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INFECTION AND ATOPIC DISEASE BURDEN IN AFRICAN COUNTRIES: KEY TO SOLVING THE ‘HYGIENE HYPOTHESIS’? Charles C Obihara, MD, PhD Department of Paediatrics, St Elisabeth Hospital, Tilburg, The Netherlands ABSTRACT While most African countries are experiencing an epidemic rise in chronic infectious diseases, such as tuberculosis, malaria, HIV and parasites, industrialised, westernised countries are experiencing an epidemic rise in atopic and auto-immune diseases. One of the most popular explanations for this increase is the so-called ‘hygiene hypothesis’, which suggests that a decrease or altered exposure to microbes in the environment, as a result of improved sanitation and personal hygiene, smaller family sizes, shorter duration of breastfeeding, immunisations and lack of serious childhood infections, results in alteration of the immunoregulation. It has been demonstrated in animal studies that some infections may modulate the expression of the immune system, resulting in the suppression of allergic inflammation. This is achieved through the priming of regulatory T-cell activity, and these cells may be responsible for the protection of populations with chronic infectious diseases against atopic disease. If the specific molecules involved in the immunomodulatory and protective defence mechanisms of the host against these infectious agents were to be defined or isolated, they could be manipulated in such a manner as to warrant application for the development of both novel therapeutic and prophylactic strategies against atopic disease. African countries, with both a high burden of chronic and persistent infection and an increasing burden of atopic diseases may form an ideal ‘nature’s own laboratory’ to investigate the hygiene hypothesis. INTRODUCTION During the last few decades, the prevalence of atopic disease has increased globally, not only in industrialised countries, but also in less industrialised countries, especially in urban centres with a westernised lifestyle.1-6 The hygiene hypothesis suggests that a relationship exists between improved hygiene and an increase in atopic disease prevalence.7 It is clear that this relationship may be more complex than initially assumed. It may be under the influence of different factors, such as genetic variability, time of exposure, amount and length of exposure, type of infection, and the prevalence of environmental allergens. An underlying mechanism for the hygiene hypothesis is that lack of microbial stimulation leads to either an inappropriate T-helper (Th) type immune response or inappropriate Th-cell regulatory mechanisms.8 There is evidence that the critical period for the establishment Correspondence: Dr Charles C Obihara, Department of Paediatrics, St Elisabeth Hospital, PO Box 90151, 5000 LC Tilburg, The Netherlands. Tel +31-13-539-13-13, fax +31-13-535-94-33, e-mail [email protected]. 178 of the Th-cell balance is early childhood, when the Th2skewed human immune system gradually becomes less Th2-skewed in non-atopic individuals, but not in atopic individuals.9,10 Among the infectious agents which have been inversely linked to atopic disease prevalence are measles in Guinea-Bissau, hepatitis A in Italian recruits and BCG-vaccination in schoolchildren from Japan.11-13 However, most of these initial findings have not been reproduced in other settings. Animal and experimental studies have consistently identified mycobacteria and parasitic infection as potential candidates in the hygiene hypothesis, by demonstrating that infection with these organisms or exposure to their products leads to regulatory mechanisms which restored the immune homeostasis.8 In contrast, the epidemiological relationship between infection and atopic disease in humans is still unclear and controversial.13,15-22 Most of these studies have been conducted in western populations with a low burden of infection. It has been suggested that inhibition of atopic inflammation in the presence of chronic infections, such as Mycobacterium tuberculosis and parasitic infection, probably occurs through the stimulation of regulatory and anti-inflammatory networks.8,22,23 In this paper we review the published papers from the African region on the relationship of mycobacterial and parasitic infection and atopic disease. In addition, we discuss, based on the most recent publications, the implication of these findings for countries in Africa, where chronic infections with mycobacteria and parasites are highly prevalent. INFECTION AND ALLERGIC DISEASE IN AFRICA Recent insight into the hygiene hypothesis of atopic disease suggests that the protective effect of chronic infections, such as that caused by M. tuberculosis and