Epidemiology and Risk Factors

Section B

Epidemiology and risk factors

* The allergy epidemic * Environmental risk factors for allergy: working * Natural history of allergy environment * Birth cohorts * Risk factors for childhood asthma: viral infection and * Environmental risk factors for allergy: outdoor/ allergic sensitization indoor pollution and climate change * Environmental risk factors for allergy: helminth * Measuring exposure to environmental airborne infections allergens * Perinatal immune development and its role in atopy * Environmental risk factors for allergy: food development * Environmental risk factors for asthma: home * Perinatal risk and protective factors for allergic environment diseases * The role of microbiome Global atlas oF allergy

The allergy 1 epidemic

Paolo Maria Matricardi Charité Medical University Berlin, Germany

The growing worldwide burden of allergic rhinitis, asthma and at- Key messages opic eczema has been properly defined as the “allergy epidemic”. • In countries undergoing the epidemiological transition phase, During the last two centuries, this allergies appear first among the richest, but soon affect the phenomenon has characterized middle class and finally the disadvantaged countries undergoing their epide- • Food allergies are emerging as a “second wave” of the allergy miological transition phase. Res- epidemic and they persist more frequently piratory allergies (allergic rhinitis • Epidemiological studies suggest that a high “antigenic burden” and asthma) appeared first among in early life, provided by infections and nutrition, can properly the richest, then spread within the “educate” the immune system and prevent childhood allergic middle class and finally affected diseases • A reduced “antigenic burden” implies a reduced stimulation of

- Epidemiology and risk factors also the disadvantaged. Following a similar pattern, respiratory aller- the immune system and contributes, in genetically predisposed gies and atopic eczema are nowa- individuals, to dysregulated immune response leading to allergy days on the rise in middle income • The discovery of the lifestyle factors promoting allergy susceptibility will inspire primary prevention strategies to revert S ection B countries, especially in the urban the allergy epidemic trend areas (Figure 1). More recently, food allergies are clearly becoming more prevalent support in several epidemiological allergic diseases later in childhood in westernized populations (Fig- studies: 1) respiratory allergies are (Figure 4). A sufficiently high an“ - ure 2). This “second wave” of the inversely related to the number of tigenic burden” in early life, provid- allergy epidemic is already gen- different foodborne infections; 2) ed by infections and nutrition, is erating a heavy burden on health a lower diversity of the gut micro- therefore necessary to properly systems not well prepared to face bial flora in the first week of life “educate” the immune system and this new challenge. The increasing is associated with atopic eczema to prevent childhood allergic dis- prevalence of food allergies is as- at 18 months (Figure 3); 3) the eases. sociated with fatal anaphylaxis in probability of developing asthma Current knowledge is a good basis children and adolescents. in farming children is inversely re- to identify the allergy protective lated to the range of exposure to A decline of microbial diversity factors and to inspire primary and environmental bacteria and fungi. was proposed since the late nine- secondary prevention strategies ties as a major cause of the allergy Two recent studies have coher- to revert the allergy epidemic epidemic. This area of the hygiene ently shown that reduced food trend. Allergy prevention based hypothesis, now defined biodiver“ - diversity in infants’ diet is associ- on the administration of probiot- sity hypothesis”, has found specific ated with atopic sensitization and ics to pregnant mothers and to in-

112 The allergy epidemic Global atlas oF allergy S ection B - Epidemiology and risk factors

Figure 1 The spread of hay fever and allergic asthma according to socio-economic status and westernization level. (Reproduced with permission from Annals of Allergy, Asthma & Immunology, Vol. 89(S1). Matricardi PM, Bouygue GR, Tripodi S. Inner-city asthma and the hygiene hypothesis, 69–74. Copyright Elsevier 2002.)

20%

18%

16% Zurich 14% Madrid Figure 2 Observed and predicted 12% Utrecht values for the prevalence of food IgE Lodz 10% sensitization in 20- to 54-year-olds Sofia in European cities. (reprinted from 8% Reykjavik Allergy, Vol. 69. Burney PGJ et al. PREVALENCE Zurich_predict 6% The prevalence of food sensitization Madrid_predict among European adults. pp. 365–71. 4% Utrecht_predict Lodz_predict Copyright 2014 (Reproduced with 2% Sofia_predict permission from Burney PGJ, Potts J, 0% Reykjavik_predict Kummeling I, et al. The prevalence of food sensitization among European Fish Egg Soya Corn Kiwi Peach Lentils Poppy Shrimp Wheat Carrot adults. Allergy, 2014 69: 365–71, with Buckwheat permission from Willey Blackwell.) FOOD

The allergy epidemic 113 Global atlas oF allergy

fants provided unfortunately conflicting and still debated results. Other strategies under investiga- tion include the safe administration of oral or intranasal bacterial extracts and earlier introduction of foods.

KEY REFERENCES 1. Matricardi PM. 99th Dahlem con- ference on infection, inflammation and chronic inflammatory disorders: controversial aspects of the 'hygiene hypothesis'. Clin Exp Immu- nol 2010;160:98-105. 2. Prescott S, Allen KJ. Food allergy: riding the second wave of the allergy epidemic. Ped Allergy Immunol Figure 3 Shannon-Wiener index after T-RFLP of 16S rDNA with AluI for 2011;22:155-160. cutting and TTGE, respectively, generated from the fecal microbiota of 1-week- 3. Rook GA, Stanford JL. Give us this old infants that at 18 months had atopic eczema or stayed healthy. For each day our daily germs. Immunol Today group, median and 10th, 25th, 75th, and 90th percentiles are shown. *For 1998;19:113-116. T-RFLP, P<.01 and for TTGE, P<.05 (Reprinted from J Allergy Clin Immunol, 121/1, 4. Haahtela T, Holgate S, Pawankar R, Wang M, Karlsson C, Olsson C, et al. Reduced diversity in the early fecal microbiota Akdis C, Benjaponpitak S, Caraballo of infants with atopic eczema, 129-134, Copyright 2008, with permission from L et al. The biodiversity hypothesis Elsevier.) and allergic disease. WAO position paper. WAO Journal 2013;6:3. 5. Wang M, Karlsson C, Olsson C, Ad- lerberth I, Wold AE, Strachan DP, et al. Reduced diversity in the early - Epidemiology and risk factors fecal microbiota of infants with atopic eczema. J Allergy Clin Immunol 2008;121:129-134. 6. Nwaru BI, Takkinen HM, Kaila M, S ection B Erkkola M, Ahonen S, Pekkanen J, et al. Food diversity in infancy and the risk of childhood asthma and allergies. J Allergy Clin Immunol 2014: 133:1084-1091.

Figure 4 Association of increasing diversity of food introduced within the first year of life with (A) asthma and (B) food allergy among 856 children who partici- pated in a birth cohort study, Protection Against Allergy Study in Rural Envi- ronments/EFRAIM. The figure shows the diversity score with all different food items for the entire study population. The solid lines represents the predicted value of (A) asthma or (B) food allergy, as a function of the score, and dashed lines represent the corresponding CI. The y-axis is the linear logit of (A) asthma or (B) food allergy, and the values are centered on 0 (50/50 odds) and extended to both positive and negative values. All models are adjusted for farmer, center, duration of breast-feeding, parents with allergy, maternal education, sex, and siblings. (Reprinted from J Allergy Clin Immunol, 133/4, Roduit C, Frei R, Depner M et al. Increased food diversity in the first year of life is inversely associated with allergic diseases, 1056-1064, Copyright 2014, with permission from Elsevier.)

