ArticleLiterature Review

Is there scientific evidence that suppression of acute diseases in childhood induce chronic diseases in the future?

Authors:
  • School of Medicine University of Sao Paulo
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Abstract

Seeking to understand the individual in his symptomatic totality has been an aim of homeopathy since its beginning. Throughout its history, homeopaths have been concerned that inadequate treatment of acute diseases in childhood may lead to future chronic diseases. Hahnemann cautioned that by treating acute diseases with allopathic medicine, with strong doses of drugs, or suppressing local symptoms of those diseases, would increase the risk of future chronic diseases. Burnett proposed the theory of vaccinosis and warned of chronic manifestations subsequent to smallpox vaccination. French homeopaths, seeking the physiopathological origin of chronic diseases, correlated it to the abnormal reaction of the reticuloendothelial system (RES). Through the study of experimental pathology, Maffei attributed symptomatic manifestations to the imbalance between the immunological phenomena of allergy and immunity. He termed the sensitizing and pathogenic effects of medications and vaccines, 'metallergy' and 'parallergy', respectively. The hygiene hypothesis is based on evidence that the imbalance of immunological response in childhood, specifically among the Th1 and Th2 lymphocyte subpopulations, is responsible for the development of some allergic and chronic diseases in the future. The deranging factor for the predisposition to future allergic response (Th2) is the obstruction of natural manifestations of infectious diseases (Th1 response) in young children. Homeopathic treatment aims to equilibrate vital reaction, corresponding to an integrative physiological response, it may regulate Th1/Th2 imbalance. However, clinical trials to support this hypothesis are lacking.

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We tested, under independent conditions, the reproducibility of evidence from two previous trials that homoeopathy differs from placebo. The test model was again homoeopathic immunotherapy. 28 patients with allergic asthma, most of them sensitive to house-dust mite, were randomly allocated to receive either oral homoeopathic imm;notherapy to their principal allergen or identical placebo. The test treatments were given as a complement to their unaltered conventional care. A daily visual analogue scale of overall symptom intensity was the outcome measure. A difference in visual analogue score in favour of homoeopathic immunotherapy appeared within one week of starting treatment and persisted for up to 8 weeks (p=0.003). There were similar trends in respiratory function and bronchial reactivity tests. A meta-analysis of all three trials strengthened the evidence that homoeopathy does more than placebo (p=0.0004). Is the reproducibility of evidence in favour of homoeopathy proof of its activity or proof of the clinical trial's capacity to produce false-positive results?
Article
Commitment of T helper 1 (Th1) or Th2 populations developing during an immune response to a pathogen, or an inappropriate immune response to an allergen or autoantigen, may determine the difference between health and chronic disease. We show that strongly polarized Th1 and Th2 populations assessed by immunoassay are heterogeneous using flow cytometry to detect single cells producing interferon gamma (IFN-gamma) and interleukin 4 (IL-4). Th1 populations arising after 1 wk of stimulation in IL-12 plus anti-IL-4 antibodies could convert to Th2 cells when restimulated in IL-4. Th2 populations resulting from stimulation for 1 wk in IL-4 could give rise to Th1 cells upon restimulation in IL-12 plus anti-IL-4. In contrast, the cytokine profiles of long-term Th1 and Th2 populations arising originally from repeated stimulation in IL-12 or IL-4 appeared more homogeneous and were not reversible, although IL-4 dramatically reduced the number of IFN-gamma-producing Th1 cells. This may explain previous reports that Th1 cells can be converted to Th2 cells.
Article
Background: We previously showed that the prevalence of allergic disease is decreased in patients with multiple sclerosis (MS); however, the mechanisms that explain this finding have not previously been defined.Objectives: We have demonstrated that protection of patients with MS from allergic disease may be caused by the production in monocytes from these patients of elevated quantities of IL-12 compared with that observed in monocytes from individuals with allergies.Methods: Purified monocytes from peripheral blood of subjects with or without allergies and from individuals with MS were directly stimulated with Staphylococcus aureus Cowan strain I in the absence of T cells. IL-12 was quantitated by a sensitive reverse transcription, competitive PCR.Results: IL-12 production was 5-fold greater in monocytes from patients with MS (n = 11) than that from individuals with allergies (n = 10) (for subjects with MS, 1.90 ± 0.18 vs 1.24 ± 0.19 log10 fmol/μL for individuals with allergies) (P = .02). Although the production of IL-12 in monocytes from patients with MS was slightly higher than that from subjects without allergies, this difference was not statistically significant.Conclusions: IL-12 production in individuals with MS is much greater than in individuals with allergies. Because IL-12 induces TH1 cytokine synthesis and reduces the production of TH2 cytokines, which amplify and prolong allergic inflammation, these studies suggest that enhanced IL-12 production may protect individuals with MS from the development of allergy but may predispose such individuals toward autoimmune inflammation in the central nervous system. (J Allergy Clin Immunol 1998;102:428-35.)