parasites, on atopic disease would logically be more evident in populations with a high burden of these infections (such as in many non-affluent, mainly rural areas in African countries, where exposure to these chronic infections is more likely to be intense and persistent) than in populations with a low infectious burden (as in most industrialised countries and in some affluent urban areas in Africa with a westernised lifestyle, where exposure is more likely to be sporadic and intermittent). Although the epidemiological relationship between atopic disease and mycobacterial and parasitic infection has been reviewed recently, this relationship has not been evaluated in African countries, which carry the highest global burden of both mycobacterial and parasitic infection.22,24 Table I summarises the characteristics and findings of studies on the relationship between mycobacterial and parasitic exposure and atopic disease in different populations in Africa.18-20, 25-30 Mycobacterial infection and atopic disease In children from Guinea-Bissau, Aaby et al.25 found less positive skin-prick test (SPT) to aeroallergens among the BCG-immunised group of children compared with the non-immunised group (odds ratio (OR) 0.19, 95% Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4 Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4 179 The Gambia S. Africa S. Africa Ota et al.20 Obihara et al.26 Obihara et al.27 MTB/BCG MTB MTB Ethiopia The Gambia Ethiopia Gabon S. Africa Scrivener et al.18 Nyan et al.19 Dagoye et al.30 Van den Biggelaar et al.15 Obihara et al.32 T. trichiura/hookworm Any intestinal parasite T. trichiura/A. lumbricoides/ hookworm T. trichiura/A. lumbricoides A. lumbricoides 2006 2004 2003 2001 2001 2000 2006 2005 2003 2000 Year of publication † Unclear the number of persons included in the analysis. * 132 children out of 520 included in the nested control trial. BCG – bacille Calmette- Guérin; MTB – Mycobacterium tuberculosis; RCT – randomised controlled trial; S. Africa – South Africa. Gabon Van den Biggelaar et al.31 Parasitic infection Schistosoma haematobium Guinea-Bissau Country Aaby et al.25 Reference Mycobacteria BCG Type of infectious agent studied Cross-sectional RCT Cross-sectional Cross-sectional Nested case-control Cross-sectional/ nested case-control Cross-sectional Cross-sectional Cross-sectional Cross-sectional Study type 359 341 563-856† 429 572 520/132* 841 337 507 271 (400) Sample size 6-14 5-13 1-4 Yes Yes No Yes Yes ≥16 15-34 Yes Yes Yes No Yes Inverse relationship? 5-14 6-14 6-14 8-12 3-14 Age (yr) Table I. Characteristics and findings of studies on the relationship between mycobacterial and parasitic exposure or infection and atopic disease in different populations in Africa confidence interval (CI) 0.06-0.59). This study’s results were however limited because BCG exposure was defined as positive history of neonatal BCG immunisation or the presence of BCG-scar only.25 There was no tuberculin skin test (TST) performed to exclude the influence of other mycobacteria in the environment. In children from a TB endemic urban suburb of Cape Town, South Africa, a significant inverse relation between M. tuberculosis infection and both questionnaire-reported atopic disease symptoms (OR adj 0.43; 95% CI 0.24-0.79) and objectively confirmed atopic rhinitis (ORadj 0.06; 95% CI 0.007-0.5) was observed.26,27 Not only was there strongly positive TST reactivity observed in more than 50% of the children (median TST size ≥ 18 mm), there was no influence of other environmental mycobacteria on the results. These findings contrast with a recent Gambian study in which no inverse relation was found between positive TST and atopy in children.20 Parasitic infection and atopic disease In Gabonese children, a lower frequency of positive SPT for house-dust mite (HDM) was observed in the group with urinary schistosomiasis (a tissue parasite) than in the group without (OR 0.32; 95% CI 0.160.63).15 In this study, a significant inverse relationship was also observed between the level of schistosomaspecific interleukin (IL) 10, an anti-inflammatory cytokine, and SPT to HDM. In Ethiopia, Scrivener et al.18 observed a reduced risk of wheeze in persons with hookworm infection (OR 0.48; 95% CI 0.24-0.93). In The Gambia, an inverse relationship was observed between atopy and intestinal parasite infection (OR adj 0.37, 95% CI 0.15-0.92).19 In another study from Ethiopia, Dagoye et al.28 reported a lower prevalence of recent wheezing (< 12 months) in children infected with Ascaris lumbricoides compared with those without (OR adj 0.5; 95% CI 0.3-0.9). This effect was doserelated. The same was not found in the group of children with hookworm or Trichuris trichiura infection. The strongest evidence