Correspondence
Endotoxin and Asthma
N Engl J Med 2003; 348:171-174January 9, 2003
- Article
To the Editor:
Investigators in the Allergy and Endotoxin (ALEX) Study have shown previously that exposure to stables and farm milk during the first year of life protects against asthma and hay fever at 6 to 13 years of age, plausibly through exposure to microbial components.1 Braun-Fahrländer et al. (Sept. 19 issue)2 substantiate this proposition by showing that current endotoxin levels in children's mattresses were inversely associated with the occurrence of hay fever and atopic asthma and that leukocytes from children with high levels of exposure to endotoxin produced less of the cytokines tumor necrosis factor α, interferon-γ, interleukin-10, and interleukin-12. Intriguingly, different protection profiles were associated with early exposure to farming (which protected against both atopic and nonatopic asthma) and later exposure to endotoxin (which protected against atopic asthma but not nonatopic asthma); this difference was considered to reflect the timing of the exposure. Although atopic dermatitis is closely related to microbial exposure,3 its occurrence was not associated with exposure to farming in the first report from the ALEX study1 and was not discussed in the current report.2 These points weaken the group's assumption that current endotoxin levels reflect long-term exposure and that the effect of farming is related to exposure to microbial components.
The picture becomes more perplexing when the suggested mechanism of the effect of endotoxin is considered, since three of the four cytokines that were down-regulated in the highly exposed children are among those best known to suppress allergic responses mediated by type 2 helper T cells (Th2).4 Interleukin-10, in particular, is an important modulator of allergic responses,5 and contrary to the interpretation offered in the editorial by Weiss,4 its down-regulation in highly exposed children is evidence against the hygiene hypothesis.
5 ReferencesWasim Maziak, Ph.D.
Institute of Epidemiology and Social Medicine, 48129 Muenster, Germany
maziak@uni-muenster.de 1
Riedler J ,Braun-Fahrlander C ,Eder W , et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129-1133
CrossRef | Web of Science | Medline2
Braun-Fahrlander C ,Riedler J ,Herz U , et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869-877
Full Text | Web of Science | Medline3
Kalliomaki M ,Salminen S ,Arvilommi H ,Kero P ,Koskinen P ,Isolauri E . Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001;357:1076-1079
CrossRef | Web of Science | Medline4
Weiss ST . Eat dirt -- the hygiene hypothesis and allergic diseases. N Engl J Med 2002;347:930-931
Full Text | Web of Science | Medline5
Bach J-F . The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911-920
Full Text | Web of Science | Medline
To the Editor:
Braun-Fahrländer et al. report that exposure to endotoxin and living on a farm in a rural community were associated with a decreased prevalence of wheezing. Elsewhere, the “hygiene hypothesis” has been extended to provide an explanation for the global increase in the occurrence of asthma.
Decreased exposure to bacteria early in life may have contributed to the probable increase in allergy in the United Kingdom in the late 19th century, when hay fever became a prevalent disease.1 It is unlikely, however, that increased cleanliness caused the asthma epidemic during the past several decades. Simply in terms of timing, for the majority of people in the United States, contact with farm animals ended more than a century ago. It is doubtful that the children with asthma born in the 1960s and 1970s grew up in substantially cleaner homes than their parents had. Heightened cleanliness cannot explain the much higher prevalence of asthma seen in indigent urban communities in the United States. Furthermore, it is unlikely that the increase in the incidence of allergic asthma seen in the transition from rural to urban living in Africa is associated with decreased exposure to bacteria.2
Alternative explanations for the asthma epidemic include widespread early use of antibiotics, increases in childhood immunization, increased concentrations of diesel particulates, dietary changes, and increasingly sedentary lifestyles. The changes that coincide with the timing of the increase and that have been most obvious in minority populations living in poverty in the United States are those that relate to diet and a progressive decline in physical activity.3
3 ReferencesMatthew S. Perzanowski, M.P.H.
Columbia University, New York, NY 10032
msperzanowski@hotmail.com Thomas A.E. Platts-Mills, M.D., Ph.D.
University of Virginia, Charlottesville, VA 229081
Emanuel MB . Hay fever, a post industrial revolution epidemic: a history of its growth during the 19th century. Clin Allergy 1988;18:295-304
CrossRef | Medline2
Perzanowski MS ,Ng'ang'a LW ,Carter MC , et al. Atopy, asthma, and antibodies to Ascaris among rural and urban children in Kenya. J Pediatr 2002;140:582-588
CrossRef | Web of Science | Medline3
Crater SE ,Platts-Mills TA . Searching for the cause of the increase in asthma. Curr Opin Pediatr 1998;10:594-599
CrossRef | Medline
To the Editor:
Braun-Fahrländer et al. conclude that children's environmental exposure to endotoxin may have a crucial role in the development of immune tolerance to ubiquitous allergens. Their results are based on analyses of dust samples from children's mattresses, where endotoxin levels were found to be inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization.
