The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients.

BACKGROUND: Fungal sensitivity has been associated with severe asthma outcomes. However, the clinical implication of Aspergillus fumigatus sensitization in difficult-to-treat (or difficult) asthma is unclear. OBJECTIVES: To characterize the clinical implications of A fumigatus sensitization in a large difficult asthma cohort. METHODS: Participants who underwent both skin prick and specific IgE testing to A fumigatus (n = 318) from the longitudinal real-life Wessex AsThma CoHort of difficult asthma, United Kingdom, were characterized by A fumigatus sensitization (either positive skin prick test result or specific IgE) and allergic bronchopulmonary aspergillosis status using clinical/pathophysiological disease measures. RESULTS: A fumigatus sensitization was found in 23.9% (76 of 318) of patients with difficult asthma. Compared with A fumigatus nonsensitized subjects, those with sensitization were significantly more often male (50% vs 31%), older (58 years) with longer asthma duration (33 years), higher maintenance oral corticosteroid (39.7%) and asthma biologic use (27.6%), raised current/maximum log10 total IgE+1 (2.43/2.72 IU/L), worse prebronchodilator airflow obstruction (FEV1 62.2% predicted, FEV1/forced vital capacity 61.2%, forced expiratory flow between 25% and 75% exhalation 30.9% predicted), and frequent radiological bronchiectasis (40%), but had less psychophysiologic comorbidities. Allergic bronchopulmonary aspergillosis diagnosis was associated with higher treatment needs and stronger eosinophilic signals. Factors independently associated with A fumigatus sensitization in difficult asthma included maintenance oral corticosteroid use (odds ratio [OR], 3.34) and maximum log10 total IgE+1 (OR, 4.30), whereas for allergic bronchopulmonary aspergillosis included maintenance oral corticosteroid use (OR, 6.98), maximum log10 total IgE+1 (OR, 4.65), and radiological bronchiectasis (OR, 4.08). CONCLUSIONS: A fumigatus sensitization in difficult asthma identifies a more severe form of airways disease associated with greater morbidity, treatment need, and airways dysfunction/damage, but fewer psychophysiologic comorbidities. Screening of A fumigatus status should be an early element in the comprehensive assessment of patients with difficult asthma.

Bioelectrical spectroscopy impedance phase angle is not associated with nutritional status in a stable cohort of paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Nutritional assessment in paediatric inflammatory bowel disease (IBD) is key to supporting growth whilst minimising adiposity. Bedside assessment using bioelectrical impedance spectroscopy (BIS) has previous identified patients with declining cellular and nutritional health. We aimed to assess BIS measures in stable paediatric IBD patient. METHODS: Stable IBD patients were recruited at routine hospital visits. All patients underwent BIS, anthropometry and disease activity assessment. Multivariable regression and receiver operator curve (ROC) analyses were undertaken to assess the utility of BIS phase angle 50 KHz (PA-50) and 200/5 KHz impedance ratio (IR) in nutritional assessment. RESULTS: There were 140 study visits from 97 patients, mean age 14.49 years, 62.9% Crohn's disease. Mean BMI Z-score (BMIZ) was 0.31 (range -2.97 to 3.99), 33% of patients were overweight (BMIZ>1) and 13.8% of patients were underweight (BMIZ < -1). Crohn's disease patients had a lower mean BMIZ score 0.14, compared to ulcerative colitis, 0.68, p = 0.007. There was no relationship between PA-50 and BMIZ or disease activity. IR was not related to disease activity but was negatively related to BMIZ in a multivariable regression, accounting for age, sex and disease subtype (beta -0.331, p = 0.001). ROC analyses did not identify a clinically useful cut off for either PA-50 or IR to identify patients with active disease, biologic use or BMIZ>1 or < -1. CONCLUSION: BIS appears to have limited added value in nutritional assessment of stable paediatric IBD patients. Nearly 1/3 patients were overweight and personalised approach to supplementation is vital to avoid overnutrition.

Clinical evaluation of type 2 disease status in a real-world population of difficult to manage asthma using historic electronic healthcare records of blood eosinophil counts.