114 The allergy epidemic Global atlas oF allergy

Natural history of 2 allergy

Susanne Lau Charité Medical University Berlin, Germany

Allergy is common in children, adolescents and adults. Epidemi- Key messages

ological studies like the German S ection B MAS (Multicentre Allergy Study) • Atopic eczema (dermatitis) is usually the first manifestation of showed age-related typical man- an atopic disease. Not all children with infantile eczema show a ifestations of atopic and allergic sensitisation to food allergens and will develop classical allergy diseases. In the “Atopic March” • Sensitisation to foods precedes sensitisation to inhalant - Epidemiology and risk factors infantile eczema and food allergy allergens. Persistent sensitisation before and after 3 years of age precede the onset of allergic air- is a risk factor for school age asthma way disease (rhinitis and asthma). • Early infantile eczema, early sensitisation during the first 3 years of life and atopic family history are predictors of allergic airway However, there are individu- disease and persistence of asthma until puberty als with isolated allergic airway • Children with infantile eczema often lose their symptoms until disease (for example hay fever) school age, although early onset is more frequently associated starting later in life at school age with persistence until puberty compared to children with later without any signs of other atopic onset of the disease disease during infancy and pre- • Remission of allergic asthma occurs not frequently up to the age school age. Equally, there are chil- of 20 years dren with infantile eczema without any signs of food or inhalant allergy. Furthermore, remission and food allergy to cow`s milk, Asthma and relapse of disease entities are hen`s egg, wheat and soy is high- In the German MAS cohort, the possible at any time. est during the first 2 years of life prevalence of asthma is 4% at 6 Studies on the molecular pattern in childhood, however, there is a years of age and more prevalent of sensitisation to pollen allergens second peak of new onset of atop- in boys and 9% at age 20 years. showed a preclinical phase, where ic eczema in puberty for females. The incidence of allergic asthma sensitization (IgE antibodies in Two third of young children with is highest during preschool and serum) to certain molecules of an infantile eczema will lose their early school age (Figure 1). There allergen source (grass or birch) symptoms up to the age of three is a second peak for new onset precedes symptoms. The likeli- years. However, those children de- of asthma in females at puberty. hood of clinical allergy increases veloping atopic eczema later in life Atopic family history is a major with the number of molecules rec- (after the age of 5 years) are more risk factor for the development ognized by IgE. likely to outgrow their eczema of asthma (Figure 2). 29% of the compared to those children, who German MAS cohort children Atopic eczema had an earlier onset of disease with complete follow-up showed The incidence of atopic eczema (during the first year of life). wheezing episodes during the

Natural history of allergy 115 Global atlas oF allergy

Figure 1 Incidence of asthma in the German MAS cohort. (From Matricardi PM, Illi S, Grüber C,et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Resp J 2008; 32:585-92; Reprinted with permission under the Creative Common Attribution License or equivalent.)

40%

30% both parents allergic

20% one allergic parent - Epidemiology and risk factors

cumulative incidence 10% non-allergic parents

S ection B 0% 0 5 10 15 20 age [years]

Figure 2 Family history for asthma and cumulative incidence of allergic diseases in offsprings. (Reprinted from J Allergy Clin Immunol, 133/4, Grabenhenrich LB, Gough H, Reich A, et al. Early-life determinants of asthma from birth to age 20 years: A German birth cohort study, 979-988, Copyright 2014, with permission from Elsevier.)

first three years of life (early tion (<3 years of age), especially to inducing IgE-mediated sensitiza- wheezers). 9% started wheezing perennial allergens, turned out to tion are hen`s egg, cow`s milk and between the age of 3 to 6 years be the major risk factors for per- peanut. Although, sensitisation to (late wheezers) and another 9% sistence of asthma/wheeze at age inhalant allergens like cat, house started wheezing after 6 years 11-13 years. dust mite and pollen allergens can of age (very late wheezers). Early be present already during the first persistent wheezers (early start IgE sensitisation to 3 years of life, in most of the chil- of wheezing before 3 years of age, allergens dren the clinical relevance is ob- wheezing also after 6 years of age) The first allergens recognized by served later, at school age. showed the highest rates of atopy. the immune system in terms of Atopy (sensitisation) in general is In this group, early atopic eczema, IgE production are food allergens. a risk factor for asthma at school parental atopy and early sensitiza- The most frequent food allergens age (Figure 3).

116 Natural history of allergy Global atlas oF allergy

80 Atopic (n=94) Children with sensitization to any Non-atopic (n=59) allergen before the age of 3 years 70 and sensitization to inhalant allergens have an increased risk for 60 asthma at school age (Figure 4). 50 Allergic Rhinitis 40 There is a constant rise for the incidence and prevalence of allergic Prevalence(%) 30 rhinitis (AR) from preschool and 20 early school age until puberty. Allergic rhinitis until the age of 5 10 years was found to be a risk factor 0 for subsequent wheezing onset 0 1 2 3 4 5 6 7 9 10 11 12 13 with an adjusted relative risk of Age (years) 3.79 (p<0.001). This association Figure 3 Prevalence of current wheeze from birth to age 13 years in children was not attributable to the type of sensitization, the severity of

with any wheezing episode at schoolage (5-7 years) stratified for atopy at school S ection B age. (Reprinted from The Lancet, 368, Illi S, von Mutius E, Lau S, et al, Perennial sensitization or atopic dermatitis allergen sensitisation early in life and chronic asthma in children: a birth cohort study, during the first 2 years of life. On 763-770, Copyright 2006, with permission from Elsevier.) a population level 41.5% (95%

CI: 20.0-61.3) of all new cases - Epidemiology and risk factors of wheezing was attributable to preceding AR. Neither AR until the age of 2 years nor non-allergic rhinitis until the age of 5 years were significantly associated with wheezing onset in childhood. The first manifestation of AR occurs in preschool children, where it is a risk factor for subsequent wheezing onset. Preschool children with rhinitis might thus benefit from early assessment of allergic sensitization to identify the children at high risk of developing wheezing. Figure 4 Prevalence of asthma and asthmatic symptoms at 7 years of age, stratified for sensitization patterns and bronchial hyper-responsiveness (BHR). Allergic Rhinitis: * p< 0.05; ** p<0.001. (Reprinted from J Allergy Clin Immunol, 108/5, Illi S, von Sensitisation to aero- Mutius E, Lau S, et al. The pattern of atopic sensitization is associated with the allergens development of asthma in childhood, 709-714, Copyright 2001, with permission The 12-month prevalence of sen- from Elsevier.) sitization to indoor or outdoor allergens in the German MAS cohort Sensitisation to indoor allergens posed to these allergens early in rose with each time point of as- (house dust mite and pets) is asso- life are at risk to have impaired sessment, reaching almost 60% of ciated with allergic asthma. lung function at school age com- all boys and a third of all girls at the pared to children without sensi- age of 13 years (in children with School children with sensitisation tisation or with sensitisation and one or two allergic parents). Chil- to perennial allergens (house dust low exposure to indoor allergens dren from non-allergic parents mite, cat dander) being highly ex- during the first year of life. were less sensitized compared to

Natural history of allergy 117 Global atlas oF allergy

Figure 5 Probability of wheezing onset stratified by the 4 rhinitis phenotypes (allergic rhinitis, non-allergic rhinitis, atopy without rhinitis and control group) .at the ages of 2 and 5 years. (Reprinted from J Allergy Clin Immunol, 126/6, Rochat MK, Illi S, Ege MJ, et al. Allergic rhinitis as a predictor for wheezing onset in school-aged children, 1170-1175, Copyright 2010, with permission from Elsevier.)