Standard management of allergic diseases includes measures to reduce exposure to allergens and house dust — for example, by intensive cleaning and replacement of natural fabrics with synthetic material for mattresses, bedding, carpets, and other items.1,2 The article by Braun-Fahrländer et al. does not describe the extent to which such measures had already been taken by the families with allergic children. This information is crucial, since one must rule out the possibility that lower endotoxin levels in mattresses were the result of a diagnosis of allergic disease and thus an indirect consequence rather than a cause of allergic sensitization.
2 ReferencesDaniel E. Speiser, M.D.
Alfred Zippelius, M.D.
University Hospital, CH-1005 Lausanne, Switzerland
daniel.speiser@hospvd. ch 1
NIH National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma — update on selected topics 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, 2002. (Accessed December 18, 2002, at http://www.nhlbi.nih.gov/guidelines/asthma/.)
2
Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Dermatology. 2nd ed. Berlin, Germany: Springer, 2000.
Author/Editor Response
Maziak expresses doubt about whether the results of our study support the hygiene hypothesis because we found an inverse relation between the current level of exposure to endotoxin and the production of interleukin-10, interleukin-12, tumor necrosis factor α, and interferon-γ. The hygiene hypothesis states that exposure to infections, microbial products, or both decreases the risk of atopic illnesses. However, this hypothesis does not explain the mechanisms by which such protection might be conferred. We have shown a strong inverse association between exposure to endotoxin and atopic outcomes that clearly supports the hygiene hypothesis. Our previous findings in the same population1 — showing differential expression of several receptors for microbial products in children from farming and nonfarming households — suggest that the innate immune system may play an important part in the observed effects. It has been proposed that the innate immune response has an instructive role in adaptive immunity2 and may thus be important for the ontogeny of the normal immune system. However, we agree with Weiss that studies in birth cohorts are needed to address the effect of the dose and timing of microbial exposure, as well as the role of other (genetic) cofactors, if we are to understand better the mechanisms by which the development of atopic diseases is impaired.3
Perzanowski and Platts-Mills question whether the hygiene hypothesis can explain the global increase in asthma. Epidemiologic studies involving farm children and their peers in rural communities do not primarily intend to explain this global increase but offer a unique opportunity to investigate the role of microbial compounds in the development of asthma and allergies. The hope is that new insights into the role of microbial compounds may foster the generation of novel strategies for the prevention of these diseases. However, our results do not preclude the possibility that other environmental factors contribute to the global increase in the occurrence of asthma and allergies or to the increases in specific areas such as inner cities in the United States, as we pointed out in our article.
Speiser and Zippelius are concerned that allergen-avoidance measures taken by parents of allergic children might have reduced the endotoxin concentrations in mattresses and thus led to the inverse relation between level of exposure to endotoxin and risk of allergy reported in our article. However, we adjusted our regression models for known allergy-avoidance measures such as removal of pets or carpets, as outlined in the Methods section.
3 ReferencesCharlotte Braun-Fahrländer, M.D.
Institute of Social and Preventive Medicine, CH-4051 Basel, Switzerland
c.braun@unibas. ch Roger P. Lauener, M.D.
University Children's Hospital, CH-8032 Zurich, SwitzerlandErika von Mutius, M.D.
Dr. Von Hauner Children's Hospital, D-80377 Munich, Germany1
Lauener R ,Birchler T ,Adamski J , et al. Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 2002;360:465-466
CrossRef | Web of Science | Medline2
Fearon DT ,Locksley RM . The instructive role of innate immunity in the acquired immune response. Science 1996;272:50-53
CrossRef | Web of Science | Medline3
Weiss ST . Eat dirt -- the hygiene hypothesis and allergic diseases. N Engl J Med 2002;347:930-931
Full Text | Web of Science | Medline
Author/Editor Response
Dr. Maziak notes that the mechanism by which exposure to lactobacillus prevents atopic dermatitis and the mechanism by which such exposure protects against hay fever and allergic asthma1 may be different. I would agree that more work is needed to sort out the molecular mechanisms involved.
As I note in my editorial, interleukin-10 down-regulates the immune responses mediated by both type 1 and type 2 helper T cells. Cross-sectional cytokine measurements in children between the ages of 6 and 13 years, as presented by Braun-Fahrländer et al., are not adequate to address the question of how interleukin-10 influences the ontogeny of the immune system. Answering this question will require the longitudinal measurement of exposure and the relevant cytokines prospectively in a birth cohort — precisely the points that I made in my editorial.
1 ReferencesScott T. Weiss, M.D.
Channing Laboratory, Boston, MA 021151
Kalliomaki M ,Salminen S ,Arvilommi H ,Kero P ,Koskinen P ,Isolauri E . Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001;357:1076-1079
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
M. S. Perzanowski, S. M. Canfield, G. L. Chew, R. B. Mellins, L. A. Hoepner, J. S. Jacobson, I. F. Goldstein. (2008) Birth order, atopy, and symptoms of allergy and asthma among inner-city children attending Head Start in New York City. Clinical & Experimental Allergy 38:6, 968-976
CrossRef2
W. Maziak. (2008) The triumph of the null hypothesis: epidemiology in an age of change. International Journal of Epidemiology 38:2, 393-402
CrossRef3
W. Maziak. (2008) Author's Response: Epidemiology between astronomy and astrology. International Journal of Epidemiology 38:2, 608-610
CrossRef
