Philip Foden

Preventing Severe Asthma Exacerbations in Children: A Randomised Trial of Mite Impermeable Bedcovers

&NA; Rationale: Allergen exposure in sensitized individuals with asthma interacts with viruses to increase the risk of asthma exacerbation. Objectives: To evaluate the use of house dust mite‐impermeable bedding and its impact on severe asthma exacerbations in children. Methods: We randomized mite‐sensitized children with asthma (ages 3‐17 yr) after an emergency hospital attendance with an asthma exacerbation to receive mite‐impermeable (active group) or control (placebo group) bed encasings. Measurements and Main Results: Over a 12‐month intervention period, the occurrence of severe asthma exacerbations was investigated. Of 434 children with asthma who consented, 286 (mean age, 7.7 yr; male sex, 65.8%) were mite sensitized, and 284 were randomized (146 to the active group and 138 to the placebo group). At 12 months, significantly fewer children in the active group than in the placebo group had attended the hospital with an exacerbation (36 [29.3%] of 123 vs. 49 [41.5%] of 118; P = 0.047). In the multivariable analysis, the risk of emergency hospital attendance was 45% lower in the active group (hazard ratio, 0.55; 95% confidence interval [CI], 0.36‐0.85; P = 0.006) than in the placebo group. The annual rate of emergency hospital attendance with exacerbations was 27% lower in the active group than in the placebo group, but this did not reach significance (estimated marginal mean [95% CI], active, 0.38 [0.26‐0.56] vs. placebo, 0.52 [0.35‐0.76]; P = 0.18). No difference between the groups in the risk of prednisolone use for exacerbation was found (hazard ratio, 0.82; 95% CI, 0.58‐1.17; P = 0.28). Conclusions: Mite‐impermeable encasings are effective in reducing the number of mite‐sensitized children with asthma attending the hospital with asthma exacerbations but not the number requiring oral prednisolone. This simple measure may reduce the health care burden of asthma exacerbations in children. Clinical trial registered with www.isrctn.com (ISRCTN 69543196).

Chronic pulmonary aspergillosis as a cause of smear negative TB and or anti-TB treatment failure in Nigerians

OBJECTIVE To evaluate chronic pulmonary aspergillosis (CPA) as an alternative diagnosis of smear-negative tuberculosis (TB) and treatment failure in TB patients in Nigeria. METHODS We conducted a cross-sectional multicentre survey in human immunodeficiency virus (HIV) positive and negative adult patients at the end of their TB treatment in clinics in Lagos and Ilorin states. All were assessed using clinical examination, chest X-ray (CXR) and aspergillus immunoglobulin G (IgG) serology, and some for sputum fungal culture. CPA was defined as a positive Aspergillus fumigatus IgG titre with compatible CXR or a positive sputum culture of Aspergillus with a visible fungal ball on CXR with symptoms of underlying lung disease. RESULTS Of 208 patients recruited between June 2014 and May 2015, 153 (73.6%) were HIV-positive. The mean age was 39.8 years, 124 (59.6%) were female and 39 (18.8%) were unable to work. The median CD4 count was 169.5 cells/ml (range 4-593) in HIV-infected patients with positive Aspergillus IgG. Overall, 109 (52.4%) had documented TB, 140 (67.3%) had a productive cough and 50 had haemoptysis. CPA prevalence was 8.7%; 10 (6.5%) had HIV infection and 8 (14.5%) were HIV-negative (Fishers exact P = 0.092). CONCLUSION CPA is a neglected disease in Nigeria, and most cases match the World Health Organization diagnostic criteria for smear-negative TB.

Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study

Summary Background Concerns have been expressed about asthma overdiagnosis. The UK National Institute of Health and Care Excellence (NICE) proposed a new diagnostic algorithm applying four lung function measures sequentially (ratio of forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] <70%, bronchodilator reversibility ≥12%, fractional exhaled nitric oxide [FeNO] ≥35 parts per billion, and peak expiratory flow variability >20%). We aimed to assess the diagnostic value of three of the tests individually, and then test the proposed algorithm in symptomatic children. Methods We used follow-up data at age 13–16 years from the Manchester Asthma and Allergy Study, a prospective, population-based, birth cohort study. We initially present results for the whole population, then by subgroup of disease. To simulate the situation in primary care, we included participants reporting symptoms of wheeze, cough, or breathlessness in the previous 12 months and who were not on regular inhaled corticosteroids. We used an epidemiological definition of current asthma, defined as all three of physician-diagnosed asthma, current wheeze, and current use of asthma treatment, reported by parents in a validated questionnaire. We assigned children with negative answers to all three questions as non-asthmatic controls. We also measured spirometry, bronchodilator reversibility, and FeNO at follow-up; data for peak expiratory flow variability were not available. We calculated the proportion of participants with a current positive lung function test at each step of the algorithm, and recorded the number of participants that met our definition of asthma. Findings Of 1184 children born into the cohort, 772 attended follow-up at age 13–16 years between July 22, 2011, and Nov 11, 2014. Among 630 children who completed spirometry, FEV1:FVC was less than 70% in ten (2%) children, of whom only two (20%) had current asthma. Bronchodilator reversibility was positive in 54 (9%) of 624 children, of whom only 12 (22%) had current asthma. FeNO was 35 or more parts per billion in 115 (24%) of 485 children, of whom 29 (25%) had current asthma. Only four of 56 children with current asthma had positive results for all three tests (spirometry, bronchodilator reversibility, and FeNO). Conversely, 24 (43%) of the 56 children with current asthma were negative on all three tests. FEV1:fvc (p=0·0075) and FeNO (p<0·0001), but not bronchodilator reversibility (p=0·97), were independently associated with asthma in multivariable logistic regression models. Among children who reported recent symptoms, the diagnostic accuracy of the algorithm was poor. Interpretation Our findings challenge the proposed cutoff values for spirometry, the order in which the lung function tests are done, and the position of bronchodilator reversibility within the algorithm sequence. Until better evidence is available, the proposed NICE algorithm on asthma diagnosis should not be implemented in children. Funding UK Medical Research Council.

Adequacy of Intraoperative Nodal Staging during Surgical Resection of NSCLC: Influencing Factors and Its Relationship to Survival

Introduction Adequate intraoperative lymph node sampling is a fundamental part of lung cancer surgery, but adherence to standards is not well known. This study sought to measure the adequacy of intraoperative lymph node sampling at a regional Thoracic Surgery Centre and a tertiary lung cancer center in the United Kingdom. Methods This retrospective study analyzed the pathological reports from NSCLC resections over the 4‐year period 2011–2014. Adequacy of sampling was assessed against International Association for the Study of Lung Cancer recommendations of at least three mediastinal lymph node stations: station 7 in all patients, station 5 or 6 in left upper lobe tumors, and station 9 in lower lobe tumors. The influence of clinical variables (age, tumor T stage, type of surgery, and laterality) on adequacy of sampling and the effect of adequacy on overall survival were also assessed. Results A total of 1301 NSCLC resections were performed from January 11, 2011, to December 31, 2014. Adequate intraoperative lymph node sampling increased significantly from 14% (22 of 160) in 2011 to 53% (206 of 390) in 2014 (p = 0.001). Secondary analysis of clinical variables also revealed that patients with T1a or T4 tumors, those undergoing sublobar resections, those undergoing video‐assisted thoracic surgery resections, and those undergoing left‐sided resections have significantly higher rates of inadequate lymph node sampling. Overall, there was no statistically significant difference in survival between patients with adequate versus inadequate intraoperative lymph node sampling or when survival was stratified according to overall stage. There was worse survival in inadequate sampling for patients with pN2 disease than for patients with pN2 disease and adequate sampling. Conclusion This study provides a much‐needed benchmark of current thoracic surgical practice in lung cancer in the United Kingdom and important granularity to facilitate changes to improve adequacy of staging.

Illness Beliefs in End Stage Renal Disease and Associations with Self-Care Modality Choice.

