The hygiene hypothesis revisited

At the end of 2002, I published an article that related ‘the clinical observation, empirically cited over the centuries’, that ‘inhibition of acute disease manifestation in childhood can predispose to future chronic diseases’, according to distinct lines from medical thought: homeopathy (Hahnemann, Burnett, French school), anthroposophic medicine, experimental pathology (Maffei).[ ¹ ] This theory assumed a modern scientific guise in the ‘hygiene hypothesis’, suggesting ‘an inverse relationship between atopic diseases and an environment that leads to increased pathogen exposure’.

Contrary to the hygiene hypothesis, Adler publishes in the last edition of Homeopathy a review of the epidemiological literature concluding that ‘childhood infections do not protect against atopy, on the contrary, they increase the risk of allergic disease’ and ‘vaccination is not a risk factor for the development of the atopy’.[ ² ]

Adler does not review indirect markers of exposure to infections, mentioned in the hygiene hypothesis (climatic and social-economic differences; farm environment; exposure to domestic animals; number of siblings and age at admission to a day care centre; use of antibiotics; positivety to hepatitis A virus antibodies and bacterial endotoxins; etc), and this limits the comprehensiveness of the analysis.

In the first quantitative systematic review on ‘infections and atopy’, Randi et al [ ³ ] carried out ‘an exploratory study for a meta-analysis of the hygiene hypothesis’, examining differences concerning the association with a history of infectious events, in terms of magnitude and homogeneity of global risks estimates (indirect markers of exposure to infections) among the three major atopic diseases (atopic dermatitis, asthma and allergic rhinitis). Using a standardised protocol to select and analyse papers cited in an authoritative review[ ⁴ ] (among 133 references, 37 articles provided pertinent information, and only 10 studies had useful information for a quantitative statistical analysis), the authors concluded: ‘with this exploratory study, we obtained a quantification (probably optimistic due to the publication bias for negative results) of the inverse association between infectious events and atopic diseases corresponding to a 20% protection for atopic dermatitis, 30% for allergic rhinitis and 40% for asthma’. Although the authors have followed the explicit descriptions of systematic methods, they are cautious in their conclusions, emphasising that ‘any measure of association cannot be interpreted as an unbiased estimator of the potential association infections-atopic disease; the value of this study is essentially as a test of a statistical methodology for data combination rather than an approach to the study of potential associations.’

In recent qualitative systematic review of the epidemiological literature (1966–2004), focusing exclusively on atopic dermatitis (AD) and the hygiene hypothesis,[ ⁵ ] using Odds ratios (OR) and 95% confidence intervals (CIs) as a measure of the association between exposure and AD. The results showed that there was prospective evidence to support an inverse relationship between AD and endotoxins, early day care and animal exposure. Two well-designed cohort studies have found a positive association between infections in early life and AD and measles vaccination and AD; antibiotic use was consistently associated with an increase in AD risk even into the antenatal period; a few small randomised-controlled trials have suggested that probiotics can reduce AD severity and may also be able to prevent AD to some degree. The authors concluded that with the majority of studies uses non-validated questionnaires rather than physician diagnosis to identify AD cases, the results are prone to bias.

In other systematic reviews, using recent findings (2003–2004),[ ⁶ ] the critical evaluation of the 111 papers selected for the authors’ shows that the number of favourable opinions largely exceeds the number of contrary ones, although there is still no unanimous consensus: ‘The association between a reduced exposure to infectious agents and a higher prevalence of atopy seems now to be confirmed by consistent evidence. Mechanisms underlying this association, however, are not yet completely clear (immune deviation or immune regulation).’

A review of the effects of BCG vaccination on the development of atopy concludes that ‘at this moment, there is insufficient evidence to accept or reject a causal relation between early BCG vaccination and the development of allergic diseases’, because ‘methodological flaws, different vaccine strains and dosages used and varying ages at vaccination have been suggested to be responsible for the conflicting results of the studies investigating the question at issue’.[ ^7,8 ] In spite of most of the studies being related to BCG, the same can be enlarged for other vaccines.

