lower level cues drive segmentation when the interpretive conditions are altered by a lack of contextual and lexical information or by white noise. Taken together, the results call for an integrated, hierarchical, and signal-contingent approach to speech segmentation.

How do syllables contribute to the perception of spoken English? insight from the migration paradigm.

The involvement of syllables in the perception of spoken English has traditionally been regarded as minimal because of ambiguous syllable boundaries and overriding rhythmic segmentation cues. The present experiments test the perceptual separability of syllables and vowels in spoken English using the migration paradigm. Experiments 1 and 2 show that syllables migrate considerably more than full and reduced vowels, and this effect is not influenced by the lexicality of the stimuli, their stress pattern, or the syllables' position relative to the edge of the stimuli. Experiment 3 confirms the predominance of syllable migration against a pseudosyllable baseline, and provides some evidence that syllable migration depends on whether syllable boundaries are clear or ambiguous. Consistent with this hypothesis, Experiment 4 demonstrates that CVC syllables migrate more in stimuli with a clear CVC-initial structure than in ambisyllabic stimuli. Together, the data suggest that syllables have a greater contribution to the perception of spoken English than previously assumed.

Segmentation by lexical subtraction in Hungarian speakers of second-language English.

Using cross-modal form priming, we compared the use of stress and lexicality in the segmentation of spoken English by native English speakers (L1) and by native Hungarian speakers of second-language English (L2). For both language groups, lexicality was found to be an effective segmentation cue. That is, spoken disyllabic word fragments were stronger primes in a subsequent visual word recognition task when preceded by meaningful words than when preceded by nonwords: For example, the first two syllables of corridor were a more effective prime for visually presented corridor when heard in the phrase anythingcorri than in imoshingcorri. The stress pattern of the prime (strong-weak vs. weak-strong) did not affect the degree of priming. For L1 speakers, this supports previous findings about the preferential use of high-level segmentation strategies in clear speech. For L2 speakers, the lexical strategy was employed regardless of L2 proficiency level and instead of exploiting the consistent stress pattern of their native language. This is clear evidence for the primacy and robustness of segmentation by lexical subtraction even in individuals whose lexical knowledge is limited.

Detecting silent pauses in speech: a new tool for measuring on-line lexical and semantic processing.

In this study, we introduce pause detection (PD) as a new tool for studying the on-line integration of lexical and semantic information during speech comprehension. When listeners were asked to detect 200-ms pauses inserted into the last words of spoken sentences, their detection latencies were influenced by the lexical-semantic information provided by the sentences. Listeners took longer to detect a pause when it was inserted within a word that had multiple potential endings, rather than a unique ending, in the context of the sentence. An event-related potential (ERP) variant of the PD procedure revealed brain correlates of pauses as early as 101 to 125 ms following pause onset and patterns of lexical-semantic integration that mirrored those obtained with PD within 160 ms of pause onset. Thus, both the behavioral and the electrophysiological responses to pauses suggest that lexical and semantic processes are highly interactive and that their integration occurs rapidly during speech comprehension.