Jeroen Douwes

Non-eosinophilic asthma: importance and possible mechanisms

There is increasing evidence that inflammatory mechanisms other than eosinophilic inflammation may be involved in producing the final common pathway of enhanced bronchial reactivity and reversible airflow obstruction that characterises asthma. A review of the literature has shown that, at most, only 50% of asthma cases are attributable to eosinophilic airway inflammation. It is hypothesised that a major proportion of asthma is based on neutrophilic airway inflammation, possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. If there are indeed two (or more) subtypes of asthma, and if non-eosinophilic (neutrophil mediated) asthma is relatively common, this would have major consequences for the treatment and prevention of asthma since most treatment and prevention strategies are now almost entirely focused on allergic/eosinophilic asthma and allergen avoidance measures, respectively. It is therefore important to study the aetiology of asthma further, including the underlying inflammatory profiles.

Respiratory and Allergic Health Effects of Dampness, Mold, and Dampness-Related Agents: A Review of the Epidemiologic Evidence

Objectives Many studies have shown consistent associations between evident indoor dampness or mold and respiratory or allergic health effects, but causal links remain unclear. Findings on measured microbiologic factors have received little review. We conducted an updated, comprehensive review on these topics. Data sources We reviewed eligible peer-reviewed epidemiologic studies or quantitative meta-analyses, up to late 2009, on dampness, mold, or other microbiologic agents and respiratory or allergic effects. Data extraction We evaluated evidence for causation or association between qualitative/subjective assessments of dampness or mold (considered together) and specific health outcomes. We separately considered evidence for associations between specific quantitative measurements of microbiologic factors and each health outcome. Data synthesis Evidence from epidemiologic studies and meta-analyses showed indoor dampness or mold to be associated consistently with increased asthma development and exacerbation, current and ever diagnosis of asthma, dyspnea, wheeze, cough, respiratory infections, bronchitis, allergic rhinitis, eczema, and upper respiratory tract symptoms. Associations were found in allergic and nonallergic individuals. Evidence strongly suggested causation of asthma exacerbation in children. Suggestive evidence was available for only a few specific measured microbiologic factors and was in part equivocal, suggesting both adverse and protective associations with health. Conclusions Evident dampness or mold had consistent positive associations with multiple allergic and respiratory effects. Measured microbiologic agents in dust had limited suggestive associations, including both positive and negative associations for some agents. Thus, prevention and remediation of indoor dampness and mold are likely to reduce health risks, but current evidence does not support measuring specific indoor microbiologic factors to guide health-protective actions.

Innate immune activation in neutrophilic asthma and bronchiectasis

Background: The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre-programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. Aim: To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. Methods: Induced sputum was obtained from non-smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll-like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. Results: Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro-inflammatory cytokines IL8 and IL1β, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. Conclusion: There is evidence of activation of the innate immune system in asthma which results in the production of pro-inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma.

Do farming exposures cause or prevent asthma? Results from a study of adult Norwegian farmers

Background: A protective effect of endotoxin exposure on atopy and asthma in farmers’ children has been postulated. Studies of adult farmers have shown conflicting results but often lack exposure data. The prevalence of asthma in farmers with different exposure levels to microbial agents and irritant gases was compared. Methods: Atopy was defined as a positive response to multiple radioallergosorbent tests (RAST) with a panel of 10 common respiratory allergens, and asthma was ascertained by a questionnaire using a stratified sample (n = 2169) of a farming population from south-eastern Norway. Exposure of farmers to total dust, fungal spores, bacteria, endotoxins, and ammonia was assessed by exposure measurements. Results: The prevalence of asthma was 3.7% for physician diagnosed asthma and 2.7% for current asthma. The prevalence of atopy was 14%, but most asthmatic subjects were non-atopic (80%). Compared with farmers without livestock, (1) asthma was significantly higher in cattle farmers (ORadj 1.8, 95% CI 1.1 to 2.8) and pig farmers (ORadj 1.6, 95% CI 1.0 to 2.5), (2) non-atopic asthma was significantly higher in pig farmers (ORadj 2.0, 95% CI 1.2 to 3.3) and in farmers with two or more types of livestock (ORadj 1.9, 95% CI 1.1 to 3.3), and (3) atopic asthma was less common in farmers with two or more types of livestock (ORadj 0.32, 95% CI 0.11 to 0.97). Exposure to endotoxins, fungal spores, and ammonia was positively associated with non-atopic asthma and negatively associated with atopic asthma. No associations were found with atopy. Conclusions: Exposure to endotoxins and fungal spores appears to have a protective effect on atopic asthma but may induce non-atopic asthma in farmers.

