A prospective study of the effects of environmental factors on eczema in children

Background: Eczema is an important condition as it affects 20% of children in the UK and is associated with significant morbidity for children and their families. Although some progress in understanding factors associated with the occurrence of eczema has been made, very little is known about factors associated with disease worsening. Most textbooks and review articles quote long lists of exacerbating factors but with very little scientific data to support them. Before I could begin to study this topic, I first had to define a disease flare in eczema, systematically review the literature on flare factors in eczema and review available outcome measures for eczema. Objectives: The objectives of the main study described in this thesis were to assess the role of various environmental factors on the severity of eczema in a cohort of children with eczema. Hypotheses: 1. In hot weather, the combination of heat, sweating and grass pollen precipitates increased severity in children with eczema in the UK. 2. In cold weather, the combination of cold weather, indoor aeroallergen exposure and reduced relative humidity from central heating lead to increased severity in children with eczema in the UK. These first two hypotheses were informed by previous research which proposed "summer" and "winter" types of eczema. 3. Detergents (soap, shampoo) increase the propensity to disease flares triggered by other factors at all temperatures, but more in cold weather due to impaired skin barrier function. 4. UK children with filaggrin mutations are more prone to the effects of climatic factors such as cold and heat than individuals who are wild type for filaggrin. 5. Any combination of greater than or equal to three exposures at any time is associated with worsening of eczema. The exposures assessed included: dust, exposure to pets, shampoo, sweating, swimming, nylon clothing next to the skin and a change in mean temperature of more than 3°C from the previous weekly average. Methods: Pilot study: 30 children with moderate to severe eczema aged 0 to 15 years participated in a panel study over a one month period in June 2003 in Cork, Ireland. This study involved daily completion of a paper diary recording eczema severity and exposures. Feasibility of a panel study design was assessed and associations between exposures and disease severity were analysed. Main study: A prospective cohort study (n=60) of children aged up to 15 years with moderate to severe eczema was studied for between six and nine months with overlapping start dates to allow study of seasonal factors. Exposures studied included: temperature, relative humidity, sun exposure, sweating, clothing, cleansing products/ washing, outdoor pollen level, extent and nature of exposure to household pets, dusty environments and swimming. Children or their parents completed daily novel electronic diaries recording eczema severity and exposures. Portable dataloggers were used to record indoor temperature and relative humidity. External meteorological data was obtained from a local monitoring centre. The primary outcome was a daily "bother" score and the secondary outcomes were daily "scratch" scores and flares of eczema. Autoregressive moving average models (ARMA) were used to model the impact of each exposure on eczema severity for each individual. Standard random effects meta-analysis techniques were used to pool estimated coefficients across participants. Heterogeneity of responses as detected using Chi-squared tests represented inter-individual variation. The body site-specificity of reactions was also examined as was the interaction between filaggrin mutations and disease worsening with exposures. Findings. Pilot study: The pilot study highlighted the issue of drop outs and missing data during the study. 83% (n=25) returned the diaries at the end of the study period, and within these, recording of disease severity was good (97% complete). However, there was variability in recording of exposures (65% to 83% complete). Preliminary findings suggested a temporal association between eczema severity and heat (lag 0, i.e. the day of exposure, p=0.04), damp (lag day 2, p=0.03), sweating and stress (lag day 3, p=0.03 and p=0.02 respectively) and damp (lag day 4, p=0.001). Main study: Primary outcome: "bother scores": Increased disease severity was associated with direct contact with nylon clothing (pooled regression coefficient 0.23, 95% CI 0.03 to 0.43), increasing exposure to dust (pooled regression coefficient 0.53, 0.23 to 0.83), exposure to unfamiliar pets (pooled regression coefficient 0.22, 0.10 to 0.34), sweating (pooled regression coefficient 0.24, 0.09 to 0.39) and shampoo exposure (pooled regression coefficient 0.07, 0.01 to 0.13). The association between shampoo use and worsening of eczema was enhanced in cold weather (pooled regression coefficient 0.30, 0.04 to 0.57). Body site specificity was observed for the reactions to nylon clothing, which was greater on covered sites (trunk p=0.02, limbs p=0.03), reactions to wool clothing on truncal covered sites (p=0.03) but not limbs (p=0.62), while worsening of hand eczema was associated with exposure to pets (p<0.001). The only interaction with filaggrin mutations was observed for the 2282del4 mutation and worsening of eczema in summer. Significant heterogeneity of responses between individuals was observed for exposure to grass pollen and outdoor temperature. In regard to the final hypothesis, a combination of any three of seven likely variables was associated with worsening of eczema (pooled regression coefficient 0.41, 0.20 to 0.63). Secondary outcome: "scratch" scores: Increased disease severity was seen associated with swimming (pooled regression coefficient 0.14,0.00 to 0.28), exposure to wool clothing (pooled regression coefficient 0.28, 0.11 to 0.45), sweating (pooled regression coefficient 0.15, 0.04 to 0.26), shampoo (pooled regression coefficient 0.07, 0.01 to 0.13), dust (pooled regression coefficient 0.36, 0.12 to 0.59) and high grass pollen levels (pooled regression coefficient 0.10, 0.01 to 0.73). Secondary outcome: flares of eczema: Only swimming was clearly associated with worsening of eczema using this outcome measure (pooled regression coefficient 0.42, 0.05 to 0.80). Conclusions: The following factors were shown to be associated with disease worsening in children with eczema in this UK study: clothing (wool and nylon), sweating, shampoo, swimming, dust, contact with unfamiliar pets and high grass pollen levels. Relative to the study hypotheses, the association between shampoo exposure and eczema worsening was shown to be increased in cold weather. There was also evidence showing an association between various combinations of exposures and disease worsening. There was insufficient evidence to support the other hypotheses tested in this study but this may be explained by low prevalence of these exposures. The implications of the findings of this study for clinical practice are that for the first time, it has been shown that shampoo exposure may be associated with eczema worsening and that this is more pronounced in cold weather. This study also suggests that worsening of eczema may be more complicated in that multiple exposures acting in concert may be associated with worsening of disease. Future research with increased participant numbers is required to specifically study possible gene-environment interactions with filaggrin mutations and their relevance in relation to disease flares and to look at shampoo formulations in relation to worsening of eczema