so far for a causal relationship between intestinal parasite infection and atopy in an African setting is derived from the intervention study conducted in Gabonese children.29 Van den Biggelaar et al.29 observed that repeated anthelminthic treatment of children infected with A. lumbricoides resulted in a significant increase in the rate of SPT for HDM compared with the control group (hazard ratio 2.51; 95% CI 1.85-3.41). In urban South African children, we observed, in contrast to previous studies, a higher frequency of atopic disease symptoms, positive SPT for HDM and bronchial hyper-responsiveness (BHR) in children with elevated A. lumbricoides specific-IgE than in those without.30 The difference in finding was attributed to the intermittent parasite infectious burden (low median number of A. lumbricoides eggs) due to periodic anthelminthic prophylaxis given to schoolchildren from the area. Surprisingly it was observed that M. tuberculosis co-infection modified the expression of atopy in the children.30 In children without M. tuberculosis co-infection, elevated Ascaris specific-IgE was associated with significantly increased risk of atopic symptoms (ORadj 6.5; 1.9-22.4), while in those with M. tuberculosis co-infection this association was not observed (ORadj 0.96; 0.4-2.8). That this effect disappeared in the group of children with M. tuberculosis infection, seems to suggest that mycobacterial coinfection might influence the relationship between intestinal parasite infection and atopy. There was no association observed between T. trichiura infection and atopy.30 180 HOW CHRONIC INFECTION MAY PROTECT AGAINST ATOPIC DISEASE The hygiene hypothesis of atopy has been supported by different epidemiological studies, especially from industrialised countries. Recent evidence stresses the importance of reduced immune suppression rather than of erratic immune deviation to explain the rising global incidence of atopy.14 According to this view, lower microbial burden does not act by directly inducing a lower production of Th1-cytokines but by decreasing the activity of regulatory T cells (Tregs).8,14 The mechanism of suppression by Treg is mediated through the production of inhibitory or anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta (TGFβ).8,23,31 Tregs selectively express several toll-like receptors (TLRs), a family of proteins with a critical role in the detection of and response to pathogens, and can suppress both Th1 and Th2 responses.22,31 Treg signalling is an essential link between innate immune system (mainly antigen-presenting cells, (APC) and adaptive immune system (mainly T cells or natural killer (NK) cells). There are indications that anergy, peripheral tolerance and active immune suppression are related to different stages of Treg cell-mediated immune deviation. Tregs normally inhibit Th2 cytokine expression and proliferation of peripheral blood mononuclear cells (PBMC) from nonatopic individuals in response to allergen exposure.31, 32 There are indications that exposure to bacterial endotoxin or lipopolysaccharide (LPS) enhances the suppressive function of Treg.33 The higher level of endotoxin, increased blood level of CD14 (another LPS receptor) and TLR2 in European children from a farming environment than in those from a non-farming environment was associated with a lower prevalence of atopic diseases.34 Experimental administration of TLR2 or TLR4 agonists leads to reduced atopic reaction after sensitisation with an allergen.35 Missing immune deviation is assumed to be the result of reduced stimulation of TLRs in westernised society.36 WHAT ARE THE IMPLICATIONS OF THIS IMMUNOLOGICAL MODEL OF THE HYGIENE HYPOTHESIS FOR THE EPIDEMIOLOGY OF ATOPY IN AFRICA? Firstly, the model of reduced immune suppression of the hygiene hypothesis refutes the previous assumption of immune deviation that the interaction between infection and allergens is limited to the ‘window of opportunity’ in early life after which it no longer took place.14 This model suggests that reduced immune suppression retains some flexibility well into later childhood and adulthood. This may, for example, logically explain why previously asymptomatic adult African migrants who move to westernised, industrialised countries develop atopic disease symptoms, if they are genetically predisposed.14 It is not yet clear, though, if this phenomenon could explain the urbanrural differences in the incidences of atopic disease in Africa. More prospective cohort or randomised controlled trials are needed to answer this question. Secondly, the importance of infection pressure on the relationship between infections and atopy in a specific population is highlighted. As earlier indicated, the mechanism of suppression