those with allergic parents. Irre- KEY REFERENCES Clin Immunol 2004;113:925-931. - Epidemiology and risk factors spective of parental allergy status 1. Bergmann RL, Bergmann KE, 5. Illi S, von Mutius E, Lau S, Nigge- the number of boys sensitized to Lau-Schadendorf S, Luck W, Dan- mann B, Gruber C, Wahn U. Peren- aero-allergens was approximate- nemann A, Bauer CP et al. Atopic nial allergen sensitisation early in ly twice the number of sensitized diseases in infancy. The German life and chronic asthma in children: S ection B multicenter atopy study (MAS-90). girls at age 13 years. a birth cohort study. Lancet 2006; Pediatr Allergy Immunol 1994;5:19- 368:763-770. At the age of 13 years, 91% out 25. 6. Matricardi P, Illi S, Grueber C, Keil of the 35 children with “severe 2. Grabenhenrich LB, Gough H, Reich T, Niggemann B, Nickel R et al. persistent” AR (ARIA) were sensi- A, Eckers N, Zepp F, Nitsche O et al. Wheezing in childhood: incidence, Early-life determinants of asthma tized to at least one aero-allergen, longitudinal patterns and factors from birth to age 20 years: A Ger- whereas this proportion was only predicting persistence. Eur Respir J man birth cohort study. J Allergy 70% among the 56 children with 2008:32;585-592. “mild persistent” AR (p=0.015). Clin Immunol 2014;33:979-988. 7. Rochat MK, Illi S, Ege MJ, Lau S, This difference was similar at the 3. Hatzler L, Penetta V, Lau S, Wagner P, Bergmann RL, Illi S et al. Molec- Keil T, Wahn U, et al. Multicentre age of 10 years, although over- Allergy study (MAS) group. Allergic all slightly less children with AR ular spreading and predictive value of preclinical IgE response to Phle- rhinitis as a predictor for wheezing were sensitized (p=0.033). Among um pretense in children with hay onset in school-aged children. J Al- the asymptomatic children 18% fever. J Allergy Clin Immunol 2012; lergy Clin Immunol 2010;126:1170- (32/175) were sensitized to at 130:894-901. 1175. least one common aero-allergen 4. Illi S, von Mutius E, Lau S, Nickel R, 8. Sears MR, Greene JM, Willan AR et at the age of 13 years, compared Grüber C, Niggemann B et al. The al. A longitudinal population-based, to 24% (49/289) at the previous natural course of atopic dermatitis cohort study of childhood asthma time point of assessment at the from birth to age 7 years and the followed to adulthood. N Engl J Med age of 10 years. association with asthma. J Allergy 2003;349:1414-1422.

118 Natural history of allergy Global atlas oF allergy

3 Birth cohorts

Adnan Custovic University of Manchester Manchester, UK

In contrast to most other complex diseases (for example diabetes or Key messages

hypertension), allergic diseases S ection B generally start early in life. There- • Allergic diseases generally start early in life, thus birth cohorts are fore, the best way to study aller- essential for elucidating disease mechanisms and natural course gies is to recruit new born babies and evidence-based strategies for prevention and management and follow them as they grow (so- • Birth cohort studies have been instrumental in demonstrating the - Epidemiology and risk factors called birth cohort). Birth cohorts existence of a gene-environment interaction in the development overcome problems related to the of allergy and in identifying children at risk for allergy • Several consortia (STELAR, MeDALL, EuroPreval/iFAM, EAGLE) lack of accuracy (or completeness) bring together a number of ongoing birth cohort studies to of the recollections when patients facilitate data sharing are asked about the events, which occurred many years ago. Such studies permit careful longitudinal strumental in demonstrating the dren taking part in different birth assessment of symptoms, sensiti- existence of a gene-environment cohorts across the continent, and zation status, physician diagnoses interaction in the development of will facilitate the generation of and medication usage, and objec- allergy, which helped to explain critically important knowledge on tive measures such as lung func- the disparities in genetic associ- the mechanisms of initiation of tion. ation studies in different settings allergy. Birth cohorts in The EArly Allergies are heritable, but despite around the world. Genetics and Lifecourse Epide- miology (EAGLE) Consortium are lots of effort, we have had limited Several consortia bring together extensively collaborating to inves- success identifying what genes are a number of ongoing birth cohort tigate the genetic basis of allergy important, and this has yet to im- studies to facilitate data sharing. and asthma-related phenotypes in pact on patient care. Many factors For example, the UK Study Team childhood. in the environment contribute to for Early Life Asthma Research the development of allergies (for (STELAR) brings together the net- Numerous early breakthroughs example diet, immunizations, an- work of all UK-based birth cohorts have already been made. The on- tibiotics, pets and tobacco smoke), designed to study allergies with going birth cohort studies offer but we don’t know how to modify the experts in machine learning the best chance of identification the environment to reduce the and epidemiologically-orient- of children at increased risk of al- risks. In birth cohorts, environ- ed health informatics. Similarly, lergy. This is the first and crucially mental exposures can be meas- EU-funded MeDALL (Mechanisms important step towards the de- ured to allow the study of complex of the Development of ALLergy)1 velopment of the evidence-based gene-environment interactions. and EuroPreval/iFAM2 projects strategies for prevention of al- Birth cohort studies have been in- bring together thousands of chil- lergy development, and stratified

Birth cohorts 119 Global atlas oF allergy

1,053 Children switch class Sensitization Class

8 Allergens

P(Sens’n) Sensitized Sensitized Sensitized Sensitized in year 1 Age 1 Age 3 Age 5 Age 8 Mite Cat Dog Pollen P(Gain) Skin Test Skin Test Skin Test Skin Test P (Loose) Age 1 Age 3 Age 5 Age 8 Egg Sens’n Milk Mold 3 intervals Peanut Blood Test Blood Test Blood Test Blood Test Sens’n state Age 1 Age 3 Age 5 Age 8

P(+ skin) P(+ blood) Sens’ Sens’ Machine learning patterns of allergic sensitisation P(+ skin) P(+ blood) Not Sens’ Not Sens’

Figure 1 Longitudinal data collected over a number of years in birth cohort studies are a foundation for utilisation of the

- Epidemiology and risk factors power of novel state-of the art data analysis techniques to build complex models to describe different types of allergic diseases. In doing so, we will understand the basic biological mechanisms that underlie the different allergies, and identify novel targets for future drug therapies. S ection B

(personalised) management of funding for such large efforts. L, Dubakiene R, Drasutiene G, Fi- allergies (Figure 1). Existing birth occhi A et al. The EuroPrevall birth cohorts of individuals now at KEY REFERENCES cohort study on food allergy: base- various ages, from childhood to 1. Holguin F. The atopic march: IgE is line characteristics of 12,000 new- adulthood, should be considered not the only road. Lancet Respir Med borns and their families from nine a treasure, and every effort should 2014;2:88-90. European countries. Pediatr Allergy be made to maintain long-term 2. McBride D, Keil T, Grabenhenrich Immunol 2012;23:230-239.