BACKGROUND: Blood eosinophil measurement is essential for the phenotypic characterization of patients with difficult asthma and in determining eligibility for anti-IL-5/IL-5Rα biological therapies. However, assessing such measures over limited time spans may not reveal the true underlying eosinophilic phenotype, as treatment, including daily oral corticosteroid therapy, suppresses eosinophilic inflammation and asthma is intrinsically variable. METHODS: We interrogated the electronic healthcare records of patients in the Wessex AsThma CoHort of difficult asthma (WATCH) study (UK). In 501 patients being evaluated in this tertiary care centre for difficult to control asthma, all requested full blood count test results in a 10-year retrospective period from the index WATCH assessment were investigated (n = 11,176). RESULTS: In 235 biological therapy-naïve participants who had 10 or more measures in this time period, 40.3% were eosinophilic (blood eosinophils ≥300 cells/µl) at WATCH enrolment whilst an additional 43.1%, though not eosinophilic at enrolment, demonstrated eosinophilia at least once in the preceding decade. Persistent eosinophilia was associated with worse post-bronchodilator airway obstruction and higher Fractional exhaled Nitric Oxide (FeNO). In contrast, the 16.6% of patients who never demonstrated eosinophilia at this blood eosinophil threshold showed preserved lung function and lower markers of Type 2 inflammation. CONCLUSIONS: This highlights the central role that type 2 inflammation, as indicated by blood eosinophilia, has in difficult asthma and suggests that longitudinal electronic healthcare record analysis can be an important tool in clinical asthma phenotyping, providing insight that may help understand disease progression and better guide more specific treatment approaches.

Can routine blood tests be modelled to detect advanced liver disease in the community: model derivation and validation using UK primary and secondary care data.

OBJECTIVES: Most patients are unaware they have liver cirrhosis until they present with a decompensating event. We therefore aimed to develop and validate an algorithm to predict advanced liver disease (AdvLD) using data widely available in primary care. DESIGN, SETTING AND PARTICIPANTS: Logistic regression was performed on routinely collected blood result data from the University Hospital Southampton (UHS) information systems for 16 967 individuals who underwent an upper gastrointestinal endoscopy (2005-2016). Data were used to create a model aimed at detecting AdvLD: 'CIRRhosis Using Standard tests' (CIRRUS). Prediction of a first serious liver event (SLE) was then validated in two cohorts of 394 253 (UHS: primary and secondary care) and 183 045 individuals (Care and Health Information Exchange (CHIE): primary care). PRIMARY OUTCOME MEASURES: Model creation dataset: cirrhosis or portal hypertension. Validation datasets: SLE (gastro-oesophageal varices, liver-related ascites or cirrhosis). RESULTS: In the model creation dataset, 931 SLEs were recorded (5.5%). CIRRUS detected cirrhosis or portal hypertension with an area under the curve (AUC) of 0.90 (95% CI 0.88 to 0.92). Overall, 3044 (0.8%) and 1170 (0.6%) SLEs were recorded in the UHS and CHIE validation cohorts, respectively. In the UHS cohort, CIRRUS predicted a first SLE within 5 years with an AUC of 0.90 (0.89 to 0.91) continuous, 0.88 (0.87 to 0.89) categorised (crimson, red, amber, green grades); and AUC 0.84 (0.82 to 0.86) and 0.83 (0.81 to 0.85) for the CHIE cohort. In patients with a specified liver risk factor (alcohol, diabetes, viral hepatitis), a crimson/red cut-off predicted a first SLE with a sensitivity of 72%/59%, specificity 87%/93%, positive predictive value 26%/18% and negative predictive value 98%/99% for the UHS/CHIE validation cohorts, respectively. CONCLUSION: Identification of individuals at risk of AdvLD within primary care using routinely available data may provide an opportunity for earlier intervention and prevention of liver-related morbidity and mortality.

Patient perceived barriers to exercise and their clinical associations in difficult asthma.

