Background

In westernised countries, asthma and related atopic disorders such as eczema and hay fever are now major public health concerns due to their high prevalence, associated significant ill health, and high societal and healthcare costs.1,2 There is convincing evidence that the prevalence of asthma and atopic disease has markedly increased in westernised countries since the early 1960s.3–12 Such rapid increases in disease prevalence are most likely to be a consequence of changing environmental influences. We describe here a protocol to evaluate systematically the evidence that residential exposure to volatile organic compounds (VOCs) increases the risk of developing asthma/atopic disease and investigate whether exposure to VOCs has adverse effects on those with established asthma/atopic disease.

VOCs are important indoor air pollutants produced by evaporation at room temperature from paints, wood, fabrics, cleaning agents, air fresheners, cosmetics, furnishings, and floor/wall coverings. Indoor VOC levels exceed those outdoors13–15 and are further increased by, for example, cigarette smoking and/or if a garage is attached to a house (i.e. petrol combustion, storage of paints, solvents, etc).16 Increasing use of VOC-containing products has contributed to increased VOC exposure along with more effective insulation and less external ventilation of modern buildings. Possible health effects of indoor VOC exposure are a cause for concern given that people in general — and children in particular — increasingly spend most of their time indoors.14,17 There is a substantial literature reporting associations between increased residential VOC exposure and respiratory symptoms, asthma, atopic disease, and reduced lung function;18–23 however, the results are overall inconsistent.24,25

Recent studies have also highlighted the potential for maternal VOC exposure during pregnancy to increase the risk of childhood asthma and atopic disease.26,27 Animal studies have shown that VOC exposure, particularly during pregnancy, can influence the immune responses of offspring, increasing Th2 polarisation and their susceptibility to the induction of experimental asthma.28,29 In humans, increased Th2 polarisation of neonatal immune responses has been associated with maternal VOC exposure during pregnancy.30 Although little evidence exists to suggest that VOCs influence fetal lung growth, embryotoxic effects from exposure to airborne VOCs on murine embryonic stem cells have been reported31 and adverse effects on rat embryo/fetal development have been linked to VOC release from their cages.32

Several developments have led to a renewed interest in the possible effects of residential VOC exposure on asthma/atopic disease: these include the fact that personalised technology able to quantify individual VOC exposure has been developed and is financially viable for inclusion in studies;33 recent longitudinal cohort data suggesting an association between antenatal VOC exposure and childhood asthma/atopic disease;34,35 and the availability of new technologies and consumer product standards to reduce residential VOC exposure.36,37 Also of relevance is the fact that interventions to reduce VOC exposure are feasible by simple advice (e.g. avoiding redecoration, new furniture, air fresheners, perfumed items, increasing ventilation)16 and products can be reformulated to have low VOC content.

There is at present no definitive systematic review of the literature relating residential levels of VOCs to the development of asthma/atopic disease in children and adults and those with established asthma/atopic disease.

Aims

We plan to conduct a systematic review and meta-analysis evaluating the relationship between VOC exposure and (1) the development of asthma/atopic disease and (2) in children and adults with established disease, the risk of exacerbations of asthma/atopic disease.

Methods

Criteria for considering studies for this review

Types of studies

All analytical studies (i.e. cohort, case-control and cross-sectional) and interventional studies (i.e. randomised controlled trials (RCTs), quasi-RCTs, controlled clinical trials (CCTs), controlled before-after and interrupted time series) will be included.

Types of participants

Studies of subjects relevant to children and adults (i.e. mothers during pregnancy, infants, children and adults) will all be eligible for inclusion.

Types of exposure

Studies investigating the role of non-occupational (residential, school, day care) exposure to VOC (antenatal, postnatal, early childhood, childhood, adult) in the development and exacerbation of asthma/atopic disease in children and adults will be included.

Types of outcome measures

  • Primary prevention: incidence or prevalence of asthma, eczema, hay fever (the number of new cases, i.e. incidence of asthma, eczema, hay fever; incidence of validated respiratory, dermal, nasal symptoms, lung function, atopic sensitisation).

