Enantioselective total synthesis of atisane diterpenoids: (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one.

Enantioselective total synthesis of (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one has been accomplished starting from enantiopure Wieland-Miescher ketone. Key features of the syntheses include a benzannulation step to construct the tricyclic core, an oxidative dearomatization step to generate the diene, and a Diels-Alder reaction with ethylene gas to establish the bicyclo[2.2.2]octane framework. Efficient late-stage functionalisation of the A-ring by aerobic oxidation and Baeyer-Villiger oxidation completed the atisane target molecules.

Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for non-invasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review we will specifically address volatile organic compounds in the breath, with a view towards fulfilling the promise of these as actionable biomarkers, in particular for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward, if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Sex differences in asthma control, lung function and exacerbations: the ATLANTIS study.

BACKGROUND: Asthma is a heterogeneous disease with a prevalence and severity that differs between male and female patients. QUESTION: What are differences between male and female patients with asthma with regard to asthma control, lung function, inflammation and exacerbations? METHODS: We performed a post hoc analysis in the ATLANTIS (Assessment of Small Airways Involvement in Asthma) study, an observational cohort study including patients with asthma from nine countries with a follow-up of 1 year during which patients were characterised with measures of large and small airway function, questionnaires, inflammation and imaging. We compared differences in baseline characteristics and longitudinal outcomes between male and female patients with asthma. RESULTS: 773 patients were enrolled; 450 (58%) of these were female. At baseline, female patients with asthma were in higher Global Initiative for Asthma (GINA) steps (p=0.042), had higher Asthma Control Questionnaire 6 (F: 0.83; M: 0.66, p<0.001) and higher airway resistance as reflected by uncorrected impulse oscillometry outcomes (ie, R5-R20: F: 0.06; M: 0.04 kPa/L/s, p=0.002). Male patients with asthma had more severe airway obstruction (forced expiratory volume in 1 s/forced vital capacity % predicted: F: 91.95; M: 88.33%, p<0.01) and more frequently had persistent airflow limitation (F: 27%; M: 39%, p<0.001). Blood neutrophils were significantly higher in female patients (p=0.014). With Cox regression analysis, female sex was an independent predictor for exacerbations. INTERPRETATION: We demonstrate that female patients are in higher GINA steps, exhibit worse disease control, experience more exacerbations and demonstrate higher airway resistance compared with male patients. The higher exacerbation risk was independent of GINA step and blood eosinophil level. Male patients, in turn, have a higher prevalence of persistent airflow limitation and more severe airflow obstruction. These findings show sex can affect clinical phenotyping and outcomes in asthma. TRIAL REGISTRATION NUMBER: NCT02123667.

Discovery and Validation of a Volatile Signature of Eosinophilic Airway Inflammation in Asthma.

RATIONALE: Volatile organic compounds (VOCs) in asthmatic breath may be associated with sputum eosinophilia. We developed a volatile biomarker-signature to predict sputum eosinophilia in asthma. METHODS: VOCs emitted into the space above sputum samples (headspace) from severe asthmatics (n=36) were collected onto sorbent tubes and analysed using thermal desorption gas chromatography-mass spectrometry (TD-GC-MS). Elastic net regression identified stable VOCs associated with sputum eosinophilia ≥3% and generated a volatile biomarker signature. This VOC signature was validated in breath samples from: (I) acute asthmatics according to blood eosinophilia ≥0.3x109cells/L or sputum eosinophilia of ≥ 3% in the UK EMBER consortium (n=65) and U-BIOPRED-IMI consortium (n=42). Breath samples were collected onto sorbent tubes (EMBER) or Tedlar bags (U-BIOPRED) and analysed by gas-chromatography-mass spectrometry (GC×GC-MS -EMBER or GC-MS -U-BIOPRED). MAIN RESULTS: The in vitro headspace identified 19 VOCs associated with sputum eosinophilia and the derived VOC signature yielded good diagnostic accuracy for sputum eosinophilia ≥ 3% in headspace (AUROC (95% CI) 0.90(0.80-0.99), p<0.0001), correlated inversely with sputum eosinophil % (rs= -0.71, p<0.0001) and outperformed FeNO (AUROC (95% CI) 0.61(0.35-0.86). Analysis of exhaled breath in replication cohorts yielded a VOC signature AUROC (95% CI) for acute asthma exacerbations of 0.89(0.76-1.0) (EMBER cohort) with sputum eosinophilia and 0.90(0.75-1.0) in U-BIOPRED - again outperforming FeNO in U-BIOPRED 0.62 (0.33-0.90). CONCLUSIONS: We have discovered and provided early-stage clinical validation of a volatile biomarker signature associated with eosinophilic airway inflammation. Further work is needed to translate our discovery using point of care clinical sensors.