Article
This work suggests that it is possible to study some key issues relevant to homoeopathy using standard trial designs. Further the results of this pilot study appear to demonstrate a difference in effect between a 30c potency and a placebo. A larger definitive study is under way to examine the reproducibility of these results
Article
Background There is increasing evidence that the T-cell reactivity to environmental allergens underlying expression of allergic disease in adulthood, develops initially during childhood. However, there is little information available on the kinetics of these early responses, or on the patterns of cytokine production during this period. Objective The purpose of this study was twofold: to obtain further information on the reported differences between responses to food versus inhalant allergens during early childhood, and to ascertain the age-range over which T-cell responses to inhalant allergens become polarized towards the TH2 cytokine profile, in potentially atopic children. Methods In vitro cytokine responses to house dust mite (HDM) and egg (OVA) were assessed by semiquantitative RT-PCR in panels of 2- and 5-year-old children and adults; lymphoproliferative responses to OVA were subjected to epitope analysis. Results At age 2 years IL-4/IL-5 responses to HDM grouped with positive atopic family history, and by age 5 years cytokine responses correlated strongly with individual SPT reactivity to HDM. In contrast, OVA responses were restricted to weak and transient IL-5 signals in the 2-year-old family history positive group. Lymphoproliferation assays performed in parallel indicate a log-scale greater postnatal expansion of T-cell reactivity to the inhalant allergen; preliminary epitope analysis of OVA responses indicate that the number of OVA epitopes recognised decrease during early childhood. Conclusions Inhalant allergen-specific in vitro cytokine production associated with positive skin-prick test (SPT) reactions, one of the hallmarks of adult atopy, manifests in children at or before 5 years of age; additionally, cytokine responses in SPT negative 5 year-olds are restricted to IFNγ, as per normal adults. In contrast, T-cell responses to a typical food allergen appear to be deleted during early childhood.
Article
BackgroundReversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in Western societies. In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life. Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora. We assessed the effect on atopic disease of Lactobacillus GG (which is safe at an early age and effective in treatment of allergic inflammation and food allergy).MethodsIn a double-blind, randomised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for 6 months to their infants. Chronic recurring atopic eczema, which is the main sign of atopic disease in the first years of life, was the primary endpoint.FindingsAtopic eczema was diagnosed in 46 of 132 (35%) children aged 2 years. Asthma was diagnosed in six of these children and allergic rhinitis in one. The frequency of atopic eczema in the probiotic group was half that of the placebo group (15/64 [23%] vs 31/68 [46%]; relative risk 0·51 [95% Cl 0·32–0·84]). The number needed to treat was 4·5 (95% Cl 2·6–15·6).InterpretationsLactobacillus GG was effective in prevention of early atopic disease in children at high risk. Thus, gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics, for prevention of atopic disease.
Article
There is controversy regarding immunization. This paper concentrates on measles although the evidence is more broadly based. Both mortality and morbidity figures strongly suggest that despite a few casualties the campaign has saved many lives and much suffering, even though its goal of eliminating measles has not yet been achieved. Unfortunately the immunizing effect of the vaccine has a shorter duration of action than the disease itself, and this has led to outbreaks of measles amongst older age-groups immunized as babies. Morbidity and mortality are higher when measles is contracted at older ages. A revaccination campaign is under way. Side effects from revaccination are less frequent than with primary vaccination. The incidence of a variety of chronic diseases, some of which are related to the immune system, has risen concurrently with the various immunization programmes. Opponents fear that the two phenomena are connected, and that by proceeding with immunization we are fundamentally damaging the race. While the evidence for such a connection is weak, it cannot entirely be dismissed as it is equally hard to disprove. We should remain alert to the possibility and research it honestly while continuing with the campaign, since abandoning it would undoubtedly result in much more loss of life and permanent disability.