120 Birth cohorts Global atlas oF allergy

Environmental risk factors for allergy: outdoor/indoor 4a pollution and climate change

Stefanie Gilles Claudia Traidl-Hoffmann Technical University of Munich Augsburg, Germany

Allergic diseases are a heavy socio-economic burden worldwide. Key messages

There is a deficit in public aware- S ection B ness, education and training and an • Allergy is an environmental disease as the most common and urgent need for efficient preven- earliest onset chronic non-communicable disease tion strategies. The rising trend in • Life-style and civilization related risk factors for allergy are allergies has been associated with encountered both indoors and outdoors - Epidemiology and risk factors changes in life-style, such as im- • Allergy-relevant indoor air pollutants include environmental proved hygiene measures, smaller tobacco smoke and volatile organic compounds family sizes and control of infec- • Anthropogenic environmental factors influence pollen tions, which, taken together, result allergenicity indirectly via their effects on pollen-producing in an “under-challenged” immune plants system. On the other hand, life- • Climate change-related effects contribute to an increased style changes include the exposure allergen burden in outdoor air to potentially harmful – indoor and • The growing evidence of man-made environmental risk factors outdoor – environmental pollut- for allergy highlights the importance of prevention strategies for ants suspected to keep our immune improving public health system in a constant state of alarm. How does this fit together? hort subgroup, prenatal and early sis of prospective, multi-center tri- INDOOR RISK FACTORS life exposure to environmental als did not find any clear associa- In the western civilization, most tobacco smoke was positively cor- tion of modeled traffic-related air individuals spend a considerable related with circulating eosinophil pollution and allergic sensitization part of their lives indoors. Indoor and basophil precursors in cord in children (Figures 1 and 2). Other exposure to mite, molds, chemi- blood, indicating allergy-promot- studies do show associations of ex- cals and inhaled particles can elicit ing effects on susceptible children. posure to diesel exhaust particles and/or exacerbate allergic diseas- In a murine allergic asthma model, (DEP), NO2, ozone and particulate es. The best assessed among the long-term exposure to VOCs emit- matter (PM), with asthma, allergic indoor pollutants are volatile or- ted from polyvinylchloride (PVC) rhinitis or sensitization to aeroal- ganic compounds (VOCs) and en- flooring increased acute and lergens. These conflicting results vironmental tobacco smoke (ETS), chronic allergic lung inflammation. illustrate how exposure and con- which is a mixture of VOCs, carbon founding factors, e.g. genetic pre- monoxide and solid particles. In OUTDOOR RISK FACTORS disposition, lifestyle and nutrition LINA (Lifestyle and environmen- A high degree of traffic and urban- interact closely in switching from tal factors and their Influence on ization are hallmarks of Western health to disease (Figure 3). Apart Newborns Allergy risk) birth co- civilization. A recent meta-analy- from direct effects of outdoor pol-

Environmental risk factors for allergy: outdoor/indoor pollution and climate change 121 Global atlas oF allergy

Figure 1 Modification induced by anthropogenic pollutants to pollen allergens. - Epidemiology and risk factors S ection B

Figure 2 Climate change impact on the ecosystem of pollen-producing plants.

122 Environmental risk factors for allergy: outdoor/indoor pollution and climate change Global atlas oF allergy

Figure 3 The complex interplay between host and environmental factors leading to allergic diseases: anthropogenic factors can act direct increasing susceptibility in genetic predisposed individuals or indirect by modifying/potentiating other biogenic factors. S ection B - Epidemiology and risk factors lutants on humans, pollen-produc- ver, exposure to Ambrosia pollen ciation with allergic sensitization ing plants are themselves subject might induce symptoms even in in European birth cohorts. J Allergy to modification by anthropogenic mugwort-sensitized patients due Clin Immunol 2014;133:767-776. pollutants (Figures 1 and 2). We to the high degree in inter-species e7. recently identified ambient ozone cross-reactivity. 5. Morgenstern V, Zutavern A, Cyrys as a major factor influencing al- J, Brockow I, Koletzko S, Kramer U et al. Atopic diseases, allergic lergen content and adjuvant lipid KEY REFERENCES sensitization, and exposure to traf- 1. Ring J, Akdis C, Behrendt H, Lauen- composition of birch pollen. This fic-related air pollution in children. er RP, Schaeppi G, Akdis M, and illustrates how anthropogenic Am J Respir Crit Care Med 2008;177: environmental factors, via their participants of the Global Allergy 1331-1337. effect on the allergen carrier, can Forum, Davos 2011. Davos Decla- ration: Allergy as a global problem. 6. Fuertes E, Standl M, Cyrys J, Ber- indirectly influence the health of del D, von Berg A, Bauer CP et al. Allergy 2012;67:141-143. allergic patients. A longitudinal analysis of associ- 2. Weisse K, Lehmann I, Heroux D, ations between traffic-related air CLIMATE CHANGE RELATED Kohajda T, Herberth G, Roeder S et pollution with asthma, allergies RISKS al. The LINA cohort: indoor chemi- and sensitization in the GINIplus cal exposure, circulating eosinophl/ Global warming is associated and LISAplus birth cohorts. Peer J basophil (Eo/B) progenitors and 2013;1:e193. with elevated CO2 levels and pro- early life skin manifestations. Clin 7. Beck I, Jochner S, Gilles S, McIntyre longed vegetation periods. This, Exp Allergy 2012;42:1337-1346. in turn, causes prolonged flower- M, Buters JTM, Schmidt-Weber C, 3. Boenisch U, Boehme A, Kohajda T, ing seasons, which might increase et al. High environmental ozone Moegel I, Schuetze N, von Bergen levels lead to enhanced allergenici- the load of allergenic pollen. The M et al. Volatile organic compounds ty of birch pollen. PLoS One 2013;8: aggressive spreading of allergen- enhance allergic airway inflam- e80147. ic neophytes, such as Ambrosia mation in an experimental mouse 8. Ziello C, Sparks TH, Estrella N, Bel- artemisiifolia, in southeastern and model. PLoS One 2012;7: e39817. monte J, Bergmann KC, Bucher E, parts of middle Europe already 4. Gruzieva O, Gehring U, Aalberse R, et al. Changes to airborne pollen led to de novo sensitizations in Agius R, Beelen R et al. Meta-anal- counts across Europe. PLoS One the exposed populations. Moreo- ysis of air pollution exposure asso- 2012;7: e34076.

Environmental risk factors for allergy: outdoor/indoor pollution and climate change 123 Global atlas oF allergy

Measuring exposure 4b to environmental airborne allergens

Isabella Annesi-Maesano French Institute of Health and Medical Research and UPMC Sorbonne Universités Paris, France

A key factor for the development of respiratory allergy is the con- Key messages tact between the respiratory or- gan and inhaled air containing the • Precise assessments of allergen concentrations is needed to allergens. Airborne allergens can define the exposure thresholds inducing sensitization, symptoms be found in a variety of sources and exacerbations of allergic diseases (Table 1). The risks of respiratory • The risks of respiratory allergy or elicitation of symptoms may be allergy or elicitation of symptoms decreased by reducing exposure may be decreased by reducing ex- • Control measures should be based on monitoring of allergen posure. Control measures should exposure performed according to well-defined and validated be based on allergen exposure methods monitoring performed according to well-defined and validated - Epidemiology and risk factors methods. in an air sample. A dust sample is modified ELISA using an amplifica- collected from the bed, carpet or tion of the generated colorimetric To measure exposure to airborne sofa by vacuuming a square yard signal. allergens, it is imperative to report