The effects of inhaled corticosteroids on healthy airways.

BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Biochemical and In Silico Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders.

INTRODUCTION: Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation. METHODS: The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC50 values between 1.6 to 13 µM, as compared to the standard drug, i.e., kojic acid (IC50 = 24.1 ± 0.5 µM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid. RESULTS: The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line. CONCLUSION: The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.

Impact of sex on severe asthma: a cross-sectional retrospective analysis of UK primary and specialist care.

INTRODUCTION: After puberty, females are more likely to develop asthma and in a more severe form than males. The associations between asthma and sex are complex with multiple intrinsic and external factors. AIM: To evaluate the sex differences in the characteristics and treatment of patients with severe asthma (SA) in a real-world setting. METHODS: Demographic, clinical and treatment characteristics for patients with SA in the UK Severe Asthma Registry (UKSAR) and Optimum Patient Care Research Database (OPCRD) were retrospectively analysed by sex using univariable and multivariable logistic regression analyses adjusted for year, age and hospital/practice. RESULTS: 3679 (60.9% female) patients from UKSAR and 18 369 patients (67.9% female) from OPCRD with SA were included. Females were more likely to be symptomatic with increased Asthma Control Questionnaire-6 (UKSAR adjusted OR (aOR) 1.14, 95% CI 1.09 to 1.18) and Royal College of Physicians-3 Question scores (OPCRD aOR 1.29, 95% CI 1.13 to 1.47). However, they had a higher forced expiratory volume in 1 second per cent (FEV1%) predicted (UKSAR 68.7% vs 64.8%, p<0.001) with no significant difference in peak expiratory flow. Type 2 biomarkers IgE (UKSAR 129 IU/mL vs 208 IU/mL, p<0.001) and FeNO (UKSAR 36ppb vs 46ppb, p<0.001) were lower in females with no significant difference in blood eosinophils or biological therapy. Females were less likely to be on maintenance oral corticosteroids (UKSAR aOR 0.86, 95% CI 0.75 to 0.99) but more likely to be obese (UKSAR aOR 1.67, 95% CI 145 to 1.93; OPCRD SA aOR 1.46, 95% CI 1.34 to 1.58). CONCLUSIONS: Females had increased symptoms and were more likely to be obese despite higher FEV1% predicted and lower type 2 biomarkers with consistent and clinically important differences across both datasets.

An examination of factorial invariance of the Asthma Control Questionnaire among adults with severe asthma.

BACKGROUND: The Asthma Control Questionnaire (ACQ) is used to assess asthma symptom control. The relationship between the questionnaire items and symptom control has not been fully studied in severe asthmatic patients, and its validity for making comparisons between subgroups of patients is unknown. METHODS: Data was obtained from patients in the United Kingdom Severe Asthma Registry whose symptom control was assessed using the five-item ACQ (ACQ5) (n = 2,951). Confirmatory factor analysis determined whether a latent factor for asthma symptom control, as measured by the ACQ5, was consistent with the data. Measurement invariance was examined in relation to ethnicity, sex and age; this included testing for approximate measurement invariance using Bayesian Structural Equation Modelling (BSEM). The fitted models were used to estimate the internal consistency reliability of the ACQ5. Invariance of factor means across subgroups was assessed. RESULTS: A one-factor construct with residual correlations for the ACQ5 was an excellent fit to the data in all subgroups (Root Mean Square Error Approximation 0.03 [90%CI 0.02,0.05], p-close fit 0.93, Comparative Fit Index 1.00, Tucker Lewis Index 1.00}. Expected item responses were consistent for Caucasian and non-Caucasian patients with the same absolute level of symptom control. There was some evidence that females and younger adults reported wakening more frequently during the night than males and older adults respectively with the same absolute level of symptom control (p<0.001). However approximate measurement invariance was tenable and any failure to observe strong measurement invariance had minimal impact when comparing mean levels of asthma symptom control between patients of different sexes or ages. Average levels of asthma symptom control were lower for non-Caucasians (p = 0.001), females (p<0.01)and increased with age (p<0.01). Reliability of the instrument was high (over 88%) in all subgroups studied. CONCLUSION: The ACQ5 is informative in comparing levels of symptom control between severe asthmatic patients of different ethnicities, sexes and ages. It is important that analyses are replicated in other severe asthma registries to determine whether measurement invariance is observed.

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma.

BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium. OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy. METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes. RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma. CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

Clinical Trial Design Innovations for Precision Medicine in Asthma.

