There are close parallels between inflammation associated with allergic disease and that caused by infections with helminth parasites. Both allergy and helminth infections are associated with elevated levels of IgE, tissue eosinophilia and mastocytosis, and CD4+ T cells that preferentially secrete the Th2 cytokines IL-4, IL-5, and IL-13 [1,2]. There is good evidence that the expression of inflammation caused by helminth infections can be modulated by the host immune response , and that the failure of the expression of similar mechanisms among individuals predisposed to allergy may be responsible for the clinical expression of allergic disease . Further, there is accumulating evidence that helminth infections, particularly those caused by intestinal helminth parasites (or geohelminths) may be capable of modulating the expression of allergic disease [5–8]. This review will examine the evidence for such a modulatory role of intestinal helminth infections (geohelminths) and will provide evidence that the expression of allergic inflammation in different regions of the Tropics may depend partly on local differences in the endemicity of geohelminth infections.
ATOPY AND ASTHMA
Human allergic disease in Western industrialized countries, commonly manifested as asthma, rhinitis and eczema, is strongly associated with atopy[9–11]. Atopy is characterized by elevated levels of both total IgE and IgE specific for common environmental allergens, and evidence of in vivo IgE-mediated immediate hypersensitivity as determined by skin prick testing with the same allergens . Most researchers consider atopy to be an important determinant of allergic asthma although only 25–30% of atopic individuals in industrialized countries may actually go on to develop clinically relevant allergic disease  and an estimated 37% of asthma is attributable to atopy at the population level . The factors that cause only a proportion of atopic individuals to develop clinical disease have not been defined although environmental factors are likely to be important.
EPIDEMIOLOGY AND ENVIRONMENTAL DETERMINANTS OF ASTHMA
Large differences in the prevalence and symptoms of asthma have emerged from the first phase of ISAAC . These studies have shown very large international differences in the prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema. Further, the prevalence of allergic diseases including asthma appears to be increasing in Western industrialized countries [12,15,16]. The causes of the underlying trend of increased prevalence of allergic diseases within the same populations and the large intercountry differences in prevalence are not clear. Some have attributed the rising prevalence to an increase in atopy , although markedly different prevalences of asthma are reported among populations with very similar rates of allergic sensitization [18–20].
The prevalence of allergic disease appears to be much greater in Western industrialized countries than in countries with more traditional agricultural economies [14,20]. Within Tropical regions, there are large differences in the prevalence of allergy between urban and rural areas with higher rates of asthma [19,21–23] in urban populations. There is some evidence for a disassociation between atopy and asthma in some regions of the Tropics [19,24] and in rural agriculture-based populations in Europe .
Environmental factors could modulate allergic sensitization to environmental allergens and the expression of allergic disease. Such environmental factors may include high-level exposure to allergens [25,26], air pollution , exposure to farm animals , and diet . Observations that children that are low in the birth order and that live in large families have a reduced risk of allergic disease has led to the suggestion that multiple and continued exposures to childhood viral and bacterial infections may protect against the development of allergy – the so-called hygiene hypothesis. Several epidemiological studies have demonstrated a protective role for infectious agents against the development of allergy including measles , gastrointestinal infections  the normal gastrointestinal flora of the gut [28,33], and helminth infections [5,6,8,34].
GEOHELMINTH INFECTIONS AND ALLERGY
The role of gastrointestinal helminth infections as environmental determinants of atopy/allergy is of considerable interest. Geohelminth parasites are ubiquitous world-wide and are estimated to infect approximately one third of the human population. Geohelminth infections are the most prevalent and persistent of all childhood infections and most individuals living in endemic areas are infected at some time during their lives and many are infected continuously from soon after birth into adulthood.
Ascaris lumbricoides, Trichuris trichiura, and Ancylostoma duodenale cause the most prevalent infections. Infection with A.lumbricoides and T.trichiura are acquired at an early age reaching a peak in prevalence and intensity between 5 and 15 years of age. Infections with A.duodenale tend to be delayed until the child is able to walk, and peak prevalence may occur later. A useful indication of the intensity of transmission is the age-prevalence profile that tends to peak earlier in areas of high transmission and later in areas where transmission is less intense. The intensity of transmission of geohelminths and the pattern of transmission throughout the year (i.e. continuous or interrupted) is likely to be an important determinant of the host immune response to the parasite  and the nature of the immune interaction between geohelminths and allergy.
