Global issues in allergy and immunology: Parasitic infections and allergy
Authors: Alvaro A. Cruz, Philip J. Cooper, Camila A. Figueiredo, Neuza M. Alcantara-Neves, Laura C. Rodrigues, Mauricio L. Barreto
Journal: Journal of Allergy and Clinical Immunology (2017)

Allergic diseases are on the increase globally in parallel with a decrease in parasitic infection. The inverse association between parasitic infections and allergy at an ecological level suggests a causal association. Studies in human subjects have generated a large knowledge base on the complexity of the interrelationship between parasitic infection and allergy. There is evidence for causal links, but the data from animal models are the most compelling: despite the strong type 2 immune responses they induce, helminth infections can suppress allergy through regulatory pathways. Conversely, many helminths can cause allergic-type inflammation, including symptoms of "classical" allergic disease. From an evolutionary perspective, subjects with an effective immune response against helminths can be more susceptible to allergy. This narrative review aims to inform readers of the most relevant up-to-date evidence on the relationship between parasites and allergy. Experiments in animal models have demonstrated the potential benefits of helminth infection or administration of helminth-derived molecules on chronic inflammatory diseases, but thus far, clinical trials in human subjects have not demonstrated unequivocal clinical benefits. Nevertheless, there is sufficiently strong evidence to support continued investigation of the potential benefits of helminth-derived therapies for the prevention or treatment of allergic and other inflammatory diseases. Allergic diseases are on the increase globally in parallel with a decrease in parasitic infection. The inverse association between parasitic infections and allergy at an ecological level suggests a causal association. Studies in human subjects have generated a large knowledge base on the complexity of the interrelationship between parasitic infection and allergy. There is evidence for causal links, but the data from animal models are the most compelling: despite the strong type 2 immune responses they induce, helminth infections can suppress allergy through regulatory pathways. Conversely, many helminths can cause allergic-type inflammation, including symptoms of "classical" allergic disease. From an evolutionary perspective, subjects with an effective immune response against helminths can be more susceptible to allergy. This narrative review aims to inform readers of the most relevant up-to-date evidence on the relationship between parasites and allergy. Experiments in animal models have demonstrated the potential benefits of helminth infection or administration of helminth-derived molecules on chronic inflammatory diseases, but thus far, clinical trials in human subjects have not demonstrated unequivocal clinical benefits. Nevertheless, there is sufficiently strong evidence to support continued investigation of the potential benefits of helminth-derived therapies for the prevention or treatment of allergic and other inflammatory diseases. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: November 2017. Credit may be obtained for these courses until October 31, 2018.Copyright Statement: Copyright © 2017-2018. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Alvaro A. Cruz, MD, Philip J. Cooper, MD, PhD, Camila A. Figueiredo, PhD, Neuza M. Alcantara-Neves, MD, PhD, Laura C. Rodrigues, MD, PhD, and Mauricio L. Barreto, MD, PhD (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: A. A. Cruz has board memberships with GlaxoSmithKline, AstraZeneca, Novartis, Mylan, and Boehringer Ingelheim; has consultant arrangements with Boehringer Ingelheim; has given expert testimony on behalf of Boehringer Ingelheim; has received grants from GlaxoSmithKline; has received payment for lectures from EUROFARMA, AstraZeneca, Novartis, CHIESI, Boehringer Ingelheim, and Mylan; has received payment for manuscript preparation from Mylan and Merck Sharp & Dohme; and has received travel support from Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest. Z. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To learn TH2 immune responses are the primary mediators in helminth infections.2.To explore structural homology between allergens derived from parasites and aeroallergens.3.To learn similar immune mechanisms exist between atopic conditions and helminth infections.4.To discover the potential negative association between helminth infection and allergy.