Flares in Childhood Eczema

From Skin Therapy Letter
S. M. Langan, MRCP, MSc, PhD

Abstract
Eczema is a major public health problem affecting children worldwide. Few studies have directly assessed triggers for disease flares. This paper presents evidence from a published systematic review and a prospective cohort study looking at flare factors in eczema.

This systematic review suggested that foodstuffs in selected groups, dust exposure, unfamiliar pets, seasonal variation, stress, and irritants may be important in eczema flares.
We performed a prospective cohort study that focused on environmental factors and identified associations between exposure to nylon clothing, dust, unfamiliar pets, sweating, shampoo, and eczema flares.
Results from this study also demonstrated some new key findings. First, the effect of shampoo was found to increase in cold weather, and second, combinations of environmental factors were associated with disease exacerbation, supporting a multiple component disease model.
This information is likely to be useful to families and may lead to the ability to reduce disease flares in the future.

Introduction
Eczema is an important condition that affects 2%-20% of children worldwide, and is associated with significant morbidity for children and their families.[1]
Although some progress has been made in understanding factors that are related to the occurrence of eczema, very little is known about factors associated with disease exacerbation. Most textbooks and review articles quote long lists of exacerbating factors, but we have found very little scientific data to support them.


Defining Flares of Eczema
In order to address the causes of flares, it is first important to define what is meant by an eczema flare. Langan et al. carried out a systematic review that assessed definitions of flare in the literature and sought parallels with definitions used in other relapsing and remitting diseases.[2]
The authors proposed that a flare could be defined as an episode requiring escalation of treatment or additional medical advice. This should be pre-defined by investigators at the onset of a study. For example, in studies of moderate or severe eczema, escalation to the use of topical corticosteroids might constitute a "flare". The need to use potent or super-potent topical corticosteroids, or to attend a primary care physician or dermatologist for disease exacerbation might be more appropriate. It is not possible to develop an entirely standardized definition for "flare", as the true meaning is related to the individual patient and his or her perception of disease worsening above baseline.

A Review of Evidence for Causes of Flares in Eczema

A systematic review was also carried out to assess the evidence for causes of eczema flares. This review highlighted the limited evidence for flare factors, but suggested that there may be a role for foodstuffs in selected groups, dust exposure, unfamiliar pets, seasonal variation, stress, and irritants in eczema flares.[3] However, scientific investigation was required to elucidate the relative impact of these factors in studies of longitudinal design over longer study periods. Another aspect requiring study was whether combinations of factors are more important than single factors, suggesting a complex disease model.

A Study of Environmental Factors
Langan et al. addressed these issues in a prospective cohort study.[4] The objectives were to assess the role of various environmental factors on eczema severity in a cohort of eczematous children with the following identified hypotheses:

Hypothesis 1: In hot weather, the combination of heat, sweating, and grass pollen precipitates increased severity in children with eczema in the UK.

Hypothesis 2: The combination of cold weather, indoor aeroallergen exposure, and reduced relative humidity from central heating led to increased severity in children with eczema in the UK. These first 2 hypotheses were informed by previous research, which proposed "summer" and "winter" types of eczema.[5]

Hypothesis 3: Detergents (i.e., soap or shampoo) increase the propensity to disease flares triggered by other factors at all temperatures, but more so in cold weather due to impaired skin barrier function.

Hypothesis 4: Any combination of greater than or equal to 3 exposures at any time is associated with worsening of eczema. The exposures assessed included dust, 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.

Study Methods
A prospective cohort study (n=60) of children with moderate-to-severe eczema between 6 and 9 months of age and up to 15 years were enrolled with overlapping start dates to allow for the study of seasonal factors. The exposures studied included temperature, relative humidity, sun exposure, sweating, clothing, cleansing products/washing, outdoor pollen level, the extent and nature of exposure to household pets, dusty environments, and swimming. On a daily basis, children or their parents completed novel electronic diaries programmed for this study recording eczema severity and exposures. Portable dataloggers were used to record temperature and relative humidity. External meteorological data was obtained from a local monitoring center.

The primary outcome was measured as a daily "bother" score; the secondary outcomes were daily "scratch" scores and flares of eczema outcome measures. The daily bother score was determined in response to the question, "How much bother did your (your child's) eczema cause today?"

Global scores by the patients and their parents were rated on a scale from 0 to 10 (where 0=no bother at all and 10=the most bother you can imagine).

Binary outcomes were recorded with respect to the question, "Have you had to step up your treatment today because your (your child's) eczema was worse?" Stepping up treatment was defined at the outset and patient-specific for each child.

Statistical Methods
A time series method, autoregressive moving average models (ARMA), was used to model the impact of each exposure on eczema severity for each individual. This method was required to deal with the autocorrelation in the data, i.e., the severity of eczema on 1 day has a relationship with the severity of eczema on the next day and the day before. Standard random effects from 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.

Findings
Primary Outcome: "Bother" Scores

Increased disease severity was associated with direct contact with nylon clothing (pooled regression coefficient 0.23, 95% confidence interval [CI] 0.03-0.43), increasing exposure to dust (pooled regression coefficient 0.53, 0.23-0.83), exposure to unfamiliar pets (pooled regression coefficient 0.22, 0.10-0.34), sweating (pooled regression coefficient 0.24, 0.09-0.39) and shampoo exposure (pooled regression coefficient 0.07, 0.01-0.13). The association between shampoo use and eczema exacerbation was enhanced in cold weather (pooled regression coefficient 0.30, 0.04-0.57). 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)], and reactions to wool clothing on truncal covered sites (p=0.03), but not limbs (p=0.62), while exacerbation of hand eczema was associated with exposure to pets (p‹0.001). Significant heterogeneity of responses between individuals was observed for exposure to grass pollen and outdoor temperature. With regard to the final hypothesis, a combination of any 3 of 7 likely variables was associated with exacerbation of eczema (pooled regression coefficient 0.41, 0.20-0.63).

Secondary Outcome: "Scratch" Scores

Increased disease severity was seen associated with swimming (pooled regression coefficient 0.14, 95% CI 0.00-0.28), exposure to wool clothing (pooled regression coefficient 0.28, 0.11-0.45), sweating (pooled regression coefficient 0.15, 0.04-0.26), and shampoo (pooled regression coefficient 0.07, 0.01-0.13).

Secondary Outcome: Eczema Flares

Only swimming was clearly associated with eczema exacerbation using this outcome measure (pooled regression coefficient 0.42, 0.05-0.80).

A summary of exposure factors associated with exacerbation of eczema includes:

Dust
Nylon
Shampoo
Shampoo + cold weather
Sweating
Swimming
Unfamiliar pets
Wool

Relative to the study hypotheses, the association between shampoo exposure and eczema exacerbation 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 a low prevalence of these combinations of exposures. The implications of these study findings for clinical practice are that for the first time, it has been shown that shampoo exposure may be associated with eczema exacerbation and this effect is more pronounced in cold weather. This study also strengthens the systematic review findings that support disease worsening with dust, pet, and irritant exposure. Furthermore, this investigation suggests that eczema exacerbation may be more complicated in that multiple exposures acting in concert may be associated with worsening of the disease. The impact of food and stress were not examined in this prospective study.

Conclusion
Future research is required to specifically explore possible gene-environmental interactions with filaggrin mutations and their relevance in relation to disease flares, and to look at shampoo formulations in relation to eczema exacerbation.