EPIDEMIOLOGICAL STUDIES OF GEOHELMINTH INFECTIONS AND ALLERGY
Numerous studies have investigated the relationship between geohelminths and allergy. These studies include anecdotal evidence , cross-sectional prevalence surveys [21,37,38] or case-control studies [39–44]. The studies that have determined geohelminth infection by the presence or absence of ova or larvae in stool samples, have provided conflicting evidence showing either no relationship [39,41–43] or a protective effect of infection [8,36,45–49]. Overall, there appears to be a negative association between helminth prevalence and asthma prevalence in Tropical regions at the population level .
Probably the most influential studies examining geohelminth–allergy interactions have been a series of studies conducted by Lynch et al.[45–47] in Venezuela. The findings of these studies indicate that the intensity of helminth transmission is an important determinant of the effect of helminth infection on allergic reactivity – in areas where transmission is low or infrequent (e.g. among urban groups of high socio-economic status), allergic reactivity is high, while among urban or rural groups exposed to intense transmission, allergic reactivity is low. Further, treatment of urban children living in a poor and geohelminth endemic environment can lead to increased allergic reactivity [6,48].
Several studies have demonstrated that anthelmintic treatment of asthmatic subjects living in endemic areas can result in an improvement in asthmatic symptoms [51–53] and/or reduction in skin test reactivity to environmental allergens , indicating that intestinal helminth infections may also be capable of enhancing allergic inflammation.
A recent case-control study from Ethiopia explored the effect of different risk factors for wheeze among asthmatics and nonasthmatic controls from both urban and rural populations . The study showed that the effect of house dust mite sensitization on the risk of wheeze was significantly decreased with increasing intensity of parasite infection (with hookworm), but that the rate of sensitization was consistently higher in individuals with the highest parasite burdens (with Trichuris). These findings were interpreted to suggest that while intestinal helminth infections may enhance allergic sensitization to aeroallergens, intestinal helminth infections with a pulmonary phase of larval migration (principally hookworm infection but perhaps also Ascaris), may actually suppress allergic inflammation in the lungs and protect against wheeze. The observation that hepatitis A seroprevalence was not associated with wheeze or atopy suggests that geohelminth infections are not simply a surrogate factor for exposure to a contaminated environment and other enteric pathogens. However, these observations were made principally on adults from an urban area in Ethiopia, and may not be generalizable to children living in rural areas where the pathoaetiology of wheeze  and the epidemiology of geohelminth infections  may be very different. The findings of increased sensitization to aeroallergens with higher parasite burdens is consistent with observations of increased rates of sensitization to aeroallergens among children who become infected with Ascaris in Eastern Germany , and in other areas where geohelminth transmission is likely to be low or intermittent [7,53]. Studies conducted among rural populations indicate a protective effect for helminth infections against atopy [8,45,49]
NATURAL HISTORY OF THE IMMUNE RESPONSE TO HUMAN GEOHELMINTH INFECTIONS
How can such contradictory observations be explained in which helminth infections can both risk factors for atopy/allergy and also protective factors? We have hypothesized that geohelminth infections may alter the immune response to parasite antigens and environmental aeroallergens to either induce or suppress allergic reactivity, and there is good evidence that human helminth infections can alter the immune response to nonparasite antigens to more closely resemble the parasite-specific response [56,57].
A useful paradigm with which to understand the immune response to helminth infections, and the changes that these responses undergo over time is to divide the natural history of helminth infections into ‘acute’ and ‘chronic’ stages. Under conditions of continuous exposure and the maintenance of high parasite burdens, the acute stage will develop into chronic infection over time. The discussion that follows will examine this paradigm using data from helminth infections in general, and then will focus on geohelminths.
THE ‘ACUTE’VERSUS‘CHRONIC’ PARADIGM OF HUMAN HELMINTH INFECTION
‘Acute’ helminth infections may follow a short period of exposure or infrequent exposure . The classic examples of ‘acute’ helminth infections are reported in expatriates with relatively short exposure histories and who frequently develop clinically apparent allergic reactions (e.g. urticarial rashes) . Similar observations have been made among groups with short periods of exposure or infrequent or intermittent exposure such as:
- •primary infections in experimental volunteers [59,60] or through accidental/malicious exposure [61,62];
- •young children living in endemic areas [63,64];
- •populations that have migrated to an endemic area from an nonendemic area [63,65] or populations that become exposed through immigration of infected individuals into a nonendemic area ;
- •nonmigrant populations that have become exposed en masse to transmission due to ecological changes ;
- •inhabitants of endemic areas where transmission is seasonal or sporadic [68,69].
‘Acute’ infections are associated with parasite-specific immunity that is characterized by a mixed Th1/Th2 (or Th0) cytokine phenotype [66,70,71], marked eosinophilia, and elevated levels of parasite-specific IgE . Acute helminth infections of humans are associated with numerous allergic syndromes [3,58]. These allergic reactions are associated with intense eosinophilic infiltration and may permit the host to immobilize and kill invasive parasite larvae .