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Mollie Alpern, MD, Joshua M. Dorn, MD, Jay J. Jin, MD, PhD, Caitlin McNulty, MD, Annely M. Richardson, MD, and James T. Li, MD, PhD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.The frequency of allergic disease has been increasing in urban and urbanizing populations,1Matricardi P.M. The allergy epidemic.in: Global atlas of allergy. European Academy of Allergy and Clinical Immunology, Zurich2014Google Scholar whereas an overall decrease in rates of infections has been observed. Studies of the inverse association between parasitic infections and allergy suggest the existence of a causal link. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: November 2017. Credit may be obtained for these courses until October 31, 2018. Copyright Statement: Copyright © 2017-2018. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Alvaro A. Cruz, MD, Philip J. Cooper, MD, PhD, Camila A. Figueiredo, PhD, Neuza M. Alcantara-Neves, MD, PhD, Laura C. Rodrigues, MD, PhD, and Mauricio L. Barreto, MD, PhD (authors); Zuhair K. Ballas, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: A. A. Cruz has board memberships with GlaxoSmithKline, AstraZeneca, Novartis, Mylan, and Boehringer Ingelheim; has consultant arrangements with Boehringer Ingelheim; has given expert testimony on behalf of Boehringer Ingelheim; has received grants from GlaxoSmithKline; has received payment for lectures from EUROFARMA, AstraZeneca, Novartis, CHIESI, Boehringer Ingelheim, and Mylan; has received payment for manuscript preparation from Mylan and Merck Sharp & Dohme; and has received travel support from Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest. Z. Ballas (editor) disclosed no relevant financial relationships. Activity Objectives:1.To learn TH2 immune responses are the primary mediators in helminth infections.2.To explore structural homology between allergens derived from parasites and aeroallergens.3.To learn similar immune mechanisms exist between atopic conditions and helminth infections.4.To discover the potential negative association between helminth infection and allergy. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Mollie Alpern, MD, Joshua M. Dorn, MD, Jay J. Jin, MD, PhD, Caitlin McNulty, MD, Annely M. Richardson, MD, and James T. Li, MD, PhD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. Although human subjects can be infected with some 300 species of worms and more than 70 species of protozoa,2Ashford R.W. Crewe W. The parasites of Homo sapiens. Liverpool School of Tropical Medicine, Liverpool (United Kingdom)1998Google Scholar we will focus on soil-transmitted helminths (STHs), also called geohelminths. Worldwide, it is estimated that 1.5 billion human subjects are infected with one of these species.3World Health Organization. Soil-transmitted helminth infections. Fact sheet, updated January 2017. Available at: http://www.who.int/mediacentre/factsheets/fs366/en/. Accessed July 15, 2017.Google Scholar We will also refer to Schistosoma species, which infect human subjects through contact of skin with water infested with larvae and are estimated to infect 230 million persons.4Colley D.G. Bustinduy A.L. Secor W.E. King C.H. Human schistosomiasis.Lancet. 2014; 383: 2253-2264Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar For example, Fig 1 shows typical features of a rural household in a village of Conde, northeast Brazil, from 2005, in which the prevalence of helminth infections was 83.5%.5Grant A.V. Araujo M.I. Ponte E.V. Oliveira R.R. Cruz A.A. Barnes K.C. et al.High heritability but uncertain mode of inheritance for total serum IgE level and Schistosoma mansoni infection intensity in a schistosomiasis-endemic Brazilian population.J Infect Dis. 2008; 198: 1227-1236Crossref PubMed Scopus (25) Google Scholar In the city of Salvador, 185 km away, the frequency of helminth infection among children was less than 20%.6Alcantara-Neves N.M. Veiga R.V. Dattoli V.C. Fiaccone R.L. Esquivel R. Cruz A.A. et al.The effect of single and multiple infections on atopy and wheezing in children.J Allergy Clin Immunol. 