Role of house-dust endotoxin exposure in aetiology of allergy and asthma.

1. Wahn U, Lau S, Bergmann R et al. Indoor allergen exposure is a risk factor for sensitisation during the first three years of life. J Allergy Clin Immunol 1997; 99: 763–769. 2. Platts-Mills TAE, et al. Indoor allergens and asthma: Report of the Third International Workshop. J Allergy Clin Immunol 1997; 100: S1–S24. 3. van der Heide S, et al. Seasonal differences in airway hyperresponsiveness in asthmatic patients: relationship with allergen exposure and sensitization to house dust mites. Clin Exp Allergy 1997; 27: 627–633. 4. Custovic A, et al. Effect of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of life: a randomised trial. Lancet 2001; 358: 188–193. 5. Harving H, et al. House dust mite and actopic dermatitis: a case-control study on the significance of house dust mites as etiologic allergens in actopic dermatitis. Ann Allergy 1990; 65: 25–31. 6. Platts-Mills TAE, de Weck AL, et al., Dust mite allergens and asthma – a worldwide problem. Report of an International Workshop, Bad Kreuznach, Federal Republic of Germany, September 1987. J Allergy Clin Immunol 1989; 83: 416–427. 7. Arlian L. Water balance and humidity requirements of house dust mites. Exp Appl Acarol 1992; 16: 15–35. 8. Tovey ER, Chapman MD, Platts-Mills TAE. The distribution of house dust mite allergen in the houses of patients with asthma. Am Rev Respir Dis 1981; 124: 630–635. 9. Ingram JM, et al. Quantitative assessment of exposure to dog (Can F I) and cat (Fel d I) allergens: relationship to sensitization and asthma among children living in Los Alamos, New Mexico. J Allergy Clin Immunol 1995; 96: 1–26, 449–456. 10. Munir A, et al. Cat (Fel d 1), dog (Can f 1) and cockroach allergens in homes of asthmatic children from three climatic zones in Sweden. Allergy 1994; 49: 508–516. 11. Rosenstreich DL, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997; 336(19): 1356–1363. 12. Quirce S, et al. Major cat allergen (Fel D1) levels in the homes of patients with asthma and their relationship to sensitization to cat dander. Ann Allergy Asthma Immunol 1995; 75(4): 325–330. 13. Custovic A, et al. Distribution, aerodynamic characteristics, and removal of the major cat allergen Fel d 1 in British homes. Thorax 1998; 53(1): 33–38. 14. Mitakakis T, et al. Personal exposure to allergenic pollen and mould spores in inland New South Wales, Australia. Clin Exp Allergy 2000; 30: 1733–1739. 15. Wood RA, et al. Antigenic analysis of household dust samples. Am Rev Respir Dis 1988; 137(2): 358–363. 16. von Mutius E, et al. Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy 2000; 30: 1230–1235. 17. Eggleston PA, Bush RK. Environmental allergen avoidance: an overview. J Allergy Clin Immunol 2001; 107(3): S403–S405. 18. Gotzshe P, Hammarquist C, Bur M. House dust mite control measures in the managment of asthma: meta-analysis. Br Med J 1998; 317: 1105–1110. 19. Platts-Mills T, et al. Sensitisation, asthma and modified Th2 response in children exposed to cat allergen a population based cross sectional study. Lancet 2001; 357(9258): 752–756. 20. De Lucca S, Tovey ER. Quantitative modelling of domestic allergen Der p 1 using amplified ELISA and nasal sampling. J Allergy Clin Immunol 2001; 107(2): S219. 21. Arlian L, Platts-Mills T. The biology of house dust mite allergens in allergeic disease. J Allergy Clin Immunol 2001; 107(3): S406–S413. 22. Price JA, et al. Measurement of airborne mite antigen in homes of asthmatic children. Lancet 1990; 336: 895–897. 23. Oliver J, et al. Allergen levels in airborne and surface dust. Int Arch Allergy Immunol 1995; 107(1Ð3): 452–453. 24. Sakaguchi M, et al. Measurement of airborne mite allergen exposure in individual subjects. J Allergy Clin Immunol 1996; 97(5): 1040–1044. 25. Bollinger M, et al. Measurement of cat allergen levels in the home by use of an amplified ELISA. J Allergy Clin Immunol 1998; 101(1): 124–125. 26. O’Meara T, Tovey ER. Monitoring personal allergen exposure. In: Gershwin M, ed. Clinical Reviews in Allergy and Immunology. Humana Press, 2000: 341–395. 27. Siebers R, et al. Reduction in airborne house dust mite allergen (Der p 1) after occlusive covering of bedding. Allergy Clin Immunol Int 2000; 2: 54. 28. Arlian L, et al. Lowering humidity in homes reduces dust mites and their allergens. J Allergy Clin Immunol 2001; 107: 99–104. 29. Owen S, et al. Control of house dust mite antigen in bedding. Lancet 1990; 335: 396–397. 