Even among reviews that criticise the hygiene hypothesis, it is evident that natural infections may regulate the immune system (Th1 response), in ways that vaccination does not, protecting against the development of allergic and autoimmune diseases: ‘Since modern subunit vaccines mostly lack these microbial antigens, they may not activate dendritic cells efficiently. Likewise, microbial antigens such as heat shock proteins seem to have an intrinsic capacity to trigger Tr cells. As a result, the absence of microbial antigens from vaccines may also impair regulation of the adaptive immune response. Recent advances in understanding how cell-mediated immunity is regulated have indicated substantial differences between responses after natural infections and vaccination that may contribute to the induction of Th1 responses after vaccination. Infants with a positive family history of atopy have a reduced Th1 response capacity. Vaccination of these genetically predisposed infants is unlikely to stimulate upregulation of Th1-type responses.[…] Therefore, the challenge is to construct vaccines that not only prevent infectious diseases, but also mimic infection-mediated immune stimulation to protect against the development of allergic and autoimmune diseases’.[ ⁸ ]

Since most of the researches are observational studies, which are prone to confounding bias, additional experimental and clinical evidences in well-designed controlled studies (with special reference to the time, duration and intensity of exposure to any specific infectious agent), systematic reviews and meta-analysis are needed to evaluate the reality and magnitude of the hygiene hypothesis.

In 2002–2005 a number of further papers have been published. Perhaps the progress made by the hygiene hypothesis in the 15 years following its introduction is best summarised by Strachan himself: ‘The hygiene hypothesis remains a credible but non-specific explanation for observed variations over time, place and person at risk for developing atopic allergic disorders. More prospective studies are needed to unravel which infectious agents exert a protective effect and the time period of importance for sensitisation. The clinical implications of these advances in understanding the etiology of atopic allergic disorders are currently limited.’[ ⁹ ]

Revisited Hygiene Hypothesis (2002–2005)—Favourable Papers

Systematic Reviews

[Curr Opin Allergy Clin Immunol 2005; 5: 147–151; Br J Dermatol 2005; 152(2): 202–216; Rev Epidemiol Sante Publique 2004; 52(6): 565–574]

General Reviews

[Curr Opin Allergy Clin Immunol 2005; 5(2): 147–151; J Pediatr Gastroenterol Nutr 2005; (Suppl): S37–S38; Allergy 2004; 59(2): 124–137; Clin Rev Allergy Immunol 2004; 26(1): 15–24; Allergy Asthma Proc 2004; 25(1): 7–10; J Allergy Clin Immunol 2004; 113(1): 179–180; Br Med Bull 2003; 68: 227–242; J Laryngol Otol 2003; 117(12): 946–950; Curr Opin Allergy Clin Immunol 2003; 3(5): 325–329; Allergy 2003; 58(9): 844–853; J Allergy Clin Immunol 2003; 111(3): 471–478; N Engl J Med 2002; 347: 911–920; Ann Allergy Asthma Immunol 2002; 89(6 Suppl 1): 69–74; Curr Drug Targets Infect Disord 2002; 2(3): 193–199; Environ Health Perspect 2002; 110 (Suppl 4): 557–560]

Specific Reviews

The role of microbial antigens (endotoxins) in stimulating immune response (Th1) and protecting the future development of atopic diseases [J Allergy Clin Immunol 2004; 114(5): 1051–1054; Paediatr Respir Rev 2004; 5 (Suppl A): S65–S71; Curr Opin Allergy Clin Immunol 2004; 4(2): 113–117; Curr Opin Otolaryngol Head Neck Surg 2004; 12(3): 232–236; Nat Immunol 2004; 5(3): 337–343; Ann Allergy Asthma Immunol 2003; 90(6 Suppl 3): 64–70; Pediatrics 2003; 111(3): 653–659; J Allergy Clin Immunol 2003; 112(1): 219–220; Curr Drug Targets Inflamm Allergy 2003; 2(2): 187–195].

Contradicting the hypothesis that toxic agents (environmental, alimentary, etc) are responsible for the increase of atopic diseases in last decades [Pediatrics 2004; 113 (4 Suppl): 1107–1113; Curr Opin Allergy Clin Immunol 2002; 2 (2): 141–145].

Inducing effect of antibiotics in the future development of atopic diseases [Infect Immun 2004; 72: 4996–5003].

Inducing effect of vaccines in the future development of atopic diseases [Med Hypotheses 2004; 63(5): 875–886; Acta Derm Venereol (Stockh) 2003; 83: 445–450].

The protective role of the childhood infections in the future development of autoimmune diseases: DM type 1 [Clin Dev Immunol 2004; 11(3–4): 191–194; N Engl J Med 2002; 347: 911–920].

The protective role of helminth infections (induce strong Th2-type response) in development of inflammatory bowel diseases (Crohn's disease; ulcerative colitis) [Can J Gastroenterol 2005; 19(2): 89–95; Inflamm Bowel Dis 2005; 11(2): 178–184; Gut 2005; 54(3): 317–320; Can J Gastroenterol 2005; 19(2): 89–95; Curr Opin Gastroenterol 2004; 20(6): 560–564; Can J Gastroenterol 2004; 18(8): 493–500; Clin Rev Allergy Immunol 2004; 26(1): 35–50; J Helminthol 2003; 77(2): 147–153; Infect Immun 2002; 70(12): 6688–6696].