To sustain transmission, helminths must maintain a state of persistent ‘infectiousness’ within the human host. As host morbidity is closely related to parasite burden, most natural helminth infections of humans are likely to have coevolved, with their hosts, mechanisms to maintain active infections but control parasite numbers. Primarily, there is the need to control the allergic reactions that are so typical of early and acute infections. Allergic phenomena are rare in individuals with long-standing chronic infections, and their immune response differs from the ‘acute’ phenotype by a more polarized Th2 response [66,70,71,74], and the secretion of significant amounts of immunosuppressive cytokines such as IL-10 and TGF-β[66,74–76]. Levels of total IgE are significantly higher in chronic infections with proportionately less parasite specific IgE . High levels of polyclonal and parasite specific IgG4 are typical also [77,78].
THE ‘ACUTE’VERSUS‘CHRONIC’ PARADIGM FOR GEOHELMINTH INFECTIONS
All geohelminth parasites with a pulmonary phase of larval migration (i.e. A.lumbricoides, hookworm, and Strongyloides stercoralis) are capable of causing an asthma–like syndrome (Loeffler’s syndrome), that is characterized by breathlessness, cough, and eosinophilia . Ascariasis is also associated with allergic rashes and acute anaphylaxis , although the former may be more common with infections in which parasite larvae migrate more widely in the tissues (e.g. S.stercoralis and larva migrans syndromes). In locations where Ascaris infections are seasonal as a result of the failure of eggs to survive throughout the year, symptoms of pulmonary ascariasis may be relatively common. Gelpi and Mustafa  reported outbreaks of eosinophilic pneumonitis associated with A.lumbricoides infections occurring every year during and after the short rainy season in Saudi Arabia.
In regions where ascariasis is highly endemic, and infections are acquired at an early age, symptomatic pulmonary ascariasis appears to be rare. For example, a large survey conducted over a year in Colombia  in communities where the prevalence of ascariasis was between 25 and 85%, was able to identify only 1 typical case of larval ascariasis among over 12000 individuals attending health centres or local hospitals. Therefore, in areas where transmission of Ascaris occurs throughout the year, larval ascariasis is either asymptomatic or is associated with mild and nonspecific symptoms.
RELEVANCE OF THE ACUTE VS. CHRONIC PARADIGM
The acute/chronic paradigm provides a useful framework within which to understand differences in parasite immune responses and clinical disease observed in different countries, and even between different communities within the same region. An important determinant of the expression of geohelminth–associated allergic inflammation may be the epidemiology of geohelminth infections in a particular area (Fig. 1) – where geohelminth transmission is sporadic or seasonal (low prevalence), an acute allergy-enhancing phenotype may predominate while in areas where transmission is continuous (high prevalence), more chronic and allergy-suppressing infections would be expected. In areas where transmission is continuous, such infections would be expected to suppress allergic responses in an age- and infection intensity-dependent fashion. In the case of infections such as A.lumbricoides and T.trichiura that are acquired at an early age, and constant exposure occurs throughout childhood, school age children with the heaviest parasite burdens would be expected to have the lowest rates of atopy and allergic disease.
MECHANISMS OF ALLERGY MODULATION
Geohelminth parasites may modulate allergic disease in two ways: (1) directly – geohelminth parasites may themselves induce allergic disease (e.g. Loeffler’s syndrome); and (2) indirectly – geohelminth parasites may modulate the immune response to environmental allergens. There are several mechanisms by which geohelminth infections can alter the immune response to environmental aeroallergens to either induce or suppress allergic reactivity. Concurrent geohelminth infections may affect immune priming for IgE as well as the development of the pathophysiological changes in the lung that are typical of asthma (airways inflammation and bronchial hyperreactivity), and may act at several levels in the allergic inflammatory pathway by affecting:
- •the initial development and polarization of Th2 helper cells;
- •Th2 helper cell action in the airways;
- •the level of nonspecific inflammation in the airways.
The mechanisms by which acute and chronic infections may modulate allergic inflammation are listed in Fig. 1 and include acute and chronic infections.
The invasive larvae of geohelminth parasites that migrate through the lungs are the primary target of parasite specific immune responses , and early during infection induce strong eosinophil-rich inflammation in the lungs . Ascaris larvae secrete large amounts of allergenic substances  that are likely to be the primary stimulus for IgE production in infected individuals. Larval antigens are likely to induce strong Th2 responses . During early infections, invasive parasite larvae may not only induce allergic inflammation directly but also may enhance allergic inflammation targeted against nonparasite allergens (such as aeroallergens) through bystander or adjuvant effects as suggested by the findings of experimental animal studies . Enhanced IL-4 and IL-13 production may result in increased synthesis of aeroallergen-specific IgE and sensitize mast cells in a number of tissues including the skin (e.g. resulting in increased atopy).