30. Arlian LG, Veselica MM. Re-evaluation of the humidity requirements of the house-dust mite Dermatophagoides farinae (Acari: Pyroglyphidae). J Med Entomol 1981; 18: 351–352. 31. Colloff MJ, Taylor C, Merrett TG. The use of domestic steam cleaning for the control of house dust mites. Clin Exp Allergy 1995; 25(11): 1061–1066. 32. Tovey ER, Woolcock AJ. Direct exposure of carpets to sunlight can kill all mites. J Allergy Clin Immunol 1993; 93: 1072–1074. 33. Colloff MJ. Use of liquid nitrogen in the control of house dust mite populations. Clin Allergy 1986; 16: 41–47. 34. Woodfolk JA, et al. Chemical treatments of carpets to reduce allergen: comparison of effects of tannic acid and other treatments on proteins derived from dust mites and cats. J Allergy Clin Immunol 1995; 96: 325–333. 35. Tovey ER, et al. Changes in mite allergen Der p I in house dust following spraying with a tannic acid/acaricide solution. Clin Exp Allergy 1992; 22: 67–74. 36. Vanlaar CH, et al. Domestic control of house dust mite allergen in children’s beds. J Allergy Clin Immunol 2000; 105: 1130–1133. 37. Rains N, et al. House dust mite allergen (Der p 1) accumulation on new synthetic and feather pillows. Clin Exp Allergy 1999; 29: 182–185. 38. Hallam C, et al. House dust mite allergens in feather and synthetic pillows. Allergy 1998; 54(1): 407–408. 39. Kemp TJ, et al. House dust mite allergen in pillows. Br Med J 1996; 313: 916. 40. De Lucca S, O’Meara T, Tovey E. Exposure to mite and cat allergens on a range of clothing items at home and the transfer of cat allergen in the workplace. J Allergy Clin Immunol 2000; 106: 874–879. 41. Vojta P, et al. Effects of physical interventions on house dust mite allergen levels in carpet, bed, and upholstery dust in low income, urban homes. Environ Health Perspect 2001; 109(8): 815–819. 42. Lewis R, et al. Factors affecting the retention of dust mite allergen on carpet. Am Ind Hyg Assoc J 1998; 59: 606–613. 43. Vyszenski-Moher D, et al. Management of house dust mites and their allergens by benzyl benzoate products. Ann Allergy Asthma Immunol 2000; 84: 136. 44. Woodfolk JA, et al. Chemical treatment of carpets to reduce allergen: a detailed study of the effects of tannic acid on indoor allergens. J Allergy Clin Immunol 1994; 94: 19–26. 45. Warner JA. Double blind trial of ionisers in children with asthma sensitive to the house dust mite. Thorax 1993; 48: 330–333. 46. Harving H, Korsgaard J, Dahl R. Mechanical ventilation in dwellings as preventive measures in mite asthma. Allergy Proc 1988; 9: 283. 47. Tovey ER, et al. Distribution of mite allergen Der p I in Australian communities. J Allergy Clin Immunol 1995; 95: 325. 48. Girgis S, et al. Thunderstorm associated asthma in an inland town in south eatern Australia. Eur Respirat J 2000; 16(1): 3–8. 49. Platts-Mills TAE, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982; 25: 675–678. Mini Reviews

caused by translocation of Gram-negative microorganisms normally present in the gut of the host to the circulation, there is continuous exposure to airborne endotoxin. The release of endotoxin from Gram-negative bacteria that colonise the respiratory tract in the majority of patients with chronic bronchitis can contribute to the lung function decrease by initiating release of inflammatory mediators from bronchial epithelial cells. 2 High levels of airborne (up to 1 mg/m 3 ) endotoxin have been reported from a variety of occupational environments (e.g. swine confinement, poultry farm, cotton mill, brewery, waste processing). 1 A number of cross-sectional studies reports an association between exposure to endotoxin measured in the dust from those occupational settings and the risk to develop non-atopic chronic obstructive pulmonary diseases, 3 -6 toxic pneumonitis and systemic effects. 7,8 In the domestic environment, there is also endotoxin contaminating house dust 9 -12 that, by itself or in association with allergen exposure, could be an important determinant of asthma severity. 9,10 Recently, Hasday et al. reported that high levels of endotoxin are produced by cigarette smoke. 13 Inhalation of pure endotoxin may elicit, in some individuals, dyspnea, chest tightness, myalgia, shivers, fatigue and malaise associated or not with fever. 14,15 A similar clinical response is observed after exposure to dust containing endotoxin such as grain handlers, 16 cotton workers, 5 fibre-glass manufacturing employees, 8 or animal farmers. 17 A large inter-individual variability in the sensitivity to endotoxin has been reported. 