2012; 129 (e1-3): 359-367Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar An ecological study including all Brazilian municipalities reported that hospitalization rates for asthma were lower in those endemic for Schistosoma mansoni or STH parasites.7Ponte E.V. Rasella D. Souza-Machado C. Stelmach R. Barreto M.L. Cruz A.A. Reduced asthma morbidity in endemic areas for helminth infections: a longitudinal ecological study in Brazil.J Asthma. 2014; 51: 1022-1027Crossref PubMed Scopus (25) Google Scholar A typical urban underserved neighborhood of Salvador is presented in Fig 2.6Alcantara-Neves N.M. Veiga R.V. Dattoli V.C. Fiaccone R.L. Esquivel R. Cruz A.A. et al.The effect of single and multiple infections on atopy and wheezing in children.J Allergy Clin Immunol. 2012; 129 (e1-3): 359-367Abstract Full Text Full Text PDF PubMed Scopus (70) Google ScholarFig 2Typical urban underserved neighborhood of Salvador, Brazil, in which the prevalence of helminth infection among children was less than 20%.6Alcantara-Neves N.M. Veiga R.V. Dattoli V.C. Fiaccone R.L. Esquivel R. Cruz A.A. et al.The effect of single and multiple infections on atopy and wheezing in children.J Allergy Clin Immunol. 2012; 129 (e1-3): 359-367Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Figure Attribution: original image by user sergio_65_ita (Sussuarana [Salvador] - DSC03080 [CC BY 2.0; http://creativecommons.org/licenses/by/2.0]), via Wikimedia Commons.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The purpose of this narrative review is to inform clinicians and researchers of the most current evidence on the interrelationship between parasitic infections and allergy from epidemiologic studies to mechanisms and molecules identified in helminths that are candidates for novel therapeutics. Allergic diseases are among the most common chronic diseases,1Matricardi P.M. The allergy epidemic.in: Global atlas of allergy. European Academy of Allergy and Clinical Immunology, Zurich2014Google Scholar particularly in populations undergoing urbanization.8Rodriguez A. Vaca M. Oviedo G. Erazo S. Chico M.E. Teles C. et al.Urbanisation is associated with prevalence of childhood asthma in diverse, small rural communities in Ecuador.Thorax. 2011; 66: 1043-1050Crossref PubMed Scopus (62) Google Scholar Individual allergy risk is considered to reflect a complex interaction between genetic predisposition and environmental exposures over the life course.9Burbank A.J. Sood A.K. Kesic M.J. Peden D.B. Hernandez M.L. Environmental determinants of allergy and asthma in early life.J Allergy Clin Immunol. 2017; 140: 1-12Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Geographic differences in the prevalence of allergy between and within populations is more likely to reflect exposures to common environmental factors that can either increase or decrease risk. The most consistent environmental exposures considered to reduce allergy risk are those associated with rural residence and include farming, animal exposure,10von Mutius E. The microbial environment and its influence on asthma prevention in early life.J Allergy Clin Immunol. 2016; 137: 680-689Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar and infections with parasites.11Maizels R.M. McSorley H.J. Regulation of the host immune system by helminth parasites.J Allergy Clin Immunol. 2016; 138: 666-675Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar Protective immunity against STHs is mediated through type 2 immune mechanisms,11Maizels R.M. McSorley H.J. Regulation of the host immune system by helminth parasites.J Allergy Clin Immunol. 2016; 138: 666-675Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar and parasites can survive to cause chronic infections by modulating these allergic inflammatory responses. The prevalence of STH infections is decreasing worldwide. This reflects a combination of factors leading to reductions in transmission of these infections, including reductions in extreme poverty and improvements in the living environment (potable water and disposal of feces) and the wide availability of anthelmintic drugs. Reductions in STH prevalence, although beneficial, might raise concerns in case of being causally associated with allergy. There is evidence in support of protection against allergy by STH infections, but many studies in human populations present discordant effects. Meta-analyses of observational studies have shown differences in effects on asthma symptoms for different parasites: although Ascaris