BACKGROUND: Exercise is recommended in guidelines for asthma management and has beneficial effects on symptom control, inflammation and lung function in patients with sub-optimally controlled asthma. Despite this, physical activity levels in patients with difficult asthma are often impaired. Understanding the barriers to exercise in people with difficult asthma is crucial for increasing their activity, and in implementing successful, disease modifying, and holistic approaches to improve their health. METHODS: 62 Patients within the WATCH Difficult Asthma Cohort (Southampton, UK) completed an Exercise Therapy Burden Questionnaire (ETBQ). The results were analyzed with contemporaneous asthma-related data to determine relationships between perceived exercise barriers and asthma and comorbidity characteristics. RESULTS: Patients were reflective of a difficult asthma cohort, 66% were female, and 63% were atopic. They had a high BMI (median [inter-quartile range]) of 29.3 [25.5-36.2], age of 53.5 [38.75, 65.25], impaired spirometry with FEV1 73% predicted [59.5, 86.6%] and FEV/FVC ratio of 72 [56.5, 78.0] and poor symptom control, as defined by an Asthma Control Questionnaire (ACQ6) result of 2.4 [1.28, 3.2]. A high perceived barriers to exercise score was significantly correlated with increased asthma symptoms (r = 0.452, p < 0.0001), anxiety (r = 0.375, p = 0.005) and depression (r = 0.363, p = 0.008), poor quality of life (r = 0.345, p = 0.015) and number of rescue oral steroid courses in the past 12 months (r = 0.257, p = 0.048). Lung function, blood eosinophil count, FeNO, Njimegen and SNOT22 scores, BMI and hospitalisations in the previous year were not related to exercise perceptions. CONCLUSION: In difficult asthma, perceived barriers to exercise are related to symptom burden and psychological morbidity. Therefore, exercise interventions combined with psychological input such as CBT to restructure thought processes around these perceived barriers may be useful in facilitating adoption of exercise.

New Perspectives on Difficult Asthma; Sex and Age of Asthma-Onset Based Phenotypes.

BACKGROUND: Asthma is a diverse condition that differs with age and sex. However, it remains unclear how sex, age of asthma onset, and/or their interaction influence clinical expression of more problematic adult "difficult" asthma. OBJECTIVES: To better understand the clinical features of difficult asthma within a real-world clinical setting using novel phenotypic classification, stratifying subjects by sex and age of asthma onset. METHODS: Participants in a longitudinal difficult asthma clinical cohort study (Wessex AsThma CoHort of difficult asthma; WATCH), United Kingdom (n = 501), were stratified into 4 difficult asthma phenotypes based on sex and age of asthma onset (early <18 years or adult ≥18 years) and characterized in relation to clinical and pathophysiological features. RESULTS: The cohort had more female participants (65%) but had similar proportions of participants with early- or adult-onset disease. Early-onset female disease was commonest (35%), highly atopic, with good spirometry and strong associations with some physical comorbidities but highest psychophysiologic comorbidities. Adult-onset females also had considerable psychophysiologic comorbidities and highest obesity, and were least atopic. Amongst male subjects, proportionately more had adult-onset disease. Early-onset male disease was rarest (14%) but associated with worst lung function, high smoking, atopy, and fungal sensitization. Despite shortest disease duration, adult-onset males had highest use of maintenance oral corticosteroid, poor lung function, and highest fractional exhaled nitrogen oxide in spite of highest smoking prevalence. CONCLUSIONS: This study shows that sex, age of asthma onset, and their interactions influence different clinical manifestations of difficult asthma and identifies a greater risk for lung function loss and oral corticosteroid dependence associated with smoking in adult-onset male subjects.

Protocol for the Wessex AsThma CoHort of difficult asthma (WATCH): a pragmatic real-life longitudinal study of difficult asthma in the clinic.