Article
We evaluated the allergy status of 134 immigrants from Asia, Africa, the Middle East and South America, who were referred to our clinic during the past 10 years. Fifty Swedish patients were used for comparison. When the atopy state was not taken into account, no significant difference was found between the two groups with respect to total IgE levels. However, IgE levels of non-atopic immigrants were significantly higher than the IgE levels of non-atopic Swedes. While there was no significant difference in IgE levels between atopic and non-atopic immigrants, this difference was significant in Swedish patients. In general, IgE levels of immigrants showed a decline with time and reached approximately the same levels as for the Swedish patients in 10.5 years. In the immigrant group atopic women had a considerably lower IgE level than the atopic men. Among the atopics there were no differences between sexes. In Swedes and immigrants pollen was the most common group of allergens. The spectrum of allergy in the immigrant group changed with time in Sweden, and gradually became more similar to the Swedish spectrum. Skin and/or RAST positivity to birch increased from 16% within 2.5 years to 53% after more than 10.5 years in Sweden. Our data indicate that environmental factors rather than hereditary differences determine the IgE state. Within a few years the immunologic status of immigrants adapts to the new environment.
Article
In human beings, as in mice, two distinct patterns of cytokine secretion have been defined among CD4+ helper T-cell clones. Human type 1 helper (Th1), but not type 2 helper (Th2), cells produce interleukin-2 (IL-2), gamma-interferon (IFN-gamma), and tumor necrosis factor-beta, whereas Th2, but not Th1, cells secrete IL-4 and IL-5, but not IL-2 or IFN-gamma. Other cytokines, such as IL-3, IL-6, GM-CSF, or TNF-alpha, are produced by both Th1 and Th2 cells. Th0 cells, a third Th subset, show combined production of Th1- and Th2-type cytokines. The different cytokine patterns are associated with different functions. In general, Th2 cells provide an excellent helper function for B-cell antibody production, particularly of the IgE class. On the other hand, Th1 cells are responsible for delayed type hypersensitivity reactions and are cytolytic for autologous antigen-presenting cells, including B cells. Most allergen- or helminth-antigen-specific human CD4+ T-cell clones exhibit a Th2 phenotype, whereas most clones specific for bacterial antigens show a Th1 profile. Allergen-specific Th2 cells seem to play a crucial role in atopy. These cells induce IgE production via IL-4 and favor the proliferation, differentiation, and activation of eosinophils via IL-5. In addition, Th2-derived IL-3 and IL-4 are mast-cell growth factors that act in synergy, at least in vitro. Recent evidence indicates that allergen-specific Th2 cells are selectively enriched in tissues affected by allergic inflammation, such as the bronchial mucosa of subjects with allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The effects exerted on the in vitro development of purified protein derivative (PPD)-specific or Dermatophagoides pteronyssinus group I (Der p I)-specific T cell lines (TCL) and T cell clones (TCC) by IL-4 or IFN-gamma addition or neutralization in human PBMC cultures were examined. PBMC from two normal individuals, which were stimulated with PPD and then cultured in IL-2 alone, developed into PPD-specific TCL and TCC able to produce IFN-gamma and IL-2 but not IL-4 and IL-5 (Th1-like). IFN-gamma or anti-IL-4 antibody addition in bulk cultures before cloning did not influence the PPD-specific TCL profile of cytokine production. In contrast, the addition of IL-4 resulted in the development of PPD-specific TCL and TCC able to produce not only IFN-gamma and IL-2 but also IL-4 and IL-5. PBMC from one atopic Der p I-sensitive patient, which were stimulated with Der p I and then cultured in IL-2 alone, developed into Der p I-specific TCL and TCC able to produce IL-5 and large amounts of IL-4 but no IFN-gamma (Th2-like). The addition in bulk cultures, before cloning, of either IFN-gamma or anti-IL-4 antibody markedly inhibited the development of Der p I-specific T cells into IL-4- and IL-5-producing TCL. Accordingly, the development into Der p I-specific Th2-like TCC was significantly reduced by the addition of IFN-gamma in bulk culture and was virtually suppressed by the presence of both IFN-gamma and anti-IL-4 antibody. These data suggest that the presence or the absence of IL-4 and IFN-gamma in bulk cultures of PBMC before cloning may have strong regulatory effects on the in vitro development of human CD4+ T cells into Th1 or Th2 clones.