18 -20 In humans, inhalation of pure endotoxin is associated with bronchoconstriction, 14,15,18 -21 change in the level of non-specific airways responsiveness, 14,20,21 and reduction in alveolar-capillary diffusion. 22 Compared with asthmatics, in normal subjects a higher dose of pure endotoxin is required to produce bronchoconstriction. 14,15,18,19,23 Although the endotoxin response is reproducible in a given subject, 19 there is a large between-subjects variability 14,18,19,20 at least partially related to the airways inflammatory status 24 and to the level of nonspecific airways responsiveness. 25 Local and systemic inflammatory responses have been measured after endotoxin inhalation in normal and asthmatic subjects. Significant blood leukocytosis and neutrophilia were observed 4-8 h after inhalation of endotoxin both in normal 14 -16,18,22,26 and asthmatic subjects. 21,27 This neutrophilia was not related with the change in lung function. 21,27 In vitro, small amounts of endotoxin (< 1 ng/ml) activate human airways macrophages, releasing several pro-inflammatory cytokines (tumour necrosis factor-a (TNF-a), interleukin (IL)-1, IL-6) and metabolites of arachidonic acid. The presence of LPS-binding protein and the soluble fraction of CD14 receptor (sCD14) in the airways 24 may increase the macrophage activation by endotoxin. 24,28 Six hours after an inhalation of endotoxin-contaminated dust, high concentrations of IL-1, IL-1 RA, IL-6, IL-8 and TNF-a and their specific mRNAs were measured in the bronchoalveolar lavage. 29 These cytokines are potential activators of the hepatic acute-phase protein response, consistent with the rise in the blood concentration of the C-reactive protein (CRP) 24 h after endotoxin inhalation. 13,17,21,26 We speculate that cytokines produced into the airways are released in the blood and stimulate the hepatocytes.
Airway inflammation characterized by neutrophil recruitment in broncho alveolar lavage (BAL) was observed after bronchial challenge with endotoxincontaminated dusts like allergen extracts, 30 grain dust 29 and swine dust, 17 while in normal subjects 100 mg of inhaled pure endotoxin induced a 100-fold increase in neutrophils from BAL. 31 A significant increase in neutrophils measured in the induced sputum occurred after 5 15,32 to 60 mg 33 endotoxin. The sputum concentrations in myeloperoxidase (MPO) (from neutrophils), eosinophil cationic protein (ECP) (from eosinophils) and TNF-a rose significantly 6 h after endotoxin. 15 There are some published data suggesting that environmental endotoxin could be a synergic factor on the amplitude of immunoglobulin E-mediated response. On one hand, in allergic mild asthmatics, an exposure to air containing low levels of endotoxin (250 ng/m 3 ) for 4 h before bronchial challenge with allergen increases significantly both bronchial reactivity and antigen-induced airway eosinophilia. 34 The airways cellular inflammation to inhaled allergen is modified by endotoxin contamination of the allergen extract. Indeed, while detoxified pure allergen extract results in bronchial eosinophil recruitment, endotoxin contamination (1 ng/ml) causes neutrophilia. 30 On the other hand, inhalation of allergen in sensitized subjects leads to airways plasma exsudation including extravasation of sCD14 and lipopolysaccharide-binding protein (LBP). 24 These proteins may enhance the capacity of inhaled endotoxin to activate an inflammatory cascade that may amplify the inflammatory response to inhaled antigen in some asthmatics, as was suggested by several field studies. 9,10,35 In the home environment, the amount of endotoxin in house dust has been related to the severity of asthma both in atopic 9,10 and non-atopic subjects. 35 In dust-mite-sensitized subjects, the level of exposure to mite allergen was higher in subjects with asthma than in those with rhinitis, while the severity of the asthmatic disease was significantly associated with a low forced expiratory volume in 1 sec (FEV1) and FEV1/forced vital capacity, and the daily need for oral and topical corticosteroid, as well as with the asthma score. 9 More recently, Douwes et al. 36 did not find an association between endotoxin exposure and peak expiratory flow (PEF) variability in a group of children defined by asthma symptoms. However, the daily PEF variability was very low (6.4%), suggesting asthma was intermittent or doubtful. Therefore, endotoxin should be considered as an enhancing rather than inducing factor in asthma.