BACKGROUND: Asthma is now widely recognised to be a heterogeneous disease. The last two decades have seen the identification of a number of biological targets and development of various novel therapies. Despite this, asthma still represents a significant health and economic burden worldwide. Why some individuals should continue to suffer remains unclear. METHODS: The Wessex Asthma Cohort of Difficult Asthma (WATCH) is an ongoing 'real-life', prospective study of patients in the University Hospital Southampton Foundation Trust (UHSFT) Difficult Asthma service. Research data capture is aligned with the extensive clinical characterisation required of a commissioned National Health Service (NHS) Specialist Centre for Severe Asthma. Data acquisition includes detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, radiological imaging (in a small subset) and collection of biological samples (blood, urine and sputum). Prospective data are captured in parallel to clinical follow up appointments, with data entered into a bespoke database. DISCUSSION: The pragmatic ongoing nature of the WATCH study allows comprehensive assessment of the real world clinical spectrum seen in a Specialist Asthma Centre and allows a longitudinal perspective of deeply phenotyped patients. It is anticipated that the WATCH cohort would act as a vehicle for potential collaborative asthma studies and will build upon our understanding of mechanisms underlying difficult asthma.

Local care and treatment of liver disease (LOCATE) - A cluster-randomized feasibility study to discover, assess and manage early liver disease in primary care.

BACKGROUND: Chronic liver disease is an escalating problem both in the United Kingdom and worldwide. In the UK mortality rates have risen sharply over the previous 50 years predominantly due to alcohol, however the increasing prevalence of non-alcohol related fatty liver disease both in the UK and elsewhere is also of concern. Liver disease develops silently hence early detection of fibrosis is essential to prevent progression. Primary care presents an opportunity to identify at risk populations, however assessment largely comprises of indirect markers of fibrosis which have little prognostic value. We hypothesised that setting up nurse-led primary care based liver clinics using additional non-invasive testing would increase the number of new diagnoses of liver disease compared to usual care. METHODS: This was a prospective, cluster randomised feasibility trial based in urban primary care in Southampton, United Kingdom. 10 GP practices were randomised to either intervention (liver health nurse) or control (care as usual). Pre recruitment audits were carried out in each practice to ascertain baseline prevalence of liver disease. Participants were subsequently recruited in intervention practices from July 2014-March 2016 via one of 3 pathways: GP referral, nurse led case finding based on risk factors or random AUDIT questionnaire mailouts. Liver assessment included the Southampton Traffic Light test (serum fibrosis markers HA and P3NP) and transient elastography (FibroScan). Cases were ascribed as 'no fibrosis', 'liver warning', 'progressive fibrosis' or 'probable cirrhosis'. Post recruitment audits were repeated and incident liver diagnoses captured from July 2014-September 2016. Each new diagnosis was reviewed in a virtual clinic by a consultant hepatologist. FINDINGS: 910 participants were seen in the nurse led clinic-44 (4.8%) probable cirrhosis, 141 (15.5%) progressive fibrosis, 220 (24.2%) liver warning and 505 (55.5%) no evidence of liver fibrosis. 450 (49.5%) cases were due to NAFLD with 356 (39.1%) from alcohol. In the 405 with a liver disease diagnosis, 136 (33.6%) were referred by GP, 218 (53.8%) from nurse led case finding and 51 (12.6%) from the AUDIT mailout. 544 incident cases were identified in the intervention arm compared to 221 in the control arm in the period July 2014-September 2016 (adjusted odds ratio 2.4, 95% CI 2.1 to 2.8). CONCLUSIONS: The incorporation of a liver health nurse into GP practices was simple to arrange and yielded a much higher number of new diagnoses of liver disease compared to usual care. Nearly half of all participants recruited had a degree of liver disease. Nurse led case finding and GP referrals were most effective compared to AUDIT questionnaire mailouts in an urban population in identifying unknown disease. Utilising study and previous data allowed quick and effective virtual review by a hepatologist. Identifying those who are at risk of liver disease from harmful alcohol use remains a challenge and needs to be addressed in future work.

Did NICE guidelines and the Quality Outcomes Framework change GP antidepressant prescribing in England? Observational study with time trend analyses 2003-2013.