A prospective study of the effects of environmental factors on eczema in children

Background: Eczema is an important condition as it affects 20% of children in the UK and is associated with significant morbidity for children and their families. Although some progress in understanding factors associated with the occurrence of eczema has been made, very little is known about factors associated with disease worsening. Most textbooks and review articles quote long lists of exacerbating factors but with very little scientific data to support them. Before I could begin to study this topic, I first had to define a disease flare in eczema, systematically review the literature on flare factors in eczema and review available outcome measures for eczema. Objectives: The objectives of the main study described in this thesis were to assess the role of various environmental factors on the severity of eczema in a cohort of children with eczema. Hypotheses: 1. In hot weather, the combination of heat, sweating and grass pollen precipitates increased severity in children with eczema in the UK. 2. In cold weather, the combination of cold weather, indoor aeroallergen exposure and reduced relative humidity from central heating lead to increased severity in children with eczema in the UK. These first two hypotheses were informed by previous research which proposed "summer" and "winter" types of eczema. 3. Detergents (soap, shampoo) increase the propensity to disease flares triggered by other factors at all temperatures, but more in cold weather due to impaired skin barrier function. 4. UK children with filaggrin mutations are more prone to the effects of climatic factors such as cold and heat than individuals who are wild type for filaggrin. 5. Any combination of greater than or equal to three exposures at any time is associated with worsening of eczema. The exposures assessed included: dust, exposure to pets, shampoo, sweating, swimming, nylon clothing next to the skin and a change in mean temperature of more than 3°C from the previous weekly average. Methods: Pilot study: 30 children with moderate to severe eczema aged 0 to 15 years participated in a panel study over a one month period in June 2003 in Cork, Ireland. This study involved daily completion of a paper diary recording eczema severity and exposures. Feasibility of a panel study design was assessed and associations between exposures and disease severity were analysed. Main study: A prospective cohort study (n=60) of children aged up to 15 years with moderate to severe eczema was studied for between six and nine months with overlapping start dates to allow study of seasonal factors. Exposures studied included: temperature, relative humidity, sun exposure, sweating, clothing, cleansing products/ washing, outdoor pollen level, extent and nature of exposure to household pets, dusty environments and swimming. Children or their parents completed daily novel electronic diaries recording eczema severity and exposures. Portable dataloggers were used to record indoor temperature and relative humidity. External meteorological data was obtained from a local monitoring centre. The primary outcome was a daily "bother" score and the secondary outcomes were daily "scratch" scores and flares of eczema. Autoregressive moving average models (ARMA) were used to model the impact of each exposure on eczema severity for each individual. Standard random effects meta-analysis techniques were used to pool estimated coefficients across participants. Heterogeneity of responses as detected using Chi-squared tests represented inter-individual variation. The body site-specificity of reactions was also examined as was the interaction between filaggrin mutations and disease worsening with exposures. Findings. Pilot study: The pilot study highlighted the issue of drop outs and missing data during the study. 