lumbricoides was associated with an increased risk of asthma, hookworm infection was associated with a reduced risk.12Leonardi-Bee J. Pritchard D. Britton J. Asthma and current intestinal parasite infection: systematic review and meta-analysis.Am J Respir Crit Care Med. 2006; 174: 514-523Crossref PubMed Scopus (239) Google Scholar In contrast, studies that have measured the presence of Ascaris species–specific IgE, which is recommended by some as a marker of infection in areas of low prevalence13Fincham J.E. Markus M.B. van der Merwe L. Adams V.J. van Stuijvenberg M.E. Dhansay M.A. Ascaris, co-infection and allergy: the importance of analysis based on immunological variables rather than egg excretion.Trans R Soc Trop Med Hyg. 2007; 101: 680-682Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar but is perhaps more appropriately used as a marker of allergic sensitization to Ascaris species, have shown consistently positive associations with asthma symptoms and even disease severity.14Ahumada V. García E. Dennis R. Rojas M.X. Rondón M.A. Pérez A. et al.IgE responses to Ascaris and mite tropomyosins are risk factors for asthma.Clin Exp Allergy. 2015; 45: 1189-1200Crossref PubMed Scopus (54) Google Scholar, 15Hunninghake G.M. Soto-Quiros M.E. Avila L. Ly N.P. Liang C. Sylvia J.S. et al.Sensitization to Ascaris lumbricoides and severity of childhood asthma in Costa Rica.J Allergy Clin Immunol. 2007; 119: 654-661Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar In the case of atopy, which is generally measured based on allergen skin prick test (SPT) reactivity, most cross-sectional studies have shown inverse associations with STH infections.16Feary J. Britton J. Leonardi-Bee J. Atopy and current intestinal parasite infection: a systematic review and meta-analysis.Allergy. 2011; 66: 569-578Crossref PubMed Scopus (99) Google Scholar A meta-analysis of cross-sectional studies showed that current STH infections were protective against atopy, an effect that was consistent for all 3 of the most common STH infections and also schistosomiasis.16Feary J. Britton J. Leonardi-Bee J. Atopy and current intestinal parasite infection: a systematic review and meta-analysis.Allergy. 2011; 66: 569-578Crossref PubMed Scopus (99) Google Scholar Although Ascaris species infections can be associated inversely with atopy, they are often associated directly with wheezing, as mentioned in the previous paragraph. STH infections are not alone in attenuating atopy. A cross-sectional study showed that several different childhood infections were associated independently and inversely with reactivity to SPTs, including the visceral worm Toxoplasma gondii, Herpes simplex, and EBV infections.6Alcantara-Neves N.M. Veiga R.V. Dattoli V.C. Fiaccone R.L. Esquivel R. Cruz A.A. et al.The effect of single and multiple infections on atopy and wheezing in children.J Allergy Clin Immunol. 2012; 129 (e1-3): 359-367Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar This observation raises the possibility that rather than mediating protection directly, STH infections might be markers of poor environmental conditions that mediate protection through alternative mechanisms. Interestingly, in the study mentioned above, T gondii was the only organism associated with a reduction in allergen-specific IgE levels in this population.6Alcantara-Neves N.M. Veiga R.V. Dattoli V.C. Fiaccone R.L. Esquivel R. Cruz A.A. et al.The effect of single and multiple infections on atopy and wheezing in children.J Allergy Clin Immunol. 2012; 129 (e1-3): 359-367Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Few prospective studies have explored the effects of geohelminths on allergy development. It has been suggested that the key effects of protective environmental exposures occur during early life, during which there might be a limited window of opportunity for such exposures to mediate their effects.9Burbank A.J. Sood A.K. Kesic M.J. Peden D.B. Hernandez M.L. Environmental determinants of allergy and asthma in early life.J Allergy Clin Immunol. 2017; 140: 1-12Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar If this is the case, prospective studies of the effects of STH infections on allergy should start in early childhood, ideally before birth, to measure any potential in utero effects of maternal STH infections. Four such prospective studies have been published to date: (1) a birth cohort in Ethiopia, where the prevalence of helminthiasis was considered too low to explore the effects on wheeze and eczema to 5 years17Amberbir A. Medhin G. Erku W. Alem A. Simms R. Robinson K. et al.Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children.Clin Exp Allergy. 2011; 41: 1422-1430Crossref PubMed Scopus (77) Google Scholar; (2) an observational analysis within a randomized controlled trial of anthelmintic treatment during pregnancy showed that maternal and childhood hookworm and childhood Trichuris trichiura were associated with a reduced risk of eczema at 5 years18Mpairwe H. Ndibazza J. Webb E.L. Nampijja M. Muhangi L. Apule B. et al.Maternal hookworm modifies risk factors for childhood eczema: results from a birth cohort in Uganda.Pediatr Allergy Immunol. 2014; 25: 481-488Crossref PubMed Scopus (34) Google Scholar; (3) a prospective study showed that T trichiura infections during the first 5 years of life were associated with a reduced risk of SPT reactivity in later childhood19Rodrigues L.C. Newcombe P.J. Cunha S.S. Alcantara-Neves N.M. Genser B. Cruz A.A. et al.Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood.Clin Exp Allergy. 2008; 38: 1769-1777PubMed Google Scholar; and (4) a birth cohort in a rural area did not show an effect of maternal STH infections on SPT reactivity, wheeze, or eczema during the first 3 years of life,20Cooper P.J. Chico M.E. Amorim L.D. Sandoval C. Vaca M. Strina A. et al.Effects of maternal geohelminth infections on allergy in early childhood.J Allergy Clin Immunol. 2016; 137: 899-906.e2Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar but follow-up of the cohort is in progress to determine whether childhood infections can affect the risk of allergy at school age.21Cooper P.J. Chico M.E. Platts-Mills T.A. Rodrigues L.C. Strachan D.P. Barreto M.L. Cohort Profile: The Ecuador Life (ECUAVIDA) study in Esmeraldas Province, Ecuador.Int J Epidemiol. 2015; 44: 1517-1527Crossref PubMed Scopus (24) Google Scholar Another method used to test the causal link has been interventional studies, in which protective exposure (ie, the STH) is removed through anthelmintic treatment, thus intending to reverse any existing effects. If helminths are truly protective, one might expect to observe an increase in the prevalence of allergy in the group receiving treatment. Several intervention studies have inconsistent findings.18Mpairwe H. Ndibazza J. Webb E.L. Nampijja M. Muhangi L. Apule B. et al.Maternal hookworm modifies risk factors for childhood eczema: results from a birth cohort in Uganda.Pediatr Allergy Immunol. 2014; 25: 481-488Crossref PubMed Scopus (34) Google Scholar, 21Cooper P.J. Chico M.E. Platts-Mills T.A. Rodrigues L.C. Strachan D.P. Barreto M.L. Cohort Profile: The Ecuador Life (ECUAVIDA) study in Esmeraldas Province, Ecuador.Int J Epidemiol. 2015; 44: 1517-1527Crossref PubMed Scopus (24) Google Scholar, 22van den Biggelaar A.H. Rodrigues L.C. van Ree R. van der Zee J.S. Hoeksma-Kruize Y.C. Souverijn J.H. et al.Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren.J Infect Dis. 2004; 189: 892-900Crossref PubMed Scopus (283) Google Scholar, 23Flohr C. Tuyen L.N. Quinnell R.J. Lewis S. Minh T.T. Campbell J. et al.Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double-blind, placebo-controlled trial in Vietnam.Clin Exp Allergy. 2010; 40: 131-142PubMed Google Scholar None of the studies were able to show an effect on the prevalence of asthma symptoms, one showed that a single dose of anthelmintic drugs given during the latter part of pregnancy was associated with an increased risk of eczema in infancy,18Mpairwe H. Ndibazza J. Webb E.L. Nampijja M. Muhangi L. Apule B. et al.Maternal hookworm modifies risk factors for childhood eczema: results from a birth cohort in Uganda.Pediatr Allergy Immunol. 2014; 25: 481-488Crossref PubMed Scopus (34) Google Scholar and 2 showed an increase in either the incidence22van den Biggelaar A.H. Rodrigues L.C. van Ree R. van der Zee J.S. Hoeksma-Kruize Y.C. Souverijn J.H. et al.Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren.J Infect Dis. 2004; 189: 892-900Crossref PubMed Scopus (283) Google Scholar or frequency23Flohr C. Tuyen L.N. Quinnell R.J. Lewis S. Minh T.T. Campbell J. et al.Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double-blind, placebo-controlled trial in Vietnam.Clin Exp Allergy. 