Article
Appendicitis was rare in the past and still is in traditional Third World populations. It began to increase a century ago, peaked about 1950, and has now fallen to about half its previous incidence. As to causation, dietetically, it was contended that the increase was promoted primarily by an associated fall in dietary fiber intake. The recently advanced hygiene hypothesis considers the increase to have stemmed from improvements in hygiene, generally; these limited exposure to enteric infections and modified response to virus infections, thereby triggering appendicitis. Major uncertainties still prevail over the promotive and precipitating factors of the disease. It is doubtful whether individuals can take any action to avoid appendicitis.
Article
Hay fever has been described as a "post industrial revolution epidemic,"' and successive morbidity surveys from British general practice suggest that its prevalence has continued to increase over the past 30 years.) Other evidence suggests a recent increase in the prevalence of asthma2 and childhood eczema.3 This paper suggests a possible explanation for these trends over time.
Article
The hypothesis that homoeopathic potencies are placebos was tested in a randomised, double-blind, placebo-controlled trial. The study model chosen compared the effects of a homoeopathic preparation of mixed grass pollens with placebo in 144 patients with active hayfever. The homoeopathically treated patients showed a significant reduction in patient and doctor assessed symptom scores. The significance of this response was increased when results were corrected for pollen count and the response was associated with a halving of the need for antihistamines. An initial aggravation of symptoms was noted more often in patients receiving the potency and was followed by an improvement in that group. No evidence emerged to support the idea that placebo action fully explains the clinical responses to homoeopathic drugs.
Article
The mechanisms regulating the onset of atopic sensitization in human beings are not yet fully clarified. We assessed the capacity of mitogen-stimulated umbilical and peripheral blood mononuclear cells to produce interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) at birth and at 9 months of age in 159 infants. Mononuclear cell production of both IFN-gamma and IL-2 at 9 months, but not at birth, was found to be inversely related to parental immediate skin test reactivity to seven local aeroallergens. Skin test reactivity at the age of 6 years was also inversely related to IFN-gamma and IL-2 production at 9 months of age. However, no relationship was evident between total serum IgE levels at 6 years and production of these cytokines at 9 months. The proportions of circulating lymphocytes and CD4+ or CD8+ cells were also unrelated to skin test reactivity at the age of 6 years. These data suggest that mechanisms regulating skin test reactivity to inhaled allergens may involve deficient IFN-gamma production, deficient IL-2 production, or both during or preceding the time of initial sensitization and that additional mechanisms are involved in regulating total serum IgE level.
Article
A large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells. Human Th1-like cells preferentially develop during infections by intracellular bacteria, protozoa, and viruses, whereas Th2-like cells predominate during helminthic infestations and in response to common environmental allergens. The cytokine profile of “natural immunity” evoked by different offending agents in the context of different host genetic backgrounds appears to be a critical factor in determining the phenotype of the subsequent specific response. Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, they can also promote different immunopathological reactions. Th1-type responses appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology. In contrast, in genetically predisposed hosts, Th2-type responses against common environmental allergens are responsible for triggering of allergic atopic disorders. Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes. The role of lymphokines produced by T cells in the pathogenesis of systemic autoimmune disorders is less clear. Further work is also required to better clarify the role of T cell-derived lymphokines in protecting against tumors or in favoring their development.
Article
The development of restricted cytokine profiles by subsets of CD4+ T cells is a pivotal point in the regulation of immune responses. T cells producing Th1 cytokines (IL-2 and interferon-gamma) induce cell-mediated immunity, whereas T cells producing Th2 cytokines (IL-4, IL-5, and IL-10) play a prominent role in the induction of humoral immunity. We examined a group of patients with multiple sclerosis, a disease caused by excess production of Th1 cytokines in myelin-reactive T cells, and control patients with noninflammatory neuroconvulsive disorders, for the presence of allergic disease, which is caused by excess production of Th2 cytokines in allergen-specific T cells. The patients with multiple sclerosis had significantly fewer allergic symptoms, a lower number of positive allergen-specific IgE test results, and lower composite allergy indexes than control subjects. These results demonstrate that the prevalence of IgE-mediated allergic disease is decreased in a group of patients with multiple sclerosis and support the hypothesis that genetic factors that promote susceptibility to Th1-mediated inflammatory disease in human beings protect against the development of Th2-mediated disease.