83% (n=25) returned the diaries at the end of the study period, and within these, recording of disease severity was good (97% complete). However, there was variability in recording of exposures (65% to 83% complete). Preliminary findings suggested a temporal association between eczema severity and heat (lag 0, i.e. the day of exposure, p=0.04), damp (lag day 2, p=0.03), sweating and stress (lag day 3, p=0.03 and p=0.02 respectively) and damp (lag day 4, p=0.001). Main study: Primary outcome: "bother scores": Increased disease severity was associated with direct contact with nylon clothing (pooled regression coefficient 0.23, 95% CI 0.03 to 0.43), increasing exposure to dust (pooled regression coefficient 0.53, 0.23 to 0.83), exposure to unfamiliar pets (pooled regression coefficient 0.22, 0.10 to 0.34), sweating (pooled regression coefficient 0.24, 0.09 to 0.39) and shampoo exposure (pooled regression coefficient 0.07, 0.01 to 0.13). The association between shampoo use and worsening of eczema was enhanced in cold weather (pooled regression coefficient 0.30, 0.04 to 0.57). Body site specificity was observed for the reactions to nylon clothing, which was greater on covered sites (trunk p=0.02, limbs p=0.03), reactions to wool clothing on truncal covered sites (p=0.03) but not limbs (p=0.62), while worsening of hand eczema was associated with exposure to pets (p<0.001). The only interaction with filaggrin mutations was observed for the 2282del4 mutation and worsening of eczema in summer. Significant heterogeneity of responses between individuals was observed for exposure to grass pollen and outdoor temperature. In regard to the final hypothesis, a combination of any three of seven likely variables was associated with worsening of eczema (pooled regression coefficient 0.41, 0.20 to 0.63). Secondary outcome: "scratch" scores: Increased disease severity was seen associated with swimming (pooled regression coefficient 0.14,0.00 to 0.28), exposure to wool clothing (pooled regression coefficient 0.28, 0.11 to 0.45), sweating (pooled regression coefficient 0.15, 0.04 to 0.26), shampoo (pooled regression coefficient 0.07, 0.01 to 0.13), dust (pooled regression coefficient 0.36, 0.12 to 0.59) and high grass pollen levels (pooled regression coefficient 0.10, 0.01 to 0.73). Secondary outcome: flares of eczema: Only swimming was clearly associated with worsening of eczema using this outcome measure (pooled regression coefficient 0.42, 0.05 to 0.80). Conclusions: The following factors were shown to be associated with disease worsening in children with eczema in this UK study: clothing (wool and nylon), sweating, shampoo, swimming, dust, contact with unfamiliar pets and high grass pollen levels. Relative to the study hypotheses, the association between shampoo exposure and eczema worsening was shown to be increased in cold weather. There was also evidence showing an association between various combinations of exposures and disease worsening. There was insufficient evidence to support the other hypotheses tested in this study but this may be explained by low prevalence of these exposures. The implications of the findings of this study for clinical practice are that for the first time, it has been shown that shampoo exposure may be associated with eczema worsening and that this is more pronounced in cold weather. This study also suggests that worsening of eczema may be more complicated in that multiple exposures acting in concert may be associated with worsening of disease. Future research with increased participant numbers is required to specifically study possible gene-environment interactions with filaggrin mutations and their relevance in relation to disease flares and to look at shampoo formulations in relation to worsening of eczema

Risk of stroke following herpes zoster: a self-controlled case-series study.