2010; 40: 131-142PubMed Google Scholar of a positive SPT response after at least 1 year of treatment. Overall, the evidence suggests that A lumbricoides infection and particularly Ascaris species–specific IgE are associated with an increased risk of asthma symptoms in endemic areas and that STH infections can reduce the prevalence of positive SPT responses but not specific IgE to aeroallergens. There is still very limited evidence that STH infections protect against allergic symptoms in human populations, and the effects of early-life exposures to STH infections on the development of allergy in childhood, either through maternal or childhood infections, are still insufficiently studied. In case of schistosomiasis, all published studies have been cross-sectional, showing an inverse association between Schistosoma mansoni infection and SPT reactivity to common aeroallergens in most cases.16Feary J. Britton J. Leonardi-Bee J. Atopy and current intestinal parasite infection: a systematic review and meta-analysis.Allergy. 2011; 66: 569-578Crossref PubMed Scopus (99) Google Scholar A recent study in Uganda was unable to demonstrate an association between S mansoni infection and wheeze, but an earlier study in Brazil showed that S mansoni infection was associated with a milder form of asthma.24Medeiros Jr., M. Figueiredo J.P. Almeida M.C. Matos M.A. Araújo M.I. Cruz A.A. et al.Schistosoma mansoni infection is associated with a reduced course of asthma.J Allergy Clin Immunol. 2003; 111: 947-951Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar See Fig 3 for a schematic representation summarizing the findings from epidemiologic studies of the relationships between helminth parasites, atopy, and asthma. Helminths are the largest organisms to infect vertebrate hosts, leading to release of large quantities of parasite molecules that interact with the immune system. It might be expected that helminth infections would induce an overwhelming immune response, resulting in elimination of parasites while causing potentially damaging inflammation. However, coevolution of hosts and parasites over the millennia has allowed both host and parasite to survive through the development of mechanisms that dampen the host inflammatory response to the parasite or even allow the parasite to evade the host immune response, resulting in infections that are often asymptomatic.11Maizels R.M. McSorley H.J. Regulation of the host immune system by helminth parasites.J Allergy Clin Immunol. 2016; 138: 666-675Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar For example, Schistosoma species adults, which live within the human vascular system, can survive for many years without inducing strong host inflammatory responses.25Nawras M. El-Saghier Mowafy Ekhlas Hamed Abdel-Hafeez Schistosomiasis with special references to the mechanisms of evasion.J Coast Life Med. 2015; 3: 914-923Crossref Google Scholar Although the most widely studied host immune response against helminths is the acquired TH2-type response, we will discuss both innate and adaptive host immune responses to helminth parasites. The TH2-type response is characterized by production of high levels of the cytokines IL-4, IL-5, IL-9, IL-10, IL-13, IL-21, and IL-33. These cytokines orchestrate immediate hypersensitivity that involves B-cell class-switching to IgG4 and IgE, eosinophilia, goblet cell hyperplasia and mastocytosis, alternative activation of macrophages, and influx of inflammatory cells, such as eosinophils, that contribute to parasite killing. Such a response can control parasite numbers by killing them in tissues or expelling them from the intestinal lumen. The host response to helminth infections is associated with allergic phenomena that are a consequence of killing or an attempt to kill or expel these parasites.26Maizels R.M. Parasitic helminth infections and the control of human allergic and autoimmune disorders.Clin Microbiol Infect. 2016; 22: 481-486Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Examples are shown in Table I.Table IExamples of helminth infections and the allergic-type inflammatory responses with which they are associatedHelminth infectionAllergic-type reactions and syndromesIntestinal helminths Ascaris lumbricoides Trichuris trichiura Hookworm Strongyloides stercoralis Enterobius vermicularisAsthma-like syndromeTropical dysentery syndromeGround itch/allergic enteritisLarva currens/urticaria/asthma-like syndromeItchy anusSchistosomiasis Schist