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There is a paucity of evidence surrounding the optimal antifungal therapy for use in chronic pulmonary aspergillosis (CPA) and the duration of therapy remains unclear. We retrospectively evaluated treatment outcomes, including change in quality of life scores (St George's Respiratory Questionnaire (QoL)), weight and Aspergillus IgG at 6 and 12 months following initiation of therapy in a cohort of 206 CPA patients referred to the UK National Aspergillosis Centre (NAC), Manchester between April 2013 and March 2015. One hundred and forty-two patients (69%) were azole naïve at presentation and 105 (74%) (Group A) were commenced on itraconazole, 27 (19%) on voriconazole, and 10 (7%) were not treated medically. The remainder (64 patients, 31%) had previously trialled, or remained on, azole therapy at inclusion (Group B) of whom 46 (72%) received itraconazole, 16 (25%) voriconazole, and 2 (3%) posaconazole. Initial therapy was continued for 12 months in 78 patients (48%) of those treated; the azole was changed in 62 (32%) patients and discontinued in 56 (29%) patients for adverse reactions (32, 57%), azole resistance (11, 20%), clinical failure (8, 14%) or clinical stability (5, 9%). Azole discontinuation rates were higher in Group B than in Group A (42% vs. 22%, p = 0.003). For all patients who survived, weight increased (median of 62.2Kg at baseline, to 64.8 at 12 months), mean Aspergillus IgG declined from 260 (baseline) to 154 (12 months) and QoL improved from 62.2/100 (baseline) to 57.2/100 (12 months). At 12 months, there was no difference in median survival between Groups A and B (95% vs. 91%, p = 0.173). The rate of emergence of resistance during therapy was 13% for itraconazole compared to 5% for voriconazole. Bronchial artery embolization was done in 9 (4.4%) patients and lobectomy in 7 (3.2%). The optimal duration of azole therapy in CPA is undetermined due to the absence of evidenced based endpoints allowing clinical trials to be undertaken. However we have demonstrated itraconazole and voriconazole are modestly effective for CPA, especially if given for 12 months, but fewer than 50% of patients manage this duration. This suggests extended therapy may be required for demonstrable clinical improvement.

Intracellular occupancy of the respiratory epithelium is a useful pathogenic strategy facilitating microbial replication and evasion of professional phagocytes or circulating antimicrobial drugs. A less appreciated but growing body of evidence indicates that the airway epithelium also plays a crucial role in host defence against inhaled pathogens, by promoting ingestion and quelling of microorganisms, processes that become subverted to favour pathogen activities and promote respiratory disease. To achieve a deeper understanding of beneficial and deleterious activities of respiratory epithelia during antimicrobial defence, we have comprehensively surveyed all current knowledge on airway epithelial uptake of bacterial and fungal pathogens. We find that microbial uptake by airway epithelial cells (AECs) is a common feature of respiratory host-microbe interactions whose stepwise execution, and impacts upon the host, vary by pathogen. Amidst the diversity of underlying mechanisms and disease outcomes, we identify four key infection scenarios and use best-characterised host-pathogen interactions as prototypical examples of each. The emergent view is one in which effi-ciency of AEC-mediated pathogen clearance correlates directly with severity of disease outcome, therefore highlighting an important unmet need to broaden our understanding of the antimicrobial properties of respiratory epithelia and associated drivers of pathogen entry and intracellular fate.

Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million people worldwide making it an under recognised, but significant health problem across the globe, conferring significant morbidity and mortality. With variable disease forms, high levels of associated respiratory co-morbidity, limited therapeutic options and prolonged treatment strategies, CPA is a challenging disease for both patients and healthcare professionals. CPA can mimic smear-negative tuberculosis (TB), pulmonary histoplasmosis or coccidioidomycosis. Cultures for Aspergillus are usually negative, however, the detection of Aspergillus IgG is a simple and sensitive test widely used in diagnosis. When a fungal ball/aspergilloma is visible radiologically, the diagnosis has been made late. Sometimes weight loss and fatigue are predominant symptoms; pyrexia is rare. Despite the efforts of the mycology community, and significant strides being taken in optimising the care of these patients, much remains to be learnt about this patient population, the disease itself and the best use of available therapies, with the development of new therapies being a key priority. Here, current knowledge and practices are reviewed, and areas of research priority highlighted.

Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of Aspergillus fumigatus. Inhaled Aspergillus spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of Aspergillus-epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of Aspergillus spores as either a curative or disease-exacerbating event.

The percentage of mucoid sputum isolates was also higher during the follicular phase, compared with the luteal phase when no mucoid strains were isolated, although again the sample size was small.

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011–2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies.