BACKGROUND: Herpes zoster is common and vaccine preventable. Stroke risk may be increased following zoster, but evidence is sparse and could be explained by differences between people with and without zoster. Our objective was to determine if stroke risk is increased following zoster. METHODS: Within-person comparisons were undertaken using the self-controlled case-series method and data from the UK Clinical Practice Research Datalink (1987-2012). Participants had a first-ever diagnosis of zoster and stroke within the study period. Stroke incidence in periods following zoster was compared with incidence in other time periods. Age-adjusted incidence ratios (IRs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 6584 individuals were included. Stroke rate was increased following zoster compared with the baseline unexposed period, then gradually reduced over 6 months: weeks 1-4 (age-adjusted IR, 1.63; 95% CI, 1.32-2.02), weeks 5-12 (IR, 1.42; 95% CI, 1.21-1.68), and weeks 13-26 (IR, 1.23; 95% CI, 1.07-1.42), with no increase thereafter. A stronger effect was observed for individuals with zoster ophthalmicus, rising to a >3-fold rate 5-12 weeks after zoster. Oral antivirals were given to 55% of individuals: IRs for stroke were lower among those receiving antivirals compared with those not treated, suggesting a protective effect. CONCLUSIONS: We have established an increased stroke rate within 6 months following zoster. Findings have implications for zoster vaccination programs, which may reduce stroke risk following zoster. The low antiviral prescribing rate needs to be improved; our data suggest that antiviral therapy may lead to a reduced stroke risk following zoster

Reporting transparency: making the ethical mandate explicit.

Improving the transparency and quality of reporting in biomedical research is considered ethically important; yet, this is often based on practical reasons such as the facilitation of peer review. Surprisingly, there has been little explicit discussion regarding the ethical obligations that underpin reporting guidelines. In this commentary, we suggest a number of ethical drivers for the improved reporting of research. These ethical drivers relate to researcher integrity as well as to the benefits derived from improved reporting such as the fair use of resources, minimizing risk of harms, and maximizing benefits. Despite their undoubted benefit to reporting completeness, questions remain regarding the extent to which reporting guidelines can influence processes beyond publication, including researcher integrity or the uptake of scientific research findings into policy or practice. Thus, we consider investigation on the effects of reporting guidelines an important step in providing evidence of their benefits

Zoster vaccination is associated with a reduction of zoster in elderly patients with chronic kidney disease.

BACKGROUND: Growing epidemiological evidence demonstrates increased zoster risks in people with chronic kidney disease (CKD). Study objectives were to determine zoster vaccine effectiveness in individuals with CKD in pragmatic use. METHODS: A population-based cohort study was undertaken in a 5% random sample of US Medicare from 2007 to 2009 involving 766 330 eligible individuals aged ≥65 years who were (29 785) and were not (736 545) exposed to the zoster vaccine. Incidence rates for zoster in vaccinated and unvaccinated individuals and hazard ratios for zoster comparing vaccinated with unvaccinated were determined for individuals with CKD. Time-updated Cox proportional hazards models were used, adjusting for relevant confounders. RESULTS: CKD was present in 183 762 (24%) of individuals (15% of vaccinees). Adjusted vaccine effectiveness [95% confidence intervals (CIs)] in individuals with CKD was 0.49 (0.36-0.65). The adjusted vaccine effectiveness in participants with both CKD and diabetes mellitus was 0.46 (95% CI 0.09-0.68). Vaccine effectiveness estimates were similar to those previously reported for the general population [vaccine effectiveness 0.48 (95% CI 0.39-0.56)]. CONCLUSIONS: Zoster vaccine is effective against incident zoster in older individuals with CKD. Extra efforts are warranted to increase vaccine uptake in individuals with CKD given the known low uptake in these higher risk individuals

Association between eczema and major cardiovascular outcomes in population-based studies: a systematic review protocol.