  • Secondary prevention: measures of increased disease activity by any objective measure (lung function, symptom scores, exacerbations, medication usage, healthcare utilisation, quality of life).

Exclusion criteria

Reviews, letters, editorials, conference abstracts, papers reporting occupational exposure to VOCs, outdoor exposure, estimated/modelled exposure, biomarkers of exposure and those that used surrogate indicators of exposure not objectively quantified (e.g. use of the household chemicals, renovation/painting in the house), and chamber exposure studies are excluded. We have also excluded studies that examined VOCs as tobacco smoke markers and studies on non-specific symptoms (e.g. nasal/throat irritation, Sick Building Syndrome [SBS]). Research methods for identification of studies Electronic searches will include MEDLINE (1966–2012), EMBASE (1980–2012), Cochrane Library (1992–2012), LILACS (1986–2012), ISI Web of Science (1970–2012), BIOSIS (1969–2012), Global Health (1987–2012), AMED (1985–2012), TRIP (2003–2012), CAB (1910–2012), CINAHL (1937–2012). The bibliographies of all eligible studies will be scrutinised to identify additional possible studies. Unpublished and ongoing work and research in progress will be studied by searching key Internet-based databases (www.clinicaltrials.gov; www.controlled-trials.com; www.scholar.google.co.uk). In addition, to extend our search for published, unpublished and ongoing studies, we will contact experts in the field. No language restrictions will be imposed and translations will be sought where necessary. Details of the search strategy are shown in Appendix 1.

Study selection

Titles and abstracts of trials identified from the searches will be checked by two members of the research team. The full text of all retrieved potentially eligible studies will be independently assessed against the above criteria by two reviewers. The decision on which of the studies fit the inclusion criteria and a record of the methodological quality of eligible studies will be made (see below). Any disagreements will be resolved by discussion between the reviewers or, if necessary, arbitration by a third reviewer.

Assessment of methodological quality

The assessment and documentation of the methodological quality of included controlled trials will follow the Cochrane approach using the methods detailed in section 8 of the Cochrane Handbook for Systematic Reviews of Interventions.38 Intervention studies will be assessed using the Cochrane Effectiveness and Practice Organisation of Care (EPOC) guidelines. The following seven parameters will be used to assess trial quality: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other bias. Each parameter of trial quality will be graded as (A) low risk of bias; (B) moderate risk of bias; or (C) high risk of bias, and an overall assessment for each controlled trial using the same three criteria will be made. Observational studies will be similarly assessed using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies.39 Reviewers will not be masked to study details. Agreement of reviewers on methodological quality assessment will be assessed and disagreements will be resolved by discussion.

Data extraction

Two reviewers will independently extract data using customised data extraction forms. For quality assessment of included papers, both reviewers will resolve any disagreements by discussion; in the case of consensus not being reached, a third reviewer will be involved and, if necessary, arbitrate.

Data analysis

Review Manager 5.1 will be used for data analysis and quantitative data synthesis. For dichotomous data, individual and pooled statistics will be calculated as relative risks (RR) with 95% confidence intervals (95% CI). For continuous data, individual and pooled statistics will be calculated as mean differences and/or standardised mean differences with 95% CI. Consideration will be given to the appropriateness of meta-analysis in the presence of significant clinical or statistical heterogeneity. Heterogeneity will be tested for using the I2 statistic and significant heterogeneity assumed if I2 is greater than 40% (i.e. more than 40% of the variability in outcome between trials could not be explained by sampling variation).40 Separate meta-analysis using random effects modelling will be undertaken for the main outcomes of interest (i.e. development of asthma/atopic disease and exacerbations of asthma/atopic disease). Subgroup analysis will be performed for various types of VOC exposure and sensitivity analysis will be performed on the basis of study quality. Evidence of publication bias will be assessed graphically using funnel plots.41,42

Sensitivity analysis

Sensitivity analysis will be undertaken on the basis of removing studies judged to be at highest risk of bias. Where there is uncertainty, authors will be contacted for clarification or additional information.

Reporting

The overall reporting of the systematic review will be guided by the PRISMA statement.43