The protective role of probiotics in development of atopic diseases [Gut 2005; 54(3): 317–320; Can J Gastroenterol 2004; 18(8): 493–500; Trends Microbiol 2004; 12(12): 562–568; Ann Allergy Asthma Immunol 2002; 89 (6 Suppl 1): 75–82; Br J Nutr 2002; 88 (Suppl 1): S19–S27].

Proposal of new strategies of treatments, using the microorganisms or their products (endotoxins) in treatment or prevention of atopic diseases [J Allergy Clin Immunol 2004; 114(5): 1051–1054; Pharmacol Ther 2004; 101(3): 193–210; Allergy 2003; 58: 461–471].

Hygiene Hypothesis Enlargement

Hygiene Hypothesis should be enlarged in three aspects: first, the importance of sources of microbial stimulation in causing immune deviance; second, immunomodulatory and suppressive immune responses complement the Th1/Th2 paradigm; third, in addition to protection against atopy, protection against infectious, inflammatory and autoimmune diseases may also depend upon healthy host–microbe interactions implicated in the hygiene hypothesis [J Pediatr Gastroenterol Nutr 2004; 38(4): 378–388; J Allergy Clin Immunol 2004; 113(3): 395–400; Immunology 2004; 112(3): 352–363; J Pediatr Gastroenterol Nutr 2004; 38(4): 378–388; Clin Rev Allergy Immunol 2004; 26(1): 25–34; J Clin Invest 2004; 114(2): 270–279; Am J Kidney Dis 2003; 42(3): 575–581].

Hygiene Hypothesis needs to be enlarged in the ‘type’ of infectious agent, in the ‘age’, ‘time’ and ‘intensity’ of agent exposure, besides the period among the exposure to the infectious and allergic agents [Curr Opin Allergy Clin Immunol 2005; Clin Exp Allergy 2005; 35(1): 8–17; Allergy 2005; 60(2): 226–232; Curr Opin Pulm Med 2005; 11(1): 14–20; Pharmacol Ther 2004; 101(3): 193–210; Curr Opin Allergy Clin Immunol 2004; 4(1):69–74; J Pediatr Gastroenterol Nutr 2004; 38(4): 378–388; Curr Opin Otolaryngol Head Neck Surg 2004; 12(3): 232–236; Ann Allergy Asthma Immunol 2003; 90(6 Suppl 3): 64–70; Br Med Bull 2002; 61: 29–43; Science 2002; 296(5567): 490–494; Eur Respir J 2002; 19(1): 158–171; Infect Immun 2002; 70(12): 6688–6696].

Descriptive and Observational Studies

Protecting effect of the childhood infections in the future development of atopic diseases [Clin Exp Allergy 2004; 34(8): 178–183; Int J Pediatr Otorhinolaryngol 2004; 68(6): 775–778; Am J Public Health 2003; 93(11): 1858–1864; Pediatr Allergy Immunol 2003; 14(5): 363–370; J Allergy Clin Immunol 2003; 111(4): 847–853; J Allergy Clin Immunol 2002; 110(3): 381–387; Arch Dis Child 2002; 87(1): 26–29].

Protecting effect of the childhood infections in the future development of autoimmune diseases [Diabet Med 2004; 21(9): 1035–1040; Diabetologia 2003; 46(2): 301–302] and cancer [Leuk Res 2004; 28(7): 713–724; Med Hypotheses 2004; 62(6): 880–888].

Inducing effect of vaccines in the future development of atopic and chronic diseases [Leuk Res 2004; 28(7): 713–724; Acta Derm Venereol 2003; 83(6): 445–450; Allergy 2002; 57(6): 472–479].

Inducing effect of antibiotics in the future development of atopic diseases [J Epidemiol Community Health 2004; 58(10): 852–857; Am J Resp Crit Care Med 2002; 166: 72–75; Am J Resp Crit Care Med 2002; 166: 827–832; J Allergy Clin Immunol 2002; 109: 43–50].

Protecting effect of childhood infectious fever in the future development of atopic diseases [JAMA 2005; 293(4): 463–469; J Allergy Clin Immunol 2004; 113(2): 291–296; Eur Respir J 2002; 20(2): 391–396].

Protecting effect of gestation infectious in the future development of atopic diseases in children of atopic women [Allergy 2004; 59(9): 961–968].

Protecting effect of household crowding in the future development of atopic diseases [BMC Public Health 2004; 34(1): 19; J Epidemiol Community Health 2002; 56(3): 209–217; Clin Otolaryngol 2002; 27(5): 352–358].

Protecting effect of farm style in the future development of atopic diseases [Eur Respir J 2002; 19(5): 853–858].