We recently challenged 15 normal subjects with inhaled endotoxin (0.5, 5, 50 mg). 18 Subjects who developed significant increase in body temperature had a larger increase in the systemic inflammatory response (blood neutrophilia and blood concentrations of CRP and LBP), while subjects who developed a significant increase in airways responsiveness had an increase in the sputum concentration of ECP. The amplitude of the systemic response and decrease in FEV1 were inversely associated with the atopic status, suggesting a link between atopy and LPS responsiveness. This observation reinforces the hypothesis for a mechanism linking the macrophage susceptibility to LPS stimulation with the increase in macrophage production of cytokines that inhibits the T helper cell (Th)-2 response and, consequently, the risk to become atopic. Environmental exposure to LPS and other bacterial wall products, present in house dust 9 -12,35,36 and/or from the intestinal tract, 37 could be a necessary step for maturation the immune system and the development of a Th1-like response through the presentation of antigen in conjunction with IL-12. 38 -40 In mice, endotoxin sensitivity is genetically determined, involving mutation in the Tolllike receptor-4 (TLR4) gene, 41 a co-receptor essential for the LPS signalling. In human, recent data suggest that polymorphisms in the genes encoding the TLR4 42 or the LPS receptor CD14 43 may be related to symptoms and diseases. exposure to endotoxin in early life could be protective for the risk of atopy, while in symptomatic asthma it could be a risk factor of a severe disease.
Finally, available data on the protective effect of anti-asthmatic drugs on the endotoxin-induced response are quite limited. An acute pre-treatment with sodium cromoglycate 44 or with short or long acting B 2 -agonists completely prevents the bronchoconstriction induced by an acute exposure to LPS 45 while, given in a single dose, an inhaled corticosteroid does not prevent the endotoxin-induced blood inflammation. 45 Studies are in progress to evaluate the possible protective effect of chronic treatment with oral corticosteroids on the response to endotoxin. The past three decades have seen an increase in reported asthma and allergic diseases from many studies around the world, recently described as an epidemic. 1 While many hypotheses have been developed to explain these changes, the hygiene hypothesis has for the past decade encompassed an expanding link between the epidemiology and immunology of both atopic sensitisation and atopic diseases. These associations and the utility of the hypothesis have recently been reviewed by David Strachan, 2 who first reported the associations between birth order and hayfever, and articulated the hygiene hypothesis as an explanation. 3 Inverse relationships between atopic and infectious disease was first raised a decade earlier by Gerrard et al. in a comparison of atopic disease amongst the Metis (native Indian) and white communities of northern Saskatchewan. 4 The immunological basis for the hypothesis rests on the concept of immune deviation in early life towards T helper cell (Th)1 immune responses induced by microbial exposure, with Th1 responses suppressing Th2 responses and immunoglobulin E (IgE) production. The hypothesis therefore refers to IgE-mediated diseases such as hayfever but is less applicable to asthma, where atopy plays an important but not exclusive role.

Asthma, atopy, antibiotics and the bowel
The relationships between asthma, bronchial hyperresponsiveness (BHR) and atopy have recently been examined among 20-to 44-year-old adults, in five Spanish centres involved in the European Community Respiratory Health Survey. The adjusted proportion of BHR attributable to atopy was 21% and the proportion of asthma symptoms and BHR attributable to atopy was 42%. 5 Factors associated with the hygiene hypothesis such as birth order or specific infections will vary in their strength of association with asthma depending on the proportion of asthma attributable to atopy. An important feature of any useful hypothesis is that it should unify disparate observations. The hygiene hypothesis does this, suggesting explanations for socio-economic variations in atopic disease both within and between countries, and a plausible explanation of some of the long-term upward trends in prevalence. Studies of the relationship between infection or microbial exposures and atopic disease also tend to support the hygiene hypothesis.
The influence of antibiotics on these associations has recently been studied. Farooqi et al. found a twofold risk of doctor-diagnosed atopic diseases with antibiotic treatment in the first 2 years of life, among a general practice birth cohort. 6 The increased risk was apparent for all classes of antibiotics, although greater for cephalosporins and macrolides; it was independent of the underlying condition being treated, and was similar for those with and without a history of maternal atopy. Antibiotic exposure was the strongest predictor of atopic disease in this study.
The other two studies have examined antibiotic use among children in Sweden and New Zealand, whose families have some association with an anthroposophic lifestyle. Families embracing this lifestyle, whose tenets were set out by Rudolph Steiner in the nineteenth century, tend to minimise their involvement with conventional medical