S ection B area of the bed/carpet/sofa per the presence of the sources of al- The prevalent outdoor allergens 2 minutes with a vacuum clean- lergens (mite counts, presence of are pollens and molds. Usually, er with a collection device. The pets), because allergen levels can pollen and mold counts are as- presence of allergens is quantified stay high when there are no sourc- sessed,and not their derived aller- with an ELISA test. Recently, an es or their number is low. gens. alternative wipe sampling method The choice of optimal procedures has been implemented to collect A pollen count is nothing more depends on the setting and ob- allergens from floor dust, where than a measurement of how much jectives of allergen monitoring allergens are measured by a re- pollen is in the air. It is expressed (Figure 1): epidemiological (pop- al-time quantitative PCR meth- in terms of a concentration of pol- ulation) studies on exposure-re- odology. However, methods using len in the air in a specific area at sponse relation, intervention settled dust might not provide ac- a certain point in time. The exact studies, diagnosis and follow-up of curate measurements of inhaled measure is grains of pollen per cu- individual patients, hazard identi- allergens. To measure airborne bic meter over a 24 hour period. fication for disease clusters, iden- allergens in the air, a technique Mold counts, like pollen counts, tification of cases of “new allergy”, has been developed that involves are a measurement of how many as part of routine monitoring or of collecting an integrated total mold spores are in the air in a a health surveillance program. suspended particulate sample certain area at any given point in Indoor airborne allergen levels through an impactor. Extracts of time. Monitoring pollen and mold may be assessed in settled dust or air samples are then analyzed by a counts on a daily basis during the

124 Measuring exposure to environmental airborne allergens Global atlas oF allergy

TABLE 1 Common airborne allergens and possible reaction(s)

Allergens Where, when

Pollen Outdoors Lpl p 1, Phl p5, Cyn d1, Amb a Spring/summer/autumn 1, Bet v ...

Both indoors (perennial) and outdoors (seasonal) . Mold Indoors, molds can be found in any moist, Alt 1, Cla 1 ... dark place. Outdoors, mold results from vegetation degradation. Mold floats easily in the air.

Indoor House Dust mite (HDM) Found in house dust, mattresses, bedding, S ection B Dermatophagoïdespteronyssi- upholstered furniture, carpets and cur- nus (European HDM), Dermato- tains phagoïdes farina (American HDM feed on shedded flakes of skin

HDM), Blomia tropiclais. - Epidemiology and risk factors Derp 1, Derf 1, Blo... HDM thrive in warm and humid environments.

Pets Indoor Major allergens are proteins secreted by oil glands in the animals' skin and shedded in dander as well as saliva proteins, which Cat (Feld1), Dog (Can1) sticks to the fur when the animal licks it- self. Urine is also a source of allergens. When the substance carrying the allergens dries they become airborne

Indoor/occupational Hamster, squirrel,rabbit Urine is the major source of allergens from these animals.

Pests Urine is the major source of allergens from Mouse, rat, these animals. (Mus m1, Rat 1)

Cockroach Tiny protein particles shed or excreted by- Blatella germanica cockroaches (German cockroach) (Bla g 1)

Measuring exposure to environmental airborne allergens 125 Global atlas oF allergy

seasons when they are present is one of the most proactive steps to Results in view of monitoring control asthma and allergies.Pol- len and mold counts are collected Allergen quantification using a special sampling trap that is typically placed on a rooftop Procedure several stories above the ground (Figure 2). The device has a sticky Sampling methods surface that collects grains of pollen and mold spore from the air. Exposure assessment strategy Specific pollen and mold are recognized using an electronic micro- Definition of objectives and setting scope. Recent data have shown that pollen and mold counts do not repre- Figure 1 Stepwise selection process of methods and tools of allergen sent allergen exposure. Air can be assessment (modified from ref. 1) sampled for pollen and mold allergens with a high-volume cascade impac to requipped with stages for particulate matter (PM)>10 µm, 10 µm>PM>2.5 µm, and 2.5 µm>PM>0.12 µm. Allergenis de- termined with specific ELISA. Precise assessment of allergen concentrations is needed to define the exposure thresholds inducing sensitization, symptoms and exac- - Epidemiology and risk factors erbations of allergic diseases.

KEY REFERENCES

S ection B 1. Raulf-Heimsoth M, Buters J, Chap- man M, Cecchi L, de Blay F, Doekes G, et al. Monitoring of occupational and environmental aeroallergens- EAACI Position Paper. Allergy (in press) 2. Polzius R, Wuske T, Mahn J. Wipe test for the detection of indoor allergens. Allergy 2002;57:143-145. 3. Krop EJ, Jacobs JH, Sander I, Raulf-Heimsoth M, Heederik DJ. Allergens and β-Glucans in Dutch Homes and Schools: Character- izing Airborne Levels. PLoS One 2014;9: e88871. 4. Buters JT, Weichenmeier I, Ochs S, Pusch G, Kreyling W, Boere AJ et al. The allergen Bet v 1 in fractions Figure 2 Pollen and mold assessment: A: pollen trap; B and E: ELISA of ambient air deviates from birch measurement; C and D:microscopic evaluation of pollens and molds. pollen counts. Allergy 2010;65:850- 858.

126 Measuring exposure to environmental airborne allergens Global atlas oF allergy

Environmental risk 4c factors for allergy: food

Scott H. Sicherer Icahn School of Medicine New York, USA

The prevalence of food allergy appears to have increased. Envi- Key messages

ronmental factors must account S ection B for the apparent rise, not genetic • Environmental risk factors that may influence food allergy, predisposition. An over-arching together with atopy, include the “hygiene hypothesis”, vitamin D effect may be the immune dys- insufficiency, reduced consumption of healthful dietary fats and regulation attributable to the antioxidants, and obesity - Epidemiology and risk factors “hygiene hypothesis”. Additional • Theories suggesting early infant ingestion of food allergens as a theories to explain increased ato- risk for allergy have been substantially disprove • Early infant avoidance of food allergens could be a risk factor py, with food allergy as a bystand- for allergy due to bypassing oral tolerance during a period of er, include vitamin D insufficiency sensitizing cutaneous exposure attributable to greater use of sun- • Food allergy is the result of a complex interaction of genetic, screens and less time outdoors, immunologic and environmental influences, indicating a reduced consumption of healthful challenge for identifying effective prevention strategies omega-3-polyunsaturated fatty acids and antioxidants, and increased obesity, which may repre- to prevent exposure to food aller- routes of exposure may be strong- sent an inflammatory state. How- gens for a presumed immature and ly sensitizing: for example, despite ever, for environmental influence allergy-prone immune system. ingestion of raw fruits, many per- on food allergy in particular, the sons develop pollen-food related role of exposure to food proteins However, mounting studies sug- syndrome caused by inhalation becomes relevant. gest that extended avoidance of food allergens may be a risk factor of food-homologous proteins in Probably as a response to early for food allergies, rather than pre- pollens, bypassing oral tolerance. studies suggesting that infants ex- ventative. Why would this be? One Similarly, it was suggested that posed to whole cow milk proteins possibility is that earlier exposure topical exposure, especially via in- were at higher risk of milk aller- allows for oral tolerance. For ex- flamed skin, i.e., atopic dermatitis, gy compared to those receiving ample, in a study of the rate of pea- during abstinence from oral expo- breast milk or hypoallergenic for- nut allergy among Jewish children sure could be a sensitizing route mula, among other observations, in the United Kingdom compared bypassing oral tolerance (Figure various expert panels and profes- to Israel, there was a ten-fold high- 2). Additional evidence is the ob- sional organizations suggested er rate of allergy in the UK, where servation that household con- avoidance of allergens for infants early peanut consumption was sumption rates of peanut, particu- at risk. Some guidelines included comparatively very low (Figure 1). larly messy products that increase allergen avoidance during preg- Timing of ingestion may only be environmental exposure, are a risk nancy and lactation. The goal was part of the story. Non-ingestion factor for peanut allergy, especial-

Environmental risk factors for allergy: food 127 Global atlas oF allergy

Figure 1 Earlier consumption of peanut was associated with a lower rate of peanut allergy. A - Prevalence of peanut allergy in children 4-18 years; B - Peanut protein consumption 8-14 month; United Kingdom n=5171; Israel n= 5615. (Data from Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR et al. B Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008; 122(5):984-91. Reprinted from J Allergy Clin Immunol, 129/5, Lack G. Update on risk factors for food allergy, 1187-1197, Copyright 2012, with permission from Elsevier.)