Background Interest in self-care haemodialysis (HD) has increased because it improves patients’clinical and quality-of-life outcomes. Patients who undertake self-management for haemodialysis may hold illness beliefs differently to those choosing institutional care at the time of making the modality choice or moulded by their illness and dialysis treatment experience. Illness perceptions amongst predialysis patients and in those undertaking fully-assisted and self-care haemodialysis are being investigated in a combined cross-sectional and longitudinal study. Study Design The study data are derived from the BASIC-HHD study, a multicentre observational study on factors influencing home haemodialysis uptake. 535 patients were enrolled into three groups: Predialysis CKD-5 group, prevalent ‘in-centre’ HD and self-care HD groups (93% at home). We explore illness perceptions in the cross-sectional analyses of the three study groups, using the revised Illness Perception Questionnaire (IPQ-R). Predialysis patients’ illness beliefs were reassessed prospectively, typically between 4 and 12 months after dialysis commencement. Results Illness belief subscales are significantly different between in-centre and self-care HD groups. In a step-wise hierarchical regression analysis, after adjustment for age, education, marital status, diabetes, dialysis vintage, depression, anxiety scores, and IPQ-R subscales, personal control (p = 0.01) and illness coherence (p = 0.04) are significantly higher in the self-care HD group. In the predialysis group, no significant associations were found between illness representations and modality choices. In prospectively observed predialysis group, scores for personal control, treatment control, timeline cyclical and emotional representations reduced significantly after commencing dialysis and increased significantly for illness coherence. Conclusions Illness beliefs differ between hospital and self-care haemodialysis patients. Patient’s affect and neurocognitive ability may have an important role in determining illness beliefs. The impact of modality upon illness representations may also be significant and remains to be explored.

Innate and Adaptive Immune Defects in Chronic Pulmonary Aspergillosis

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43–21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36–15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10–0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30–6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39–17.57; p = 0.014). Several subtle immune defects are found in CPA.

Comparative performance of Aspergillus galactomannan ELISA and PCR in sputum from patients with ABPA and CPA

OBJECTIVES Galactomannan (GM) and Aspergillus DNA detection are useful tools for the diagnosis of invasive pulmonary aspergillosis (IPA), primarily in blood and bronchoscopy samples. This study aimed to evaluate the utility of both markers for detection of Aspergillus in sputum from patients with allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). METHODS ABPA or CPA demographic patient data were retrieved. This retrospective observational audit included 159 patients with at least one sputum pair. 223 sputum sample pairs were analysed, as well as six control samples for GM only. Real time PCR was performed following sputum DNA extraction using the MycAssay™ Aspergillus kit and cycle thresholds were subtracted from 38 to give positive values (transformed Ct, TCt). RESULTS The mean age of the patients was 61.81years (SD: ±11.06; range 29-100). One hundred and twenty-six (79.2%) had CPA. Cultures were positive for fungi in 13.1% of the samples, and A. fumigatus was the commonest (11.9%) fungus isolated. Receiver operating characteristic (ROC curve) analysis of sputum GM comparing TCt of >0.0, and >2.0 to derive GMI cut-off values showed a cut-off of 6.5. About 50% of sputa with strongly positive PCR values had GM values>6.5. Two of six (33%) control samples had GM indices>6.5. CONCLUSION It is not clear that GM determinations in sputum are useful for diagnosis of either CPA or ABPA, or following therapy.

The Burden of Cognitive Impairment in Patients With End-Stage Renal Disease and Impact on Dialysis Modality Choice

Introduction Kidney disease is associated with significant cognitive dysfunction. Subjective reports of cognitive ability have not been studied extensively in chronic kidney disease. We investigated the association between objective and subjective cognitive functions in predialysis patients and their association with self-care dialysis modality choice. Methods Cross-sectional data from the Barriers to Successful Implementation of Care in Home Haemodialysis study were used for the study of cognition in 220 predialysis patients. The data were used to ascertain the demographics, clinical, laboratory, and neuropsychometric variables. The latter includes Trail Making Tests (TMT) parts A and B, Modified Mini Mental State Examination, and metacognition questionnaire for subjective assessment of one’s cognitive ability. The outcome variable was fully assisted and self-care dialysis modality choice. Results Within the study cohort, 90 patients chose fully assisted hemodialysis and 114 patients chose self-care dialysis. The median Modified Mini Mental State Examination, TMT part A, and TMT part B scores were greater for the assisted versus the self-care group. Metamemory was not significantly different between groups, but the metaconcentration score was significantly worse in the group choosing assisted dialysis. Higher (i.e., better) metaconcentration scores were significantly associated with the self-care modality choice in the univariate and hierarchical regression analyses. Adjusted and unadjusted analyses showed a significant association between perceived concentration and TMT part B scores (P < 0.01). With every 1.6-minute increase in TMT part B score, there was a 1-unit reduction in metaconcentration score, and the latter was associated with 20% lower odds of choosing self-care dialysis over a fully assisted dialysis modality. Discussion Patients’ self-perception of cognitive ability is a significant predictor of self-care dialysis modality choice. Subjective report of “metaconcentration” is also strongly associated with poorer outcome on the TMT part B.