by Treg is mediated through the production of inhibitory or anti-inflammatory cytokines (mainly IL-10 and TGFβ).23,31 Pathogens that cause chronic infections might have evolved strategies to subvert the host immune responses, through the stimulation of increased production of Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4 these anti-inflammatory mediators, which normally function to contain excessive immune effector reponses of the host.31 These regulatory mechanisms might be beneficial to the host by maintaining a balance between effector and memory responses, but with low inflammatory response that causes minimal damage to the host.37 One practical positive ‘spin-off’ of this effect would be the suppression of allergic inflammation in populations exposed to a very high chronic infectious burden. This suggests that the protective effect of infections on atopic disease would logically be more evident in populations with a high and persistent burden of these infections (such as those living in rural and non-affluent urban areas of Africa, where exposure to these chronic infections is more likely to be intense and persistent) than in populations with a low burden (as in most industrialised countries and westernised, affluent, mainly urban areas in Africa, where exposure is more likely to be sporadic and intermittent). FACTORS POSSIBLY INFLUENCING HETEROGENEITY IN STUDY RESULTS IN AFRICAN POPULATIONS Among the important factors which may explain the heterogeneity in study results on this topic from the African region, next to differences in the study population, design and methodology (Table I), are differences in type, definition, amount and persistence of exposure to infection in the populations studied, and the lack of uniformity in the definition of atopy.22 One of the reasons for studying the relationship between infections and atopic disease is not only to understand the mechanism involved, but also to utilise it for future prevention and/or treatment of atopic disease. It is logical to assume that to solve the riddle of the hygiene hypothesis, studies need to be carried out in populations with both a high burden of chronic infections and a high prevalence of environmental allergens, as in some African regions. These studies would have to be multicentre, prospective cohort and interventional in design, in order to study effectively the urban-rural, genetic and interregional differences. Type of infectious agent. The species of microbe or parasite may be very important in determining the degree of immune activation strong enough to induce suppression of atopic inflammation. For instance, there are suggestions that BCG immunisation evokes a weaker and shorter immune stimulation and memory, and is therefore not able to mimic the persistent immune stimulation provided by frequent exposure to wild-type M. tuberculosis.14 To support this are studies showing that M. bovis BCG is a poorer inducer of IL-12 than natural M. tuberculosis infection.38 Moreover, M. tuberculosis infection is associated with a larger TST size than M. bovis BCG or environmental mycobacteria.39 Although in African children neonatal BCG immunisation caused a transient TST reactivity, this became weak or even non-reactive at 5 years of age.40 Moreover, while some of the studies on the relationship between A. lumbricoides and atopic disease observed an inverse relationship, none of the studies in Africa which studied the relationship between T. trichiura infection and atopic disease observed a relationship. This seems to suggest either a weaker immune modulatory effect or a different mechanism of immune activity. Amount of infection. There are indications that triggering the innate immune system through endotoxin exposure and the derived effect (increased or decreased atopic inflammation) may not only depend on the exposure but also on the amount of endotoxin.22 This has been shown in children from farming environ- ments in Europe.33,34 In line with this observation it has been proposed that the difference in the amount and persistence of infections which trigger the innate immune system may be important in explaining the lower prevalence of atopic disease in the developing world.14 The same mechanism might be applicable in explaining the differences in atopic disease prevalence between rural and urban Africa. Simultaneous exposure to infection and allergen. There are suggestions that the simultaneous exposure to both environmental allergens and infectious agents may be the key factor to the suppression of atopy.41,42 This may partly explain the differences in findings in the studies carried out in areas with comparable prevalences of infectious disease, but difference in the prevalence of allergen