Figure 2 Cutaneous exposure to a food allergen, especially to inflamed skin, may be a sensitizing route. With a concomitant lack of oral exposure to induce tolerance, the effect could - Epidemiology and risk factors be promoting food allergy. (Reprinted from J Allergy Clin Immunol, 129/5, Lack G. Update on risk factors for food allergy, 1187-1197, Copyright 2012, S ection B with permission from Elsevier.)

ly if the infant has not ingested senting a challenge for identifying 3. Fox AT, Sasieni P, Du Toit G, Syed peanut early. Prior recommenda- prevention strategies (Figure 4). H, Lack G. Household peanut con- tions to avoid food allergens dur- sumption as a risk factor for the ing pregnancy, breastfeeding and KEY REFERENCES development of peanut allergy. J Al- for children during weaning have 1. Sicherer SH, Sampson HA. Food allergy Clin Immunol 2009;123:417- been substantially rescinded, allergy: Epidemiology, pathogenesis, 423. though counter-examples remain diagnosis, and treatment. J Allergy 4. Fleischer DM, Spergel JM, Assa'ad (Figure 3) and more studies are Clin Immunol 2014;133:291-307. AH, Pongracic JA. Primary preven- needed. Ultimately, the environ- 2. Lack G. Update on risk factors for tion of allergic disease through nu- mental and genetic determinants food allergy. J Allergy Clin Immunol tritional interventions. J Allergy Clin of food allergy are complex, pre- 2012; 129:1187-1197. Immunol Pract 2013;1:29-36.

128 Environmental risk factors for allergy: food Global atlas oF allergy S ection B - Epidemiology and risk factors Figure 3 Although some studies suggest maternal ingestion of allergens during pregnancy or lactation does not increase the risk of sensitization/food allergy, there remains some controversy and more studies are needed. Here, a study of high risk infants suggests higher maternal ingestion of peanut during pregnancy is related to higher peanut IgE antibody levels in early infancy (P trend < 0.001). (Reprinted from J Allergy Clin Immunol, 126/6, Sicherer SH, Wood RA, Stablein D, et al. Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants, 1191-1197, Copyright 2010, with permission from Elsevier.)

Figure 4 A complex interplay of genetic, immunologic and environmental influences likely conspires to result in food allergy, here with peanut as an example. (Reprinted from J Allergy Clin Immunol, 120/3, Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and approaches for an apparent epidemic, 491-503, Copyright 2007, with permission from Elsevier.)

Environmental risk factors for allergy: food 129 Global atlas oF allergy

Environmental risk 4d factors for ALLERGY: home environment

Thomas A.E. Platts-Mills University of Virginia Charlottesville, USA

The rise in indoor living and the rise in asthma Key messages The dramatic rise in electronic indoor entertainment from 1950 to • During the last half of the 20th century, the perennial indoor 2000 paralleled the rise in asth- allergens progressively increased in importance and became the ma among children. The resulting primary allergens related asthma worldwide changes in lifestyle led to both a • While the individual’s home is an important site of exposure, it major increase in time spent in- is now clear that exposure to indoor allergens in other homes doors and progressive “improve- or schools can play an important role in sensitization and in ments” in homes. These changes symptoms not only allowed accumulation • Comparing sensitization of children with asthma in different of allergens in fitted carpets, so- communities makes it clear that the community prevalence of a fas, bedding, etc. but in humid cli- particular allergen may be as important as the specific levels in - Epidemiology and risk factors mates allowed abundant growth the child’s home of dust mites. Over this same pe- • Although dust mites are ubiquitous in damp climates, they may be riod, almost all studies have shown completely absent in ultra-dry environments such as Norbotten in Sweden and apartments in Chicago S ection B strong associations between sensitization to indoor allergens and asthma in children over 5 years old and young adults (Table 1). The explanation for that find- is present in schools and homes ing appears to be that relevant without a cat. Thus, exposure Exposure in the home and exposure to mite allergens can of children without a cat is suffi- in the community as a occur in other houses. In cities cient to cause sensitization. cause of sensitization in the UK or coastal Australia Children spend up to 95% of their most other houses in the com- Relationship of time at home, at school or in other munity will contain mites. In sensitization to Asthma enclosed spaces. Initially it was Northern Sweden or Chicago, Although sensitization to indoor assumed that the home had to be very few children become aller- allergens is strongly associated the primary site of sensitization; gic to mites because the houses with asthma this relationship is however, two findings have con- are too dry for mite growth. not simple. Sensitization as judged fused the simple message. 2. Many but not all studies on cat by skin prick tests is common in 1. Studies designed to avoid expo- exposure have found less sensi- non-asthmatic children and also sure to dust mite carried out in tization to cats among children may be common in rural villages in Manchester and Sydney have with higher exposure (Figure 1). Africa or Ecuador, where none of not succeeded in preventing For cat allergens, it is now clear the children have allergic asthma. sensitization to this allergen. that Fel d 1 on dander particles However, one of the striking fea-

130 Environmental risk factors for asthma: home environment Global atlas oF allergy

TABLE 1 The allergens related to asthma

Source Particles Allergen MW (kDa) Structure Der p 1 25 Der p 2 16 Der p 10 33

Dust mite Der p 11 102 Bla g 1 47 Bla g 2 39 Bla g 4 21

Cockroach Frass Bla g 5 23 Fel d 1 10 Fel d 2 69 Fel d 4 10 S ection B

† Cat Cat IgA 200 Alt a 1 17 - Epidemiology and risk factors Alt a 2 22

Alt a 3 14 Alternaria

Lol p 1 17*

Grass The allergens related to asthma are predominantly in the molecular weight range 15 KD to 50 KD, and most of the major allergens are present as a significant proportion (>10%) of the extracts used for skin testing or in vitro assays (www.allergen.org) However, the sources of cat, mite, cockroach or mold allergens generally do not become airborne, and the allergens themselves are too large to be volatile because the saturated vapor pressure of molecules >10,000 MW approaches zero. Thus all relevant exposure is in the form of particles. The aerodynamic properties of the particles determine how long they remain airborne and their volume decides how much allergen they can carry (5). †Glycosylated with alpha-gal; *Glycosylated with MUXF3 tures of asthma among children tween the titer of IgE antibodies sensitization has shown a strong and adults in westernized or post to mite and the impact of commu- correlation between asthma and hygiene societies is that titers of nity acquired rhinovirus infection the perennial and predominantly IgE antibodies to mite, cockroach, on wheezing (Figure 2). indoor allergens. In rural settings cat and Alternaria may be very in Africa, Ecuador, Nepal, etc., sen- high i.e. ≥30 IU/ml. We have seen Conclusions sitization as judged by skin prick highly significant association be- The increase in asthma has been tests may be present, but wheez- tween the titer of IgE antibodies documented as “wheezing” in ing is more likely to correlate with to mite or cat and the severity of ISAAC, as use of inhalers, or as evidence of Ascaris or other par- asthma (Figure 2). Furthermore, presentation with acute asthma asitic infections. In recent stud- studying children in Costa Rica, either to ED or hospital. In each ies, in Costa Rica, New Zealand, we found a strong association be- of these settings, evaluation of Ghana, Ecuador and Norbotten,

