Dysfunctional breathing is a term describing breathing disorders where chronic changes in breathing pattern result in dyspnoea and other symptoms in the absence or in excess of the magnitude of ...physiological respiratory or cardiac disease. We reviewed the literature and propose a classification system for the common dysfunctional breathing patterns described. The literature was searched using the terms: dysfunctional breathing, hyperventilation, Nijmegen questionnaire and thoraco-abdominal asynchrony. We have summarised the presentation, assessment and treatment of dysfunctional breathing, and propose that the following system be used for classification. 1) Hyperventilation syndrome: associated with symptoms both related to respiratory alkalosis and independent of hypocapnia. 2) Periodic deep sighing: frequent sighing with an irregular breathing pattern. 3) Thoracic dominant breathing: can often manifest in somatic disease, if occurring without disease it may be considered dysfunctional and results in dyspnoea. 4) Forced abdominal expiration: these patients utilise inappropriate and excessive abdominal muscle contraction to aid expiration. 5) Thoraco-abdominal asynchrony: where there is delay between rib cage and abdominal contraction resulting in ineffective breathing mechanics.This review highlights the common abnormalities, current diagnostic methods and therapeutic implications in dysfunctional breathing. Future work should aim to further investigate the prevalence, clinical associations and treatment of these presentations.
Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug ...discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.
Exhaled breath is a robust matrix of biomarkers divided between three fractions – gaseous breath, volatile breath, and breath condensate. Breath is collected non-invasively through bags (for gaseous ...breath), cold condensation chambers (breath condensate), and adsorbent traps (volatile breath). Due to the incredibly dilute nature of breath matrices, breath biomarker analysis requires precise analytical techniques, highly sensitive technology and often challenges the limit of detection of even the most advanced assays. Interest and advances in breath collection, analysis, and use have increased in recent years largely due to advances in analytical technology. Approved and validated breath tests are available as tools for researchers and clinicians. Novel development is ongoing. This article reviews the current applications for exhaled breath biomarkers.
Exhaled breath contains thousands of volatile organic compounds that reflect the metabolic process occurring in the host both locally in the airways and systemically. They also arise from the ...environment and airway microbiome. Comprehensive analysis of breath volatile organic compounds (breathomics) provides opportunities for noninvasive biomarker discovery and novel mechanistic insights. Applications in patients with obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease, include not only diagnostics (especially in children and other challenging diagnostic areas) but also identification of clinical treatable traits, such as airway eosinophilia and risk of infection/exacerbation, that are not specific to diagnostic labels. Although many aspects of breath sampling and analysis are challenging, proof-of-concept studies with mass spectrometry and electronic nose technologies have provided independent studies with moderate-to-good diagnostic and phenotypic accuracies. The present review evaluates the data obtained by using breathomics in (1) predicting the inception of asthma or chronic obstructive pulmonary disease, (2) inflammatory phenotyping, (3) exacerbation prediction, and (4) treatment stratification. The current findings merit the current efforts of large multicenter studies using standardized sampling, shared analytic methods, and databases, including external validation cohorts. This will position this noninvasive technology in the clinical assessment and monitoring of chronic airways diseases.
The larynx is one of the most highly innervated organs in humans and serves a number of vitally important, complex, and highly evolved biological functions. On a day-to-day basis, the larynx ...functions autonomously, addressing several roles including airway protection, swallowing, and phonation. In some situations the larynx appears to adopt a functional state that could be considered maladaptive or "dysfunctional." This laryngeal dysfunction can underpin and account for a number of respiratory symptoms that otherwise appear incongruous with a clinical disease state and/or contribute to the development of symptoms that appear "refractory" to treatment. These include conditions associated with a heightened tendency for inappropriate laryngeal closure (e.g., inducible laryngeal obstruction), voice disturbance, and chronic cough. Recognition of laryngeal dysfunction is important to deliver targeted treatment and failure to recognize the condition can lead to repeated use of inappropriate treatment. Diagnosis is not straightforward, however, and many patients appear to present with symptoms attributable to laryngeal dysfunction, but in whom the diagnosis has been overlooked in clinical work-up for some time. This review provides an overview of the current state of knowledge in the field of laryngeal dysfunction, with a focus on pragmatic clinical assessment and management.