Is allergen exposure the major primary cause of asthma

In recent decades a number of authors have argued that allergen exposure is the major primary cause of asthma, and that the global increases in asthma prevalence are due to increases in exposure to aeroallergens. We have assessed the epidemiological evidence in support of this hypothesis. No longitudinal studies were identified in which allergen exposure during infancy in a random population sample has been related to asthma risk after the age of six years. Two studies have been conducted in selected populations chosen on the basis of a family history of asthma or allergy; one study found a non-statistically significant association whereas the other study found no association. Many of the identified prevalence studies in children showed negative associations between allergen exposure and current asthma, and the weighted averages of the population attributable risks in children were 4% for Der p 1, 11% for Fel d 1, –4% forBla g 2, and 6% for Can f 1. There was little change in these estimates in studies in which children whose parents had adopted allergen avoidance measures were excluded. Furthermore, evidence from population studies is equivocal and provides little consistent evidence that allergen exposure is associated with the prevalence of asthma at the population level. Population-based cohort studies are clearly required, but currently available evidence does not indicate that allergen exposure is a major risk factor for the primary causation of asthma in children.

Occurrence of alternative flame retardants in indoor dust from New Zealand: Indoor sources and human exposure assessment

Due to worldwide restrictions on polybrominated diphenyl ethers (PBDEs), the demand for alternative flame retardants (AFRs), such as organophosphate flame retardants (OPFRs), novel brominated FRs (NBFRs) and hexabromocyclododecanes (HBCDs), has recently increased. Little is known about human exposure to NBFRs and OPFRs and that their levels in dust have been scarcely evaluated worldwide. To increase the knowledge regarding these chemicals, we measured concentrations of five major NBFRs, ten OPFRs and three HBCD isomers in indoor dust from New Zealand homes. Dust samples were taken from living room floors (n=34) and from mattresses of the same houses (n=16). Concentrations (ngg(-1)) of NBFRs were: 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) (<2-175), decabromodiphenyl ethane (DBDPE) (<5-1430), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) (<2-2285) and bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (TBPH) (<2-640). For OPFRs, concentrations (ngg(-1)) ranged between: tri-ethyl-phosphate (TEP) (<10-235), tri-n-butyl-phosphate (TnBP) (<20-7545), tris-(2-chloroethyl)-phosphate (TCEP) (<20-7605), tris-(1-chloro-2-propyl) phosphate (TCPP) (20-7615), tri-(2-butoxyethyl)-phosphate (TBEP) (50-27325), tris-(2,3-dichloropropyl)-phosphate (TDCPP) (20-16560), tri-phenyl-phosphate (TPhP) (20-35190), and tri-cresyl-phosphate (TCP) (<50-3760). HBCD concentrations fell in the range <2-4100ngg(-1). BTBPE, DBDPE, TBPH, TBEP, and TnBP showed significant positive correlation (p<0.05) between their concentrations in mattresses and the corresponding floor dust (n=16). These data were used to derive a range of plausible exposure scenarios. Although the estimated exposure is well below the corresponding reference doses (RfDs), caution is needed given the likely future increase in use of these FRs and the currently unknown contribution to human exposure by other pathways such as inhalation and diet.

Chronic Bronchitis, COPD, and Lung Function in Farmers: The Role of Biological Agents

BACKGROUND Farmers have an increased risk of respiratory morbidity and mortality. The causal agents have not been fully established. METHODS In a cross-sectional study of 4,735 Norwegian farmers, we assessed respiratory symptoms and lung function. Atopy was assessed in a subsample (n = 1,213). Personal exposures to dust, fungal spores, actinomycete spores, endotoxins, bacteria, storage mites, (1-->3)-ss-D-glucans, fungal antigens, organic dust, inorganic dust, silica, ammonia, and hydrogen sulfide were measured for 127 randomly selected farms. RESULTS Compared to crop farmers, livestock farmers were more likely to have chronic bronchitis (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.4 to 2.6) and COPD (OR, 1.4; 95% CI, 1.1 to 1.7). FEV(1) (-41 mL; 95% CI, -75 to -7) was significantly reduced, but FVC (-15 mL; 95% CI, -54 to 24) was not. Exposure to most agents were predictors of respiratory morbidity, except FVC. Ammonia, hydrogen sulfide, and inorganic dust were most strongly associated in multiple regression models adjusted for coexposures, but the effects of specific biological agents could not be assessed in multiple regression models because they were too highly correlated. Farmers with atopy had a significantly lower FEV(1) (OR, -87 mL; 95% CI, -170 to -7), but atopy was not directly associated with chronic bronchitis, COPD, and FVC. However, the effects of farming and specific exposures on COPD were substantially greater in farmers with atopy. CONCLUSIONS Livestock farmers have an increased risk of chronic bronchitis, COPD, and reduced FEV(1). Ammonia, hydrogen sulfide, inorganic dust, and organic dust may be causally involved, but a role for specific biological agents cannot be excluded. Farmers with atopy appear more susceptible to develop farming-related COPD.