Environmental risk factors for asthma: home environment 131 Global atlas oF allergy

there is consistent evidence that 25 Sensitized to Cat Allergen the western model of asthma re- IgG > 125 lates to higher titers of IgE anti- 20 bodies to one or more of the perennial allergens. Thus, overall we have a model where, increased 15 time spent indoors in overheat- ed and under ventilated buildings 10 leads to sensitization to the pre- dominant allergen in the community, which may be derived from 5

N u m b e r o f C h i l d n mites, cockroaches, or animal dander. The major rise in prevalence 0 of asthma in children is most likely < 0.69 0.7-1.69 1.7-4.39 4.4-22.9 23-106 106-3840 to be due to the combination of in- (n=37) (n=38) (n=38) (n=37) (n=38) (n=38) creased exposure to indoor allergen and the associated sedentary Exposure to Cat (mcg Fel d 1/g) lifestyle. Figure 1 Prevalence of sensitization to cat allergens and of IgG antibodies to Fel d 1 for six groups of middle school children (age 11 years) with a wide KEY REFERENCES range of concentrations of Fel d 1 in the dust from their homes. In the highest 1. Sears, M.R., Greene JM, Willan AR, exposure groups, the prevalence of IgG to Fel d 1 was higher while the Wiecek EM, Taylor DR, Flannery prevalence of sensitization was significantly lower. Reprinted( from The Lancet, EM, Cowan JO, Herbison GP, Silva 357, Platts-Mills T,Vaughan J, Squillace S, et al. Sensitisation, asthma, and a modified PA, Poulton Ret al. A longitudinal, Th2 response in children exposed to cat allergen: a population-based cross-sectional population-based, cohort study study, 752-756, Copyright 2001, with permission from Elsevier.) of childhood asthma followed to adulthood. N Engl J Med 2003;349: A RV Negative B RV Positive 1414-1422. 1.0 1.0 2. Erwin, E.A., Wickens K, Custis NJ, - Epidemiology and risk factors Siebers R, Woodfolk J, Barry D, Crane J, Platts-Mills TA et al Cat

eez e 0.8 0.8 and dust mite sensitivity and toler- h h ance in relation to wheezing among W S ection B t children raised with high exposure

rre n to both allergens. J Allergy Clin Im-

u 0.6 0.6 C munol 2005;115:74-79. f C

o 3. Platts-Mills, T., Vaughan J, Squillace ili t y 0.4 0.4 S, Woodfolk J, Sporik R. Sensitisa- a b a

b tion, asthma, and a modified Th2

Pr o response in children exposed to cat allergen: a population-based 0.2 0.2 cross-sectional study. Lancet 2001;357:752-756. 4. Perzanowski , M.S., Ronmark E, 0.0 0.0 Platts-Mills TA, Lundack B. Effect of 1 10 100 1000 1 10 100 1000 cat and dog ownership on sensiti- IgE to Mite (IU/ml) IgE to Mite (IU/ml) zation and development of asthma Figure 2 Probability of current wheeze based on increasing titers of IgE among preteenage children. Am J antibodies to D. pteronyssinus in children with negative tests for rhinovirus Respir Crit Care Med 2002;166:696- by using real time PCR (A) compared to children with positive test results for 702. rhinovirus (B). (Reprinted from J Allergy Clin Immunol, 129/6, Soto-Quiros M, Avila 5. Platts-Mills TA, Woodfolk JA. Al- L, Platts-Mills TA, et al, High titers of IgE antibody to dust mite allergen and risk for lergens and their role in the aller- wheezing among asthmatic children infected with rhinovirus., 1499-1505, Copyright gic immune response. Immunol Rev 2012, with permission from Elsevier.) 2011;242:51-68.

132 Environmental risk factors for asthma: home environment Global atlas oF allergy

Environmental risk 4e factors for allergy: working environment

Roy Gert van Wijk Erasmus Medical Center Rotterdam, Netherlands

Environmental agents at the work place may lead to several aller- Key messages

gic and non-allergic conditions. S ection B Occupational rhinitis or asthma, • Sensitizers (high and low molecular weight allergens, HMW, but also occupational chronic LMW) and irritants may lead to work-related respiratory cough may develop upon expo- disease. There is overlap between the different categories of sure to agents at work. Sensitizing eliciting agents. Sensitizers may also have irritating properties. - Epidemiology and risk factors agents - in most cases high molec- Irritants may lead to new onset occupational disease, but also to ular weight (HMW) allergens, and worsening of pre-existing disease sometimes low molecular weight • The level of exposure is considered as the key factor for the (LMW) allergens – may induce an development of occupational rhinitis and asthma IgE mediated allergic reaction, re- • Atopy is a risk factor for the development of IgE-mediated sponsible for allergic occupational sensitization to HMW allergens. However, the presence of atopy rhinitis and asthma. Less frequent- cannot be used to identify and exclude susceptible workers ly, single or multiple exposures to • The influence of smoking on development of occupational allergy irritants will lead to non-allergic may dependent on the specific allergens involved irritant-induced occupational rhinitis or asthma. Apart from these occupational diseases caused by work, environmental stimuli at disease, but also to worsening of vironment, and to a lesser extent work may also lead to worsening pre-existing disease. for development of occupational of pre-existent rhinitis, asthma or The level of exposure is consid- rhinitis or asthma. The presence cough (work exacerbated rhinitis, ered as the key factor for the de- of atopy, however cannot be used asthma or cough). Figure 1 shows velopment of occupational disor- to identify and exclude suscepti- examples of allergens and stim- ders. The risk increases with high ble workers. Smoking has been as- uli responsible for the different exposure. Less is known of the sociated with some work-related work-related disorders. Chronic impact of exposure pattern (dura- allergies such as allergies to bell cough at work can be considered tion, continuous or intermittent, peppers and platinum salts, but not as a separate work-related disor- peak exposures). der. Table 1 shows the occupations in others. Possibly, the influence of and causes of work-related chron- Apart from exposure, host factors smoking on development of occu- ic cough. There is some overlap may determine the risk of occupa- pational allergy dependents on the between the different categories tional rhinitis and asthma. Atopy is specific allergens involved. Finally, of eliciting agents. Sensitizers may a risk factor for the development genetic factors may be associated also have irritating properties. Ir- of IgE-mediated sensitization to with increased susceptibility to oc- ritants may lead to occupational HMW allergens in the working en- cupational asthma.

Environmental risk factors for allergy: working environment 133 Global atlas oF allergy

Work-related rhinitis or asthma

Occupational Work exacerbated rhinitis or asthma rhinitis or asthma

Allergic occupational Non-allergic rhinits or asthma Irritant-induced rhinits or asthma

HMW allergens Commonly reported agents Agents most frequesntly Flour dust with irritating properties reported Enzymes Isocyanates Gases and mists Latex Cleaning agents Fumes Proteins from animals Chlorine Inorganic dusts, fibres Proteins from fish, crustaceans Metam sodium Organic aerosols shelfish Ammonia Organic chemicals Pollen and other proteins Diesel exhaust Physical stimuli Solvents LMW allergens Sulfur dioxide Persufate Dinitrogen tetraoxide Metals (salts): chromium, nickel, KEY REFERENCES platinum 1. Baur X, Bakehe P, Vellguth H. Isocynates Bronchial asthma and COPD due Acid anhydrides to irritants in the workplace - an Acrylates evidence-based approach. J Occup Soldering flux (colophony) Med Toxicol 2012;7:19. Uncertain components Figure 1 Causes of work-related 2. Gautrin D, Malo JL. Risk fac- Wood dust (red celar, oak, iroko) rhinitis or asthma. tors, predictors, and markers for work-related asthma and