exposure. For instance, Janssen et al.41 argued that it might not be the Th1-inducing properties of mycobacteria, but simultaneous exposure to both mycobacteria and allergen, which induced an allergen-specific Th1 response strong enough to prevent induction of atopy. Recombinant mycobacteria mice challenged with a peptide of Der p I, underwent a switch from Th2 to Th1 profile, which was specific only for vaccines expressing allergen peptide. This means that priming of allergen-specific Th1 responses may be crucial in establishing a memory response capable of long-term protection against allergen-specific Th2 response.41 In support of this, Sano et al.42 demonstrated in an experimental mouse model that simultaneous M. tuberculosis infection and allergen challenge might stimulate an immune response strong enough to suppress Th2 activity. They also observed that stimulation of T cells with ovalbumin only induced Th2 dominant responses, whereas concomitant stimulation with both ovalbumin and M. tuberculosis caused induction of antigen-specific Th1 responses, with secretion of interferon-gamma (IFN-γ), mediated by IL-12.42 If this phenomenon, where both M. tuberculosis and allergens are simultaneously presented by APC to the Tcell, also applies to humans, then it is most likely to occur where M. tuberculosis infection and allergen exposure are both highly prevalent. In such a setting, exposures to environmental allergens and M. tuberculosis would be more likely to occur simultaneously than in a low prevalence setting. Low positive predictive value of allergy testing. A recent analysis highlighted the discrepancy between environmental allergen exposure, clinical allergy and laboratory or clinical measurements of atopy in African populations.43 In Africa, allergen-specific serum IgE and allergen-specific SPT seem to be poorer predictors of clinical allergy than in populations in western Europe and the USA. It was hypothesised that this may be related to the influence of (as yet) unidentified local allergens, such as mites, grass and tree allergens in Africa. The authors stressed the need for developing assays to identify important local environmental allergens.43 Although genetic factors may also play an important role in this discrepancy, there are indications that other environmental factors, such as co-infections, may partly influence the sensitivity of blood and skin tests for allergy in African populations. For instance, recent findings in South Africa suggest that M. tuberculosis infection might modify the expression of atopy in populations with a high burden of disease (Fig. 1).27 It was observed that in a group of children with a negative TST (N = 158), more than 70% of those with atopic symptoms versus only 13% of those without symptoms had positive allergy SPT (p < 0.001). In contrast, in a group of genetically comparable children with positive TST (N = 179) from the same area, only 7% of those with atopic symptoms and 18% of those without symptoms had a positive allergy SPT (p = 0.7).27 Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4 181 4. Faniran AO, Peat JK, Woolcock AJ. Prevalence of atopy, asthma symptoms and diagnosis, and the management of asthma: comparison of an affluent and non-affluent country. Thorax 1999; 54: 606-610. 5. Yemaneberhan H, Bekele Z, Venn A, Lewis S, Parry E, Britton J. Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia. Lancet 1997; 350: 8590. 6. Calvert J, Burney P. Effect of body mass on exercise-induced bronchospasm and atopy in African children. J Allergy Clin Immunol 2005; 116: 773-779. ■ Recent allergic symptom ■ No allergic symptom 7. Strachan D. Hay fever, hygiene and household size. BMJ 1989; 289: 1259-1260. TST negative children (N = 158) TST positive children (N = 179) Fig. 1. Percentage of skin-prick test (SPT) positivity in symptomatic and asymptomatic children with negative or positive tuberculin skin test (TST). Prospective intervention studies are needed to confirm these findings. Discrepancy in the definition of atopy. Lack of uniformity in the definition of atopy makes it difficult to compare results of studies carried out in African countries. This may also account for some of the heterogeneity of study results from the continent. While some studies defined atopy as questionnaire-reported symptoms or positive SPT or elevated serum specific IgE to common environmental allergens, others used both definitions. The use of the recently accepted World Allergy Organization (WAO) definition of atopy, as clinical allergic symptoms in combination with a positive SPT and/or an elevated serum IgE antibody level, makes it possible for future studies to define atopy more uniformly.44 CONCLUSION The results of epidemiological studies