Pets and vermin are associated with high endotoxin levels in house dust.

Background Previous studies have shown that the risk for allergic sensitization is lower in children who grew up on farms and in young adults who were exposed to dogs in early childhood. A higher microbial exposure in general and in particular to endotoxin in early childhood might contribute to this lower risk of atopy.

Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood

Background: The “hygiene hypothesis” postulates that infections during infancy may protect against asthma and atopy. There is also some evidence that antibiotic and/or paracetamol use may increase the risk of asthma. Methods: The study measured the association between infections, and medication use early in life and the risk of asthma at age 6–7 years. It involved 1584 children who had been notified to public health services with serious infections at age 0–4 years, and 2539 children sampled from the general population. For both groups, postal questionnaires were completed by parents. Results: There was little difference in the prevalence of current wheezing between the childhood infections group (prevalence  =  23.5%) and the general population group (prevalence  =  24.3%). There was also little difference whether the major site of infection was gastrointestinal (prevalence  =  24.1%), invasive (prevalence  =  24.6%) or respiratory (prevalence  =  21.1%). However, in both groups, there were associations with antibiotic (OR = 1.78, 95% CI 1.49 to 2.14) or paracetamol (OR = 1.38, 95% CI 1.04 to 1.83) use in the first year of life or recent paracetamol use (OR = 2.10, 95% CI 1.78 to 2.49) and current wheezing. There was a weak protective effect of childhood infections in children who had not used antibiotics in the first year of life (OR = 0.78, 95% CI 0.55 to 1.10). Conclusions: These findings are consistent with other evidence that antibiotic use early in life may increase the risk of asthma. They are also consistent with some preliminary evidence associating paracetamol use with an increased risk of asthma. Any protective effect of notifiable childhood infections was weak.

Fungal extracellular polysaccharides in house dust as a marker for exposure to fungi: Relations with culturable fungi, reported home dampness, and respiratory symptoms☆☆☆

BACKGROUND Epidemiologic studies have demonstrated an association between indoor fungal growth and respiratory symptoms. However, in only a few studies was fungal exposure actually measured. OBJECTIVE The purpose of this study was to evaluate the measurement by enzyme immunoassay of extracellular polysaccharides of Aspergillus and Penicillium species (EPS-Asp/Pen ) in house dust as a marker for fungal exposure and to study the relations between EPS-Asp/Pen levels and home dampness and respiratory symptoms in children. METHODS Extracts of house dust samples from bedroom and living room floors and mattresses from homes of 31 children with chronic respiratory symptoms and 29 children with no chronic respiratory symptoms were analyzed for EPS-Asp/Pen. RESULTS EPS-Asp/Pen were readily detectable (40 to 46,513 nanogram equivalent/g dust) in 161 house dust extracts, with highest concentrations in living room floor dust. EPS-Asp/Pen levels were 2 to 3 times higher on carpeted floors than on smooth floors. EPS-Asp/Pen were significantly correlated with total culturable fungi (r = 0.3 to 0.5) and with house dust mite allergens (r = 0.3 to 0.5). EPS-Asp/Pen levels in living room floor dust were positively associated with occupant-reported home dampness. This was not observed for EPS-Asp/Pen in bedroom floor and mattress dust. EPS-Asp/Pen levels in living room floor dust were positively associated with respiratory symptoms. EPS-Asp/Pen in bedroom floor and mattress dust showed a reversed association with respiratory symptoms, possibly because of allergen-avoidance measures taken in the bedroom. CONCLUSION The enzyme immunoassay for fungal EPS-Asp/Pen may be a useful method for exposure assessment of indoor fungi.