INTRODUCTION: Chronic inflammatory diseases such as eczema (also known as atopic dermatitis) have been inconsistently linked to cardiovascular disease and stroke in both mechanistic and epidemiological studies. There is a need to review the existing epidemiological data examining the association between eczema and major cardiovascular outcomes, including angina, myocardial infarction, coronary revascularisation, heart failure, cardiac arrhythmias, stroke and cardiovascular death, in order to improve our understanding of the comorbidities of eczema. METHODS AND ANALYSIS: We will systematically review population-based studies, including cohort, case-control and cross-sectional studies, reporting on the association between eczema and cardiovascular outcomes. We will search Medline, Embase and Global Health, from their date of inception to April 2017, using a comprehensive search strategy formulated with the help of a librarian. Two reviewers will independently screen titles and abstracts in duplicate, followed by independent data extraction and quality assessment. We will group studies by the cardiovascular outcome under study and synthesise them narratively. If sufficient numbers of homogeneous studies are returned, we will perform meta-analyses to obtain pooled effect estimates. Preferred Reporting Items for Systematic Review and Meta-Analysis will be used to inform the reporting of this study. TRIAL REGISTRATION NUMBER: CRD42017060359

Association between eczema and major cardiovascular outcomes in population-based studies: a systematic review protocol.

INTRODUCTION: Chronic inflammatory diseases such as eczema (also known as atopic dermatitis) have been inconsistently linked to cardiovascular disease and stroke in both mechanistic and epidemiological studies. There is a need to review the existing epidemiological data examining the association between eczema and major cardiovascular outcomes, including angina, myocardial infarction, coronary revascularisation, heart failure, cardiac arrhythmias, stroke and cardiovascular death, in order to improve our understanding of the comorbidities of eczema. METHODS AND ANALYSIS: We will systematically review population-based studies, including cohort, case-control and cross-sectional studies, reporting on the association between eczema and cardiovascular outcomes. We will search Medline, Embase and Global Health, from their date of inception to April 2017, using a comprehensive search strategy formulated with the help of a librarian. Two reviewers will independently screen titles and abstracts in duplicate, followed by independent data extraction and quality assessment. We will group studies by the cardiovascular outcome under study and synthesise them narratively. If sufficient numbers of homogeneous studies are returned, we will perform meta-analyses to obtain pooled effect estimates. Preferred Reporting Items for Systematic Review and Meta-Analysis will be used to inform the reporting of this study. TRIAL REGISTRATION NUMBER: CRD42017060359

Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink.

BACKGROUND: Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship. METHODS AND FINDINGS: We conducted a matched cohort study using primary care data from the UK Clinical Practice Research Datalink. All men initiating a PDE5 inhibitor and with no prior cancer diagnosis were identified and matched on age, diabetes status, and general practice to up to four unexposed controls. Ever use of a PDE5 inhibitor and time-updated cumulative number of PDE5 inhibitor prescriptions were investigated as exposures, and the primary outcome was malignant melanoma. Basal cell carcinoma, solar keratosis, and colorectal cancer were investigated as negative control outcomes to exclude bias. Hazard ratios (HRs) were estimated from Cox models stratified by matched set and adjusted for potential confounders. 145,104 men with ≥1 PDE5 inhibitor prescription, and 560,933 unexposed matched controls were included. In total, 1,315 incident malignant melanoma diagnoses were observed during 3.44 million person-years of follow-up (mean 4.9 y per person). After adjusting for potential confounders, there was weak evidence of a small positive association between PDE5 inhibitor use and melanoma risk (HR = 1.14, 95% CI 1.01-1.29, p = 0.04). A similar increase in risk was seen for the two negative control outcomes related to sun exposure (HR = 1.15, 95% CI 1.11-1.19, p < 0.001, for basal cell carcinoma; HR = 1.21, 95% CI 1.17-1.25, p < 0.001, for solar keratosis), but there was no increased risk for colorectal cancer (HR = 0.91, 95% CI 0.85-0.98, p = 0.01). There was no evidence that risk increased with number of prescriptions received (p-trend = 0.83). In a post hoc analysis, there was strong evidence that solar keratosis was associated with future PDE5 inhibitor use (odds ratio = 1.28, 95% CI 1.23-1.34, p < 0.001), suggesting that men with higher sun exposure were more likely to become PDE5 inhibitor users. However, a limitation of our study was that we did not have individual-level data on sun exposure, so we could not directly control for this in the primary analysis. CONCLUSIONS: Our results were not consistent with PDE5 inhibitors being causally associated with melanoma risk, and strongly suggest that observed risk increases are driven by greater sun exposure among patients exposed to a PDE5 inhibitor