Experimental Studies

Mice experimental model that demonstrated the role of antibiotics in driving pulmonary allergic [Infect Immun 2005; 73(1): 30–38; Infect Immun 2004; 72(9): 4996–5003].

Mice experimental models that demonstrated the capacity of the Mycobacterium bovis Bacillus Calmette–Guerin (M. bovis BCG) infection stimulate Th1 response and suppress Th2 response [Curr Opin Allergy Clin Immunol 2004; 4(1): 57–62; Eur J Immunol 2004; 34(3): 631–638; Clin Exp Allergy 2003; 33(8): 1083–1089; J Immunol 2003; 171(2): 754–760; Nat Med 2002; 8(6): 625–629], preventing the development of the Graves’ disease experimentally induced [Endocrinology 2004; 145(11): 5075–5079] and modifying the course of autoimmune encephalomyelitis experimentally induced [Immunol Lett 2002; 82(1–2): 101–110], that mimic the human multiple sclerosis.

Murine experimental allergic-asthma model that evidenced the capacity of Mycoplasma pneumoniae infection modulate lung allergic diseases [Infect Immun 2003; 71(3): 1520–1526].

Mice experimental models that demonstrated the capacity of the helminth infection protects from anaphylaxis via IL-10-producing B cells [J Immunol 2004; 173(10): 6346–6355].

Animal experimental models that suggest the use of pathogenic microorganism genetic materials (CpG oligodeoxynucleotides), that mimic childhood infections, to stimulate Th1 response and suppress Th2 response, preventing the future manifestation of allergic diseases [J Investig Dermatol Symp Proc 2004; 9(1): 23–28; Clin Exp Allergy 2003; 33(10): 1330–1335].

Congenital experimental model of asthma in mice that identified the family gene TIM-1, related to previous infections for the Hepatitis A, that presents an important role in the modulatory immune response in the development of atopic diseases [Springer Semin Immunopathol 2004; 25(3–4): 335–348; Nature 2003; 425: 576].

Mice experimental model that related the alleles of the gene Nramp1 with resistance or susceptibility to allergic diseases [Trends Immunol 2004; 25(7): 342–347; J Immunol 2003; 171(2): 754–760; FASEB J 2003; 17(8): 958–960].

Review on the genetic studies that describe the gene CD14, expressed in the monocytes and macrophages membrane, as a multifunctional receiver to endotoxins and other microbial products, waking up the Th1 immune response and preventing the manifestation of atopic diseases [Curr Opin Allergy Clin Immunol 2003; 3(5): 347–352].

Review on mice experimental models of Diabetes and Gastritis (Helicobacter) that demonstrated the improvement of these diseases for the induction of the Th2 response for parasite antigens [Curr Top Med Chem 2004; 4(5): 531–538].

T cell maturation linear model interpreting how changes in cytokine production by T cell populations are regulated [Clin Exp Allergy 2005; 35(1): 8–17].

• References

• 1 Teixeira M.Z. Is there scientific evidence that suppression of acute diseases in childhood induce chronic diseases in the future?. Homeopathy 2002; 91: 207-216.
• 2 Adler U.C. The influence of childhood infections and vaccination on the development of atopy: a systematic review of the direct epidemiological evidence. Homeopathy 2005; 94: 182-195.
• 3 Randi G, Altieri A, Chatenoud L, Chiaffarino F, La Vecchia C. Infections and atopy: an exploratory study for a meta-analysis of the ‘hygiene hypothesis’. Rev Epidemiol Sante Publique 2004; 52: 565-574.
• 4 Bach J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347: 911-920.
• 5 Flohr C, Pascoe D, Williams H.C. Atopic dermatitis and the ‘hygiene hypothesis’: too clean to be true. Br J Dermatol 2005; 152: 202-216.
• 6 Bresciani M, Parisi C, Manghi G, Bonini S. The hygiene hypothesis: does it function worldwide?. Curr Opin Allergy Clin Immunol 2005; 5: 147-151.
• 7 Krishna M.T, Salvi S.S. Could administration of bacile Calmette–Guerin vaccination at birth protect from the development of asthma and allergic diseases in the western world? Has this question been adequately investigated?. Pediatr Allergy Immunol 2002; 13: 172-176.
• 8 Koppen S, de Groot R, Neijens H.J, Nagelkerke N, van Eden W, Rümke H.C. No epidemiological evidence for infant vaccinations to cause allergic disease. Vaccine 2004; 22: 3375-3385.
• 9 Strachan D.P. Family size, infection and atopy: the first decade of the ‘hygiene hypothesis’. Thorax 2000; 55 Suppl 1 S2-S10.