Severe asthma is a spectrum disorder with numerous subsets, many of which are defined by clinical history and a general predisposition for T2 inflammation. Most of the approved therapies for severe asthma have required clinical trial designs with population enrichment for exacerbation frequency and/or elevation of blood eosinophils. Moving beyond this framework will require trial designs that increase efficiency for studying nondominant subsets and continue to improve upon biomarker signatures. In addition to reviewing the current literature on biomarker-informed trials for severe asthma, this chapter will also review the advantages of master protocols and adaptive design methods for establishing the efficacy of new interventions in prospectively defined subsets of patients. The incorporation of methods that allow for data collection outside of traditional study visits at academic centers, called remote decentralized trial design, is a growing trend that may increase diversity in study participation and allow for enhanced resiliency during the COVID-19 pandemic. Finally, reaching the goals of precision medicine in asthma will require increased emphasis on effectiveness studies. Recent advances in real-world data utilization from electronic health records are also discussed with a view toward pragmatic trial designs that could also incorporate the evaluation of biomarker signatures.

Principles of patient partnership: integrating patient perspectives into ERS Clinical Research Collaborations.

Patient and public involvement in research is increasingly considered a cornerstone of good research practice, and the research community recognises people with lived experience as valuable stakeholders within the research process. European Respiratory Society (ERS) strongly encourages patient input into its research programme and scientific activities, working in partnership with the European Lung Foundation (ELF) to facilitate this. Based on the ERS and ELF experience and best practice in the field of patient and public involvement, we developed a set of principles to which future ERS and ELF collaborations should adhere. These principles provide guidance on how to address key challenges when planning and conducting patient and public involvement in order to develop successful partnerships with patients and drive forward patient-centred research.

Eosinophils and tissue remodeling: Relevance to airway disease.

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.

Safety and Efficacy of Dexpramipexole in Eosinophilic Asthma (EXHALE): A randomized controlled trial.

BACKGROUND: There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma. OBJECTIVE: We sought to evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma. METHODS: We performed a randomized, double-blind, placebo-controlled proof-of-concept trial in adults with inadequately controlled moderate to severe asthma and blood absolute eosinophil count (AEC) greater than or equal to 300/µL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID (twice-daily) or placebo. The primary end point was the relative change in AEC from baseline to week 12. Prebronchodilator FEV1 week-12 change from baseline was a key secondary end point. Nasal eosinophil peroxidase was an exploratory end point. RESULTS: A total of 103 subjects were randomly assigned to dexpramipexole 37.5 mg BID (N = 22), 75 mg BID (N = 26), 150 mg BID (N = 28), or placebo (N = 27). Dexpramipexole significantly reduced placebo-corrected AEC week-12 ratio to baseline, in both the 150-mg BID (ratio, 0.23; 95% CI, 0.12-0.43; P < .0001) and the 75-mg BID (ratio, 0.34; 95% CI, 0.18-0.65; P = .0014) dose groups, corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory end point of nasal eosinophil peroxidase week-12 ratio to baseline in the 150-mg BID (median, 0.11; P = .020) and the 75-mg BID (median, 0.17; P = .021) groups. Placebo-corrected FEV1 increases were observed starting at week 4 (nonsignificant). Dexpramipexole displayed a favorable safety profile. CONCLUSIONS: Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand the clinical efficacy of dexpramipexole in asthma.

Asthma innovations from the first International Collaborative Asthma Network forum.

Background: Many patients have uncontrolled asthma despite available treatments. Most of the new asthma therapies have focused on type 2 (T2) inflammation, leaving an unmet need for innovative research into mechanisms of asthma beyond T2 and immunity. An international group of investigators developed the International Collaborative Asthma Network (ICAN) with the goal of sharing innovative research on disease mechanisms, developing new technologies and therapies, organising pilot studies and engaging early-stage career investigators from across the world. This report describes the purpose, development and outcomes of the first ICAN forum. Methods: Abstracts were solicited from interdisciplinary early-stage career investigators with innovative ideas beyond T2 inflammation for asthma and were selected for presentation at the forum. Breakout sessions were conducted to discuss innovation, collaboration and research translation. Results: The abstracts were categorised into: 1) general omics and big data analysis; 2) lung-brain axis and airway neurology; 3) sex differences; 4) paediatric asthma; 5) new therapeutic targets inspired by airway epithelial biology; 6) new therapeutics targeting airway and circulating immune mediators; and 7) lung anatomy, physiology and imaging. Discussions revealed that research groups are looking for opportunities to further their findings using larger scale collaboration and the ability to translate their in vitro findings into clinical treatment. Conclusions: Through ICAN, teams that included interdisciplinary early-stage career investigators discussed innovation, collaboration and translation in asthma and severe asthma research. With a combination of fresh ideas and energetic, collaborative, global participation, ICAN has laid a firm foundation and model for future collaborative global asthma research.