Chronic infections with geohelminth parasites may suppress parasite-specific and aeroallergen-specific immune responses through several mechanisms:
Mast cell saturation. Geohelminth parasites secrete potent allergens [82,85] and are considered to be the principal explanation for the high levels of polyclonal IgE that are observed in endemic populations [58,86]. Children living in endemic areas often have total IgE levels in excess of 10 000IU/ml . The production of large amounts of polyclonal IgE in helminthiases may modulate immediate hypersensitivity reactions by inhibition of the activity of mast cells by saturation of high affinity FcɛR1 receptors on mast cells and basophils [5,46,87,88]. Saturation of mast cells could explain reduced sensitivity to aeroallergens and also reduced inflammation in the airways (bronchial hyperresponsiveness). Likewise, saturation of low-affinity FcɛR11 with nonspecific IgE on antigen presenting cells may prevent optimal IgE-dependent antigen focusing and presentation to T cells .
IgG4 ‘blocking’ antibodies Polyclonal activation of IgG4 by parasite products and the production of large amounts of IgG4 including IgG4 antibodies specific to IgE-reactive epitopes of environmental allergens, may block IgE-driven inflammation by saturation of available reaginic epitopes [77,89,90].
Bystander suppression by anti-inflammatory cytokines. Observations from tissue invasive helminth infections would support the development of cellular immune down-regulatory mechanisms following persistent exposure and chronicity of infection that may suppress allergic inflammation. The principal mechanism by which this occurs appears to be the increased production of anti-inflammatory cytokines (IL-10 and TGF-β) [74–76]. The production of large amounts of anti-inflammatory cytokines such as IL-10 by parasite-antigen stimulated T cells could cause bystander suppression of immune responses to environmental allergens  or the induction of T cells specific for environmental allergens that secrete IL-10/TGF-β (e.g. Th3 or Tr-1 cells) and that directly down-regulate allergic responses to environmental allergens .
Tolerization. There is some evidence to suggest that ‘tolerization’ to parasite antigens may occur in early infancy or neonatally through the transfer of parasite antigens from infected mothers. Tolerization could occur either peripherally or through thymic deletion of reactive cells [91,92], and could be induced to environmental aeroallergens that are immunologically cross-reactive with parasite allergens [93,94].
There are large international differences in the prevalence of allergic disease, that appears to be much lower in Tropical regions, particularly among rural populations. Environmental factors including childhood infections have been implicated as important determinants of the expression of allergic disease. Geohelminth infections are the most prevalent and persistent of all childhood infections and are most prevalent among rural populations in the Tropics. There is evidence from different epidemiological studies that geohelminth infections may modulate the expression of atopy and also of allergic disease, and may be protective against atopy/allergic disease in some populations but risk factors for atopy/allergic disease in others. A partial explanation for such contradictory observations may be provided by a paradigm in which acute geohelminth infections enhance allergic reactivity and chronic infections suppress allergic inflammation (Fig. 1). Acute or early helminth infections appear to enhance allergic inflammation directed against both parasite and nonparasite antigens (e.g. environmental allergens), while chronic infections appear to suppress allergic inflammation. Suppression of atopy and allergic disease among individuals with chronic or long-standing geohelminth infestations may occur through several mechanisms that include mast cell saturation by polyclonal IgE and the enhanced production of anti-inflammatory cytokines (i.e. IL-10 and TGF-β). The overall effect of geohelminth infections on allergic inflammation is likely to vary between different regions and even between different communities in the same area depending on the endemicity of infection with different geohelminth parasites and on the age (and history of infection) of the study group selected. Clearly, the interaction between geohelminth infections and allergy is highly complex, and there remain a number of unanswered questions regarding the modulatory role of geohelminth infections against atopy/allergic disease. Future studies could address the following questions:
- •What are the important mechanisms of geohelminth-mediated immunomodulation of atopy/allergic disease in populations of different endemicity for geohelminths?
- •Are atopic individuals more resistant to geohelminth infections or are geohelminth-infected individuals more protected against atopy (i.e. reverse causality)?
- •Can the suppression of atopy associated with chronic geohelminth infections be reversed by anthelmintic treatment and can the reacquisition of infection after treatment have the reverse effect?
- •Has the prevalence of atopy/allergy increased in areas where sustained anthelmintic control programmes are in place?
- •What are the risk factors for allergy in geohelminth-endemic populations and do these differ from nonendemic populations?