in African populations on the relationship between chronic infection such as that caused by mycobacteria and parasites are as inconclusive as those in other parts of the world. Part of this inconclusiveness may be attributed to differences in study design, population and methodology. However, it is not unthinkable that other environmental factors such as the type, amount and persistence of infection, prevalence of environmental allergens and sensitivity of allergy tests in the African populations may equally be of influence. Last but not least is the lack of uniformity in the definition of atopy used in the different studies. Despite the above-mentioned shortcomings of the present epidemiological studies on the relation of infection and atopic disease, the high prevalence of chronic infections and the rising incidence of atopic disorders due to westernisation in some communities in the African region, indicate that these communities form an ideal epidemiological platform to investigate the possible protective effect of infection on the development of atopy. REFERENCES 1. ISAAC Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998; 351: 1225-1232. 2. Addo-Yobo EO, Woodcock A, Allotey A, Baffoe-Bonnie B, Strachan D, Custovic A. Exercise-induced bronchospasm and atopy in Ghana: two surveys ten years apart. Plos Medicine 2007; 4 (e70): 355-360. 3. Weinberg EG. Urbanization and childhood asthma: an African perspective. J Allergy Clin Immunol 2000; 105: 224-231. 182 8. Zuany-Amorim C, Sawicka E, Manlius C, et al. 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Allergy and Asthma: Practical Diagnosis and Management Massoud Mahmoudi September 2007, ISBN 9780071471732, paperback, 400 pp, McGraw-Hill, R395 Clear, authoritative guidance for your day-to-day allergy and asthma practice Allergy and Asthma: Practical Diagnosis and Management is a concise guide that puts the most salient insights in allergy medicine right at your fingertips. Written by a leading allergy clinician, along with 30 nationally recognized expert contributors, this resource is perfect for front-line general practitioners, especially primary care physicians and allied health care providers. Inside, you’ll find the most clinically relevant information on the pathophysiology, diagnosis, treatment, and prevention of all major allergic disorders. Features Need-to-know coverage that spans the entire scope of adult allergy and asthma-geared for real world medical practice A timely look at occupational allergies and allergies linked to unhealthy environments Organization by specific organ, which guides you to diagnostic and therapeutic solutions quickly and easily Essential chapters on the principles of diagnosis and on medications used in the management of simple and complex allergy Coverage of new complementary and alternative medicine techniques in the management of allergic disorders Over 100 outstanding illustrations Key concepts, management protocols, and recent references that deliver a highly accessible over view of today’s allergy practice Contents 1: Introduction to Immune System. 2:The History and physical examination of the allergic patient. 3: Prevalence and changes of allergic diseases in childhood, adults and elderly. 4: Allergic diseases of the eye. 5: Prevalence of pollens in the United States and the other continents. 6: Allergic rhinitis. 7: The Effect of rhinitis on sleep, quality of life, daytime somnolence and fatigue. 8: Sinusitis. 9: Allergic Diseases of the Ear. 10: Cough and allergic diseases. 11: Urticaria and Angioedema. 12: Atopic dermatitis. 13: Allergic contact dermatitis. 14: Pediatric Asthma. 15: Adult asthma. 16: Exercise induced asthma. 17: Occupational Asthma. 18: Asthma and pregnancy. 19: Pseudo- asthma: when cough, wheezing, and dyspnea are not asthma. 20: Hypersensitivity pneumonitis. 21: Allergic bronchopulmonary aspergillosis. 22: Serum sickness. 23: Complement systems and allergic diseases. 24: Food allergy. 25: Insect allergy. 26: Latex allergy. 27: Drug Allergy. 28: Smoke, pollution and allergies. 29: Sick building syndrome. 30: Allergy in Elderly. 31: Diagnostic testing in allergic diseases. 32: Immunodeficiency. 33: HIV infection. 34: Complementary and alternative therapy in treatment of allergic diseases. 35: Nutrition, diet, and allergic diseases. 36: Prevention and control measures in management of allergic diseases. 37: Antihistamines and mast cell stabilizers. 38: Bronchodilators. 39: Glucocorticoids. 40: Anti IgE antibody. 41: Allergy Immunotherapy. 42: Anaphylaxis and its management ORDERS: Medical Book Seller, PO Box 3784, Tygervalley 7536. Tel 083 303 8500. Fax (021) 975 1970. E-mail: [email protected] Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4 183