...we have shown that using a cutoff of 0.45 x 109 cells/L for blood eosinophilia can usefully predict airway eosinophilia in patients with severe asthma receiving high levels of treatment.
Background Cough in asthmatic patients is a common and troublesome symptom. It is generally assumed coughing occurs as a consequence of bronchial hyperresponsiveness and inflammation, but the ...possibility that airway nerves are dysfunctional has not been fully explored. Objectives We sought to investigate capsaicin-evoked cough responses in a group of patients with well-characterized mild-to-moderate asthma compared with healthy volunteers and assess the influences of sex, atopy, lung physiology, inflammation, and asthma control on these responses. Methods Capsaicin inhalational challenge was performed, and cough responses were analyzed by using nonlinear mixed-effects modeling to estimate the maximum cough response evoked by any concentration of capsaicin (Emax ) and the capsaicin dose inducing half-maximal response (ED50 ). Results Ninety-seven patients with stable asthma (median age, 23 years interquartile range, 21-27 years; 60% female) and 47 healthy volunteers (median age, 38 years interquartile range, 29-47 years; 64% female) were recruited. Asthmatic patients had higher Emax and lower ED50 values than healthy volunteers. Emax values were 27% higher in female subjects ( P = .006) and 46% higher in patients with nonatopic asthma ( P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than nonatopic asthmatic patients ( P = .04). The ED50 value was 65% lower in female patients ( P = .0001) and 71% lower in all asthmatic patients ( P = .0008). ED50 values were also influenced by asthma control and serum IgE levels, whereas Emax values were related to 24-hour cough frequency. Age, body mass index, FEV1 , PC20 , fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters. Conclusion Patients with stable asthma exhibited exaggerated capsaicin-evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2–low asthma phenotypes.
Asthma is one of the neglected diseases in Africa with a high prevalence. Allergic fungal diseases have been reported to complicate asthma progression and treatment outcomes. However, data about ...fungal asthma and its associated complications are limited in Africa. We aimed to estimate the burden of fungal asthma among adults and children in Africa using a systematic review.
We first engaged the Institute for Health Metrics and Evaluation (IHME) to highlight the trend in morbidity and mortality attributed to asthma in Africa. We then searched PubMed, HINARI and Google Scholar for all studies of any design focusing on fungal asthma in any African country. Languages were restricted to English and French, but not year of publication. We estimated the weighted prevalence of allergic fungal infections among asthmatics with a 95% CI and pooled the results using a random effects model. This study is registered with PROSPERO, number CRD42019117319.
The IHME data showed that there has been a gradual increase in morbidity and mortality due to asthma in African adults with a prevalence of 4%. Our search retrieved 5233 citations. We retained 20 studies that met our selection criteria. These were from 13 African countries published between 1967 and 2018. There were eight cross-sectional studies and twelve review articles. The average asthma prevalence in Africa was 6% from these studies. The prevalence of fungal sensitisation was relatively high (3-52%) in the asthmatic population with an average of 28% and a pooled estimate of 23.3%, mostly due to Aspergillus species. Prevalence of Allergic bronchopulmonary apsergillosis was estimated at 1.6-21.2%. Diagnosis of fungal allergy was mostly made by skin prick tests. There was no data on the use of medication to manage fungal asthma. None of the studies evaluated the association between fungal allergy and asthma severity. Data were lacking in children.
There is a high prevalence of fungal sensitization among Africans with asthma. Fungal asthma is a significant problem in Africa but there remains a paucity of data on the epidemiology and associated complications. There is urgent need for national epidemiological studies to estimate the actual burden of fungal asthma in Africa.
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