Self-concept clarity (SCC) is defined as the “extent to which the contents of an individual's self-concept (e.g., perceived personal attributes) are clearly and confidently defined, internally consistent, and temporally stable” (Campbell et al., 1996, p.141). This thesis set out to identify and explore the role of SCC and its associations with adult attachment, adverse childhood experiences (ACEs) and the development of psychotic-like experiences (PLEs). Section 1 describes a systematic literature review examining whether there is an association between SCC and close interpersonal relationships. Four subject databases (PsychINFO; CINAHL plus; PsychArticles; Academic Search Complete) were searched to identify relevant literature. Eight papers met the inclusion criteria, reporting on 15 studies. These explored romantic, parental and peer relationships in addition to global measures of attachment within adult and adolescent populations. There was strong evidence to support the association between SCC and close relationships, whereby high levels of SCC were association with greater relationship quality/satisfaction. Section 2 described a study which aimed to explore whether SCC mediated the relationship between anxious and avoidant attachment styles and PLEs, along with ACEs and PLEs. Participants from the general population were recruited via social media and completed measures via an online survey which aimed to capture data on SCC, ACEs, adult attachment and PLEs. Analyses revealed that SCC was a significant mediator of insecure attachment styles and PLEs, and ACEs and PLEs, indicating the importance in considering the role of SCC in psychological intervention for individuals who experience distress as a result of PLEs. Limitations of the study are discussed as well as considerations for future research and clinical practice. Section 3 describes a critical and reflective appraisal of aspects of the whole thesis. This includes an overview of the main findings, personal reflections, and further discusses the strengths and limitations of the research.

IntroductionAfter 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.AimTo evaluate the sex differences in the characteristics and treatment of patients with severe asthma (SA) in a real-world setting.MethodsDemographic, 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.Results3679 (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).ConclusionsFemales 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.

Aspergillus fumigatus and the human response to infection - the role of the bronchial epithelium Gemma Elizabeth Hayes, The University of Manchester, Doctor of Philosophy, January 2017 Background: A. fumigatus is an important human pathogen with disease manifestations being entirely dependent on the underlying state of the host immune system. Inhalation of A. fumigatus conidia forms the major route of infection and the bronchial epithelium forms the primary barrier to initial infection. However a paucity of data exists surrounding epithelial response in the presence of A. fumigatus, although recent evidence suggests it is more than a passive bystander. The contribution of genetic mutations and subtle immune deficiency to the pathogenesis of the most common forms of aspergillosis, severe asthma with fungal sensitisation (SAFS), allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are also poorly defined. Aim: This thesis explores these areas using a variety of techniques to address three key hypotheses: 1.The bronchial epithelium mounts an inflammatory response to the presence of inhaled conidia over the first 12 hours of infection. 2.The tyrosine kinase Fer, mutated in some individuals with asthma, is involved in the response of the healthy bronchial epithelium to A. fumigatus 3.Patients with CPA with deficiencies in the IL12-IFN gamma axis display a specific disease phenotype and benefit from replacement IFN gamma Results: A combination of RNASeq analysis, computer modelling, flow cytometry and ELISA suggest that the bronchial epithelium mounts a permissive, perhaps phagocytic, transcriptional response; raising the possibility of the development of unchecked latent reservoirs of bronchial infection within the bronchial epithelium in early infection. There is no evidence of a transcriptional or secretory inflammatory epithelial response. Transcriptional and translational evaluation of Fer, using qRT-PCR and Western Blot, demonstrates the presence of Fer in multiple cell types, including bronchial and alveolar lung cell lines, and reduced expression in the presence of serum. No changes in the quantity or phosphorylation state of Fer were demonstrated over the first 12 hours of infection, or in the face of escalating conidial dose. Preliminary data also suggests that Fer may be secreted into the extracellular environment. Retrospective cohort analysis of 41 patients treated with IFN gamma demonstrates that replacement therapy is tolerated and may be a useful adjunctive therapy in patients with deficiencies in the IL12-IFN gamma axis. However no specific patient phenotype most associated with response could be identified, and multiple areas for future research were highlighted. Conclusion: This is the first description of the transcriptional response of the bronchial epithelium to A. fumigatus over 12 hours and the first significant exploration of Fer within the respiratory epithelium. In terms of therapy the demonstration of possible benefit from IFN gamma therapy paves the way for further studies and highlights the need for greater research into assessment of the underlying disease phenotype in CPA. Overall important areas for further research have been highlighted and effective assays developed to facilitate this.

Background The sensitivity of patient-reported outcomes (PROs) to detect the effects of treatment change depends on the match between the change in items of the PRO and the change that takes place in a sample of people. The aim of this study is to compare the sensitivity of different PROs in detecting changes following the initiation of biologic treatment in asthma. Methods: Patients starting a biologic treatment as part of clinical care completed the Asthma Control Questionnaire (ACQ-6), the Severe Asthma Questionnaire (SAQ and SAQ-global scores) and the EQ5D (EQ-5D-5L and EQ5D-VAS) at baseline. They completed the ACQ-6, SAQ, SAQ-global and a retrospective global rating of change (GRoC) scale at weeks 4, 8 and 16 and completed the EQ-5D-5L and EQ5D-VAS at week 16. The SAQ-global and EQ5D-VAS differ but both are single item 100-point questions. Sensitivity was measured by Cohen’s D effect size at each of the three time points. Results: 110 patients were recruited. Depending on the time of assessment, effect size varied between 0.45 and 0.64 for the SAQ, between 0.50 and 0.77 for the SAQ-global; between 0.45 and 0.69 for ACQ-6; between 0.91 and 1.22 for GRoC; 0.32 for EQ-5D-5L and 0.49 for EQ5D-VAS. Conclusion: The sensitivity to change of a questionnaire varies with the time of measurement. The three asthma-specific prospective measures (SAQ, SAQ-global and ACQ-6) have similar sensitivity to change. The single-item EQ5D-VAS was less sensitive than the asthma specific measures and less sensitive than the single-item SAQ-global. The EQ-5D-5L was least sensitive.