Article
The increase in atopic diseases may be partly explicable by a decline of certain infectious diseases, or changes in childhood vaccination programmes, or both. We investigated whether BCG vaccination against tuberculosis influences the development of atopy. We did a retrospective cohort study of 216 children with atopic heredity, born in Stockholm between 1989 and 1992, who received BCG vaccination when they were younger than 6 months, and 358 age-matched controls who had not been vaccinated. Both groups attended Sachs' Children's Hospital, Stockholm, Sweden, during 1995-96 for assessment of atopic history and clinical signs of atopic disease. All children also underwent skin-prick testing (SPT) and serum was analysed for allergen-specific IgE antibodies. Serum from parents was also analysed for IgE antibodies. 77 (36%) children in the BCG group and 145 (41%) in the control group had a positive history or clinical signs of atopic disease. In the vaccinated group, 26 (12%) children had one or more positive SPT, and 61 (31%) had circulating allergen-specific IgE antibodies, whereas in the control group, the numbers were 35 (10%) and 84 (27%) respectively. Atopy was confirmed by serology in parents of almost two-thirds of the children in each group. Other risk factors for atopic disease were evenly distributed between the two groups. Early BCG vaccination in children with atopic heredity does not seem to affect the development of atopic disease before school age.
Article
There is increasing evidence that the T-cell reactivity to environmental allergens underlying expression of allergic disease in adulthood, develops initially during childhood. However, there is little information available on the kinetics of these early responses, or on the patterns of cytokine production during this period. The purpose of this study was twofold: to obtain further information on the reported differences between responses to food versus inhalant allergens during early childhood, and to ascertain the age-range over which T-cell responses to inhalant allergens become polarized towards the TH2 cytokine profile, in potentially atopic children. In vitro cytokine responses to house dust mite (HDM) and egg (OVA) were assessed by semiquantitative RT-PCR in panels of 2- and 5-year-old children and adults; lymphoproliferative responses to OVA were subjected to epitope analysis. At age 2 years IL-4/IL-5 responses to HDM grouped with positive atopic family history, and by age 5 years cytokine responses correlated strongly with individual SPT reactivity to HDM. In contrast, OVA responses were restricted to weak and transient IL-5 signals in the 2-year-old family history positive group. Lymphoproliferation assays performed in parallel indicate a log-scale greater postnatal expansion of T-cell reactivity to the inhalant allergen; preliminary epitope analysis of OVA responses indicate that the number of OVA epitopes recognised decrease during early childhood. Inhalant allergen-specific in vitro cytokine production associated with positive skin-prick test (SPT) reactions, one of the hallmarks of adult atopy, manifests in children at or before 5 years of age; additionally, cytokine responses in SPT negative 5 year-olds are restricted to IFNgamma, as per normal adults. In contrast, T-cell responses to a typical food allergen appear to be deleted during early childhood.
Article
The incidence of acute lymphoblastic leukemia (ALL) in children has shown temporal and geographic variation during the 20th century, with higher rates in developed nations appearing in the first half of the century, but with persisting low rates in developing nations. We sought to assess the relation of childhood ALL with hygiene conditions, an aspect of socioeconomic development affecting rates of exposure to infectious agents. Infection patterns for hepatitis A virus (HAV), an agent with a fecal-oral route of transmission, were used to indicate hygiene conditions in different populations, with emphasis on instructive United States and Japanese data. A catalytic model was fit to these data, estimating the HAV force of infection and age-specific seroprevalence rates over time. These analyses were used to assess the temporal relationship of changes in HAV infection rates to changes in childhood leukemia mortality and incidence rates. We observed an inverse relationship between HAV infection prevalence and rates of childhood leukemia. Further, decreases in the HAV force of infection in the United States and Japan appear to have preceded increases in childhood leukemia rates. We describe a model based on a putative leukemia-inducing agent with a change in infection rate over time correlated with that of HAV that describes well the temporal trends in childhood leukemia rates for White children in the US and for Japanese children. The data suggest that improved public hygiene conditions, as measured by decreased prevalence of HAV infection, are associated with higher childhood ALL incidence rates. The model that we present supports the plausibility of the hypothesis that decreased childhood exposure to a leukemia-inducing agent associated with hygiene conditions leads to higher rates of ALL in children by increasing the frequency of in utero transmission caused by primary infection during pregnancy (or by increasing the number of individuals infected in early infancy because of lack of protective maternal antibodies).