BACKGROUND: Both the 2004 NICE depression guidelines and 2006 general practice Quality Outcomes Framework (QOF) encouraged improved targeting of antidepressant treatment for depression. METHODS: Possible effects of the NICE guideline from January 2005, and QOF from April 2006, on rates of GP antidepressant prescribing were examined using time trend analyses of anonymised data from 142 English practices contributing to the Clinical Practice Research Datalink (CPRD), 2003-2013. RESULTS: Sustained reductions were found in the proportion of first-ever depression episodes treated within 12 months, of 4.2% (95% C.I. 1.0-7.3%) following introduction of the NICE guideline, and 4.4% (2.3-6.5%) following introduction of the QOF. Treatment rates for first-ever episodes fell from 72.5% (70.8-74.1%) in Quarter 2 (Q2) 2003 to 61.0% (59.3-62.7%) in Q1 2012, but treatment rates for recurrent episodes increased from 74.3% (72.8-75.8%) to 77.8% (76.5-79.1%), so overall rates remained around 70%. Mean prescriptions per patient per year doubled from 2.06 (2.05-2.07) to 3.98 (3.97-3.99). LIMITATIONS: Participating practices were larger than average and not representative across regions. Inferences of cause and effect from time trend analyses are subject to the possibility of unidentified confounders. No data were available on depression severity or appropriateness of prescribing. CONCLUSIONS: Rates of GP antidepressant treatment for patients with incident depression fell following introduction of NICE depression guidelines and the QOF, but treatment rates for recurrent depression increased. Prescription numbers increased due to longer treatment courses. To impact on antidepressant prescribing rates, guidelines and performance indicators must address recurrent and long-term prescribing, rather than initial treatment decisions.

Changes in rates of recorded depression in English primary care 2003-2013: Time trend analyses of effects of the economic recession, and the GP contract quality outcomes framework (QOF).

BACKGROUND: Depression may be increasing, particularly since the economic recession. Introduction of quality outcomes framework (QOF) performance indicators may have altered GP recording of depression. METHODS: Time trend analyses of GP recording of depression before and after the recession (from April 2008), and the QOF (from April 2006) were conducted on anonymised consultation data from 142 English practices contributing to the Clinical Practice Research Datalink, April 2003-March 2013. RESULTS: 293,596 patients had computer codes for depressive diagnoses or symptoms in the 10 years. Prevalence of depression codes fell from 44.6 (95% CI 44.2, 45.0) per 1000 person years at risk (PYAR) in 2003/2004 to 38.0 (37.7, 38.3) in 2008/2009, rising to 39.5 (39.2, 39.9) in 2012/2013. Incidence of first-ever depression codes fell from 11.9 (95% CI 11.7, 12.1) per 1000 PYAR in 2003/2004 to 9.5 (9.3, 9.7) in 2008/2009, rising to 10.0 (9.8, 10.2) in 2012/1203. Prevalence increased in men but not women following the recession, associated with increased unemployment. Following introduction of the QOF, GPs used more non-QOF-qualifying symptom or other codes than QOF-qualifying diagnostic codes for new episodes. LIMITATIONS: Clinical data recording is probably incomplete. Participating practices were relatively large and not representative across English regions. CONCLUSIONS: Rates of recorded depression in English general practices were falling prior to the economic recession but increased again subsequently, among men, associated with increased unemployment. GPs responded to the QOF by switching from diagnostic to symptom codes, removing most depressed patients from the denominator for measuring GP performance in assessing depression.

Social exposure to an antiretroviral treatment programme in rural KwaZulu-Natal.

OBJECTIVE: To investigate the prevalence of social exposure to a large, government-run ART programme in rural South Africa. METHOD: Clinical data on 6681 patients were matched with demographic data on a nearly complete cohort of 102,359 people residing in the programme catchment area. We calculated the proportion of residents in the demographic surveillance area that were members of a household, or resided in a compound where someone had initiated ART or received pre-ART care. RESULTS: By January 2010, 3% of the population had initiated ART. However, 25% of the population shared household membership or resided in a compound with someone who had initiated ART; 40% shared household or living arrangements with people who had either initiated ART or were enrolled in pre-ART care. CONCLUSION: Such high rates of social exposure suggest that ART programmes in HIV endemic areas are likely to have significant population-level effects on social norms and economic welfare. These results also point to the opportunity to reach large numbers of people with health and social services through existing ART programmes.