- Epidemiology and risk factors rhinitis. Curr Allergy Asthma Rep 2010;10:365-372. TABLE 1 3. Lemiere C, Begin D, Camus M, Causal agents of work related chronic cough Forget A, Boulet LP, Gerin M. Oc- S ection B Occupation Agents cupational risk factors associated with work-exacerbated asthma Miners Methylmethacrylate in Quebec. Occup Environ Med Cement and glass bottle production Aliphatic polyamines 2012;69:901-907. Construction workers Grain and flour mills 4. Malo JL, Chan-Yeung M. Agents causing occupational asthma. J Al- Farming workers Spices lergy Clin Immunol 2009;123:545- 550. Food industry Dust due to World Trade Center Mushroom factory collapse 5. Moscato G, Pala G, Cullinan P, Folletti I, Gerth van Wijk R, Pignat- Wood industry Vapor Gases Dusts Fumes ti P et al. EAACI Position Paper on Dental technicians Cattle and swine confinement farms assessment of cough in the workplace. Allergy 2014;69:292-304. Fire-fighters Cleaning products 6. Moscato G, Vandenplas O, Van Bakery Second-hand smoking Wijk RG, Malo JL, Perfetti L, Quirce S, et al. EAACI position paper on Mechanic and repair jobs Reproduced with permission from Mosca- occupational rhinitis. Respir Res Spice factory to G, Pala G, Cullinan P,et al. EAACI Posi- 2009;10:16. tion Paper on assessment of cough in the 7. Tarlo SM. Irritant-induced asthma Greenhouse workplace. Allergy 2014; 69: 292–304, in the workplace. Curr Allergy Asth- Cleaners with permission from Willey Blackwell. ma Rep 2014;14:406.

134 Environmental risk factors for allergy: working environment Global atlas oF allergy

Risk factors for childhood 4f asthma: viral infection and allergic sensitization

Frederick J. Rubner Robert F. Lemanske Jr. University of Wisconsin Madison, Wisconsin

Asthma is the most prevalent chronic disease of childhood. Giv- Key messages

en its significant health as well as S ection B socioeconomic burden, investiga- • Preschool viral wheezing illnesses are risk factor for the tors around the world have sought development of childhood asthma, with human rhinovirus (HRV) to define environmental and ge- having the greatest impact netic factors that contribute to • Aeroallergen sensitization in the first two to three years of life - Epidemiology and risk factors asthma inception in early life. One further increases the risk of developing asthma in children, who important environmental factor have viral-induced wheezing demonstrable in multiple studies • Rhinovirus wheezing illnesses may lead to asthma development has been respiratory tract infec- through two pathways, dependent and independent on allergic tions. From a genetics perspective, sensitization atopy and genetic variation at the 17q21 locus (that appears to be independent of atopy), are risk in the first three years of life was the unfolded protein response, factors for asthma development. the virus most significantly asso- it is possible that alterations in Interestingly, both appear to be ciated with the development of these pathways may further independent, at least in part, on an- asthma at age 6 years (Figure 1). fluence host immune response to tecedent preschool human rhino- Mechanisms responsible for these viral infections at critical times in virus (HRV) wheezing illnesses. developments are currently being the lung development. Recently, intensely evaluated. Wark et al. infections with HRV-C have been Early childhood found that cells from asthmatic pa- noted to be associated with more respiratory viral tients had decreased production of significant clinical illnesses that infection and asthma in both type I and III interferons, two may be of even greater severity in childhood important cytokines in the host’s atopic children. Although early childhood respira- innate immune response to viral tory syncytial viral (RSV) infec- infections. Recently, Caliskan and Combined viral infection tions have been documented to colleagues demonstrated that al- and aeroallergen contribute to future asthma risk, lelic variation at a highly replicable sensitization recent advances in molecular diag- genetic locus for asthma was asso- The relationship of atopy with the nostic testing have enabled inves- ciated with significant asthma risk subsequent development of asth- tigators to establish a relationship only in children who wheezed with ma is widely recognized. Aeroal- between HRV wheezing illnesses HRV (not RSV) infections in early lergen sensitization in the first 2 and asthma. In an evaluation of a life. Since genes contained within to 3 years of life has been report- high risk birth cohort, Jackson et this locus have functions that in- ed to be a risk factor for the sub- al. found that infection with HRV volve calcium membrane flux and sequent development of asthma.

Risk factors for childhood asthma: viral infection and allergic sensitization 135 Global atlas oF allergy

Figure 2 Aeroallergen sensitization without documented Figure 1 In an a high risk birth cohort infection with preschool RV wheezing increases asthma risk by age six HRV in the first three years of life was the virus most years. If both RV wheezing and aeroallergen sensitization significantly associated with the development of asthma at are present at age three, the risk of developing asthma by age 6 years. age 6 years is substantially increased.

The development of multiple early found that allergic sensitization type-attributable increased risk sensitizations increases not only is more likely to precede viral-in- is totally independent of allergic the risk of developing childhood duced wheezing. Moreover, HRV sensitization (atopy). asthma, but its clinical severity in wheezing illnesses were the most terms of hospital admission rates likely infections accounting for Conclusion as well. this temporal developmental se- At least two distinct mechanistic quence. Allergic sensitization may pathways may predispose chil- Preschool viral wheezing illness- increase lower airways inflamma- dren to asthma (Figure 4), both es and the development of aller- tion and symptoms based on the dependent on antecedent HRV - Epidemiology and risk factors gic sensitization can both inde- ability of IgE receptor numbers wheezing illnesses. The first path- pendently increase asthma risk. and bridging to be associated with way, termed 17q21, appears to be The presence of both can further reduced dendritic cell production dependent on an asthma suscepti- influence the development of bility locus and totally independ- S ection B of type I and type III interferons asthma, as demonstrated by data with decreased viral host defense ent of the presence of allergic sen- generated independently in two (Figure 3). sitization. The second pathway, high-risk birth cohorts. In one of termed FcεRI, is dependent on the high-risk birth cohort, aeroal- Influence of HRV wheezing the development of allergic sensi- lergen sensitization without doc- illnesses independent of tization. Continued evaluation of umented preschool RV wheezing atopy mechanisms responsible for these increased asthma risk by age six Genome-wide association studies pathways hopefully will provide years (OR = 3.4) (Figure 2). If both of childhood asthma risk have re- insight into disease treatment and RV wheezing and aeroallergen vealed a high susceptibility locus prevention strategies. sensitization were present at age on chromosome 17q21. Genetic three, the risk of developing asth- variation in this 17q21 region has KEY REFERENCES ma by age 6 years was substantial- been associated with increased 1. Jackson DJ, Gangnon RE, Evans ly increased (OR = 80). MD, Roberg KA, Anderson EL, Pap- childhood asthma risk but not pas TE et al. Wheezing rhinovirus Jackson et al. longitudinally eval- with atopy. Caliskan and col- illnesses in early life predict asthma uated which development occurs leagues demonstrated that this development in high-risk children. first: allergic sensitization predis- association is in fact limited only Am J Respir Crit Care Med 2008;178: posing to viral-induced wheez- to children who had HRV wheez- 667-672. ing, or the reverse. Using a four ing illnesses in the first three years 2. Sly PD, Boner AL, Bjorksten B, Bush A, stage statistical model, the study of life.3 Importantly, this geno- Custovic A, Eigenmann PA et al. Early

136 Risk factors for childhood asthma: viral infection and allergic sensitization Global atlas oF allergy

identification of atopy in the predic- Hypothesis: Allergy Inhibits Innate Immune tion of persistent asthma in children. Responses Through Fc RI Lancet 2008;372:1100-1