Self-cannulation for haemodialysis: patient attributes, clinical correlates and self-cannulation predilection models.

Background and Objectives With emerging evidence in support of home haemodialysis (HHD), patient factors which determine uptake of the modality need to be better understood. Self-cannulation (SC) is a major step towards enabling self-care ‘in-centre’ and at home and remains the foremost barrier to its uptake. Human factors governing this aspect of HD practice are poorly understood. The aim of this study is to better understand self-cannulation preferences and factors which define them in end stage renal disease (ESRD). Design In this multicentre study, 508 of 535 patients from predialysis (Group A: n = 222), in-centre (Group B: n = 213), and home HD (Group C: n = 100) responded to a questionnaire with 3 self-cannulation questions. Simultaneously, data on clinical, cognitive and psychosocial variables were ascertained. The primary outcome measure was ‘perceived ability to self-cannulate AV access’. Predictive models were developed using logistic regression analysis. Results 36.6% of predialysis patients (A) and 29.1% of the ‘in-centre’ haemodialysis patients (B) felt able to consider SC for HD. Technical-skills related apprehension was highest in Group B (14.4%) patients. Response to routine venepuncture and the types of SC concerns were significant predictors of perceived ability to self-cannulate. There was no significant difference in concern for pain across the groups. In multivariable regression analysis, age, education level, 3MS score, hypoalbuminemia in Groups B & C and additionally, attitude to routine phlebotomy and the nature of specific concern for self-cannulation in Groups A, B and C, are significant predictors of SC preference. The unadjusted c-statistics of models 1 (derived from Group A and validated on A) and 2 (derived from B+C and validated on B), are 0.76(95% CI 0.69, 0.83) and 0.80 (95% CI 0.74, 0.87) respectively. Conclusions There is high prevalence of perceived ability to self-cannulate. Modifiable SC concerns exist in ESRD. The use of predictive models to objectively define and target education and training strategies could potentially impact on HD self-management and future uptake of home HD.

Prior subclinical histoplasmosis revealed in Nigeria using histoplasmin skin testing

Objectives Disseminated histoplasmosis is an AIDS-defining illness. Histoplasmosis is commonly misdiagnosed as tuberculosis. Nigeria has the second highest number of people living with HIV/AIDS in Africa. The present study was carried out to investigate the prevalence of skin sensitivity amongst Nigerians to histoplasmin. Design A cross-sectional study was conducted in six centres across five geopolitical zones of Nigeria. Methods We recruited both healthy non-HIV and HIV-positive adults with CD4 count ≥ 350 cells/mm3 regardless of their ART status from March to May 2017. Skin tests were performed intradermally; induration ≥5 mm were considered to be histoplasmin positive. Results 750 participants were recruited from Lagos (n = 52), Yola (n = 156), Ilorin (n = 125), Calabar (n = 120), Ibadan (n = 202) and Benin (n = 95). 467 (62.3%) were HIV negative, 247 (32.9%) were HIV positive and 36 (4.8%) did not know their HIV status. A total of 32/735 (4.4%) participants had a positive skin test. Study centre (p<0.001), education (p = 0.002) and age (p = 0.005) appeared to be significantly associated with positive skin reactivity at the 0.5% significance level, while sex (p = 0.031) and occupation (p = 0.031) would have been significant at the 5% significance level. Males had a higher rate of reactivity than females (p = 0.031, 7% vs 3%). The highest positive rates were recorded from Benin City (13/86 (15%)) and Calabar (7/120 (6%)) and no positives were recorded in Lagos (p<0.001). HIV status was not statistically significant (p = 0.70). Conclusion Histoplasmosis diagnostics should be included in the Nigerian HIV guidelines. Epidemiological vigilance of progressive disseminated histoplasmosis should be considered by local health authorities.