IoT-based disease prediction using machine learning.

COVID-19 disrupted lives and livelihoods and affected various sectors of the economy. One such domain was the already overburdened healthcare sector, which faced fresh challenges as the number of patients rose exponentially and became difficult to deal with. In such a scenario, telemedicine, teleconsultation, and virtual consultation became increasingly common to comply with social distancing norms. To overcome this pressing need of increasing 'remote' consultations in the 'post-COVID' era, the Internet of Things (IoT) has the potential to play a pivotal role, and this present paper attempts to develop a novel system that implements the most efficient machine learning (ML) algorithm and takes input from the patients such as symptoms, audio recordings, available medical reports, and other histories of illnesses to accurately and holistically predict the disease that the patients are suffering from. A few of the symptoms, such as fever and low blood oxygen, can also be measured via sensors using Arduino and ESP8266. It then provides for the appropriate diagnosis and treatment of the disease based on its constantly updated database, which can be developed as an application-based or website-based platform.

Characteristics and risk factors for post-COVID-19 breathlessness after hospitalisation for COVID-19.

Background: Persistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation. Methods: PHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0-10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness. Results: We included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median 5 months after discharge, 50% reported post-COVID-19 breathlessness. Risk factors for post-COVID-19 breathlessness were socioeconomic deprivation (adjusted OR 1.67, 95% CI 1.14-2.44), pre-existing depression/anxiety (adjusted OR 1.58, 95% CI 1.06-2.35), female sex (adjusted OR 1.56, 95% CI 1.21-2.00) and admission duration (adjusted OR 1.01, 95% CI 1.00-1.02). Black ethnicity (adjusted OR 0.56, 95% CI 0.35-0.89) and older age groups (adjusted OR 0.31, 95% CI 0.14-0.66) were less likely to report post-COVID-19 breathlessness. Post-COVID-19 breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. The prediction model had fair discrimination (concordance statistic 0.66, 95% CI 0.63-0.69) and good calibration (calibration slope 1.00, 95% CI 0.80-1.21). Conclusions: Post-COVID-19 breathlessness was commonly reported in this national cohort of patients hospitalised for COVID-19 and is likely to be a multifactorial problem with physical and emotional components.

Development of a tool to detect small airways dysfunction in asthma clinical practice.

BACKGROUND: Small airways dysfunction (SAD) in asthma is difficult to measure and a gold standard is lacking. The aim of this study was to develop a simple tool including items of the Small Airways Dysfunction Tool (SADT) questionnaire, basic patient characteristics and respiratory tests available depending on the clinical setting to predict SAD in asthma. METHODS: This study was based on the data of the multinational ATLANTIS (Assessment of Small Airways Involvement in Asthma) study including the earlier developed SADT questionnaire. Key SADT items together with clinical information were now used to build logistic regression models to predict SAD group (less likely or more likely to have SAD). Diagnostic ability of the models was expressed as area under the receiver operating characteristic curve (AUC) and positive likelihood ratio (LR+). RESULTS: SADT item 8, "I sometimes wheeze when I am sitting or lying quietly", and the patient characteristics age, age at asthma diagnosis and body mass index could reasonably well detect SAD (AUC 0.74, LR+ 2.3). The diagnostic ability increased by adding spirometry (percentage predicted forced expiratory volume in 1 s: AUC 0.87, LR+ 5.0) and oscillometry (resistance difference between 5 and 20 Hz and reactance area: AUC 0.96, LR+ 12.8). CONCLUSIONS: If access to respiratory tests is limited (e.g. primary care in many countries), patients with SAD could reasonably well be identified by asking about wheezing at rest and a few patient characteristics. In (advanced) hospital settings patients with SAD could be identified with considerably higher accuracy using spirometry and oscillometry.

Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study.

BACKGROUND: Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study. METHODS: In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort. FINDINGS: Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43 years in non-PAL group), longer duration of asthma (24 years vs 12 years), male sex (51% vs 38%), higher blood eosinophil counts (median 0·27 × 109 cells per L vs 0·20 × 109 cells per L), more small airway dysfunction, and more exacerbations during 1 year of follow-up. Associations between PAL, age, and eosinophilic inflammation were validated in the U-BIOPRED cohort, whereas associations with sex, duration of asthma, and risk of exacerbations were not validated. INTERPRETATION: PAL is not only present in severe disease, but also in a considerable proportion of patients with milder disease. In patients with mild asthma, PAL is associated with eosinophilic inflammation and a higher risk of exacerbations. Our findings are important because they suggest that increasing treatment intensity should be considered in patients with milder asthma and PAL. FUNDING: Chiesi Farmaceutici and Dutch Ministry of Economic Affairs and Climate Policy (by means of the public-private partnership programme).