Article
We previously showed that the prevalence of allergic disease is decreased in patients with multiple sclerosis (MS); however, the mechanisms that explain this finding have not previously been defined. We have demonstrated that protection of patients with MS from allergic disease may be caused by the production in monocytes from these patients of elevated quantities of IL-12 compared with that observed in monocytes from individuals with allergies. Purified monocytes from peripheral blood of subjects with or without allergies and from individuals with MS were directly stimulated with Staphylococcus aureus Cowan strain I in the absence of T cells. IL-12 was quantitated by a sensitive reverse transcription, competitive PCR. IL-12 production was 5-fold greater in monocytes from patients with MS (n = 11) than that from individuals with allergies (n = 10) (for subjects with MS, 1.90+/-0.18 vs 1.24+/-0.19 log10 fmol/microL for individuals with allergies) (P = .02). Although the production of IL-12 in monocytes from patients with MS was slightly higher than that from subjects without allergies, this difference was not statistically significant. IL-12 production in individuals with MS is much greater than in individuals with allergies. Because IL-12 induces TH1 cytokine synthesis and reduces the production of TH2 cytokines, which amplify and prolong allergic inflammation, these studies suggest that enhanced IL-12 production may protect individuals with MS from the development of allergy but may predispose such individuals toward autoimmune inflammation in the central nervous system.
Article
Atopy is of complex origins but the recent rise in atopic diseases in westernized communities points to the action of important environmental effects. One candidate mechanism is the changing pattern of microbial exposure in childhood. This epidemiological study investigated the relationship between childhood infections and subsequent atopic disease, taking into account a range of social and medical variables. A total of 1934 subjects representing a retrospective 1975-84 birth group at a family doctor practice in Oxfordshire were studied. Public health and practice records were reviewed; temporal records were made of all diagnoses of infections and their treatments, all immunisations, and diagnoses of asthma, hay fever and eczema; maternal atopy and a number of other variables were documented. Logistic regression analysis identified three statistically significant predictors of subsequent atopic disease: maternal atopy (1.97, 95% CI 1.46 to 2.66, p < 0.0001), immunisation with whole-cell pertussis vaccine (1.76, 95% CI 1.39 to 2.23, p < 0.0001), and treatment with oral antibiotics in the first two years of life (2.07, 95% CI 1.64 to 2.60, p < 0.0001). There was no significant association found for maternal smoking, bottle feeding, sibship size, or social class. The prediction of atopic disease by maternal atopy mainly reflects the effect of acknowledged genetic factors. Interpretation of the prediction of atopic disorders by immunisation with wholecell pertussis vaccine and treatment with oral antibiotics needs to be very cautious because of the possibilities of confounding effects and reverse causation. However, plausible immune mechanisms are identifiable for the promotion of atopic disorders by both factors and further investigation of these association is warranted.
Article
Recent decades have seen a significant shift in the main causes of illness among infants and young children. Until the 1950s and 196Os, acute infectious diseases affecting the gastrointestinal tract were the most common conditions requiring medical attention. This pattern of morbidity persists to this day in the poorest regions of the world and still claims the lives of millions of children. In developed countries, however, and also in developing countries where successful programmes of vaccination and prevention have been established, chronic, recurrent illnesses of the respiratory tract have taken the place of acute diarrhoea. A very high proportion of children (up to half in populations of northern European origin) are affected by allergies, and the prevalence of asthma and other forms of recurrent airway obstruction is rising.’ Paradoxically, the increases seem most striking in areas where the quality of outdoor air has significantly improved’ and where good sanitation and nutrition prevail. Some years ago we separately proposed3,* similar hypotheses to explain these findings. This so-called “hygiene hypothesis” was an immunological extension of a concept introduced by Strachan.5 Its cornerstone is that changes in the type and level of stimulation from the microbial environment associated with improvements in public health and hygiene may have indirectly influenced the postnatal development of immune function(s), so as to increase predisposition to chronic allergic conditions during childhood. These changes involve both a general decrease in infectious burden during early life (in particular, respiratory infections) and variations in gastrointestinal flora. In this paper, we review how recent advances in understanding of the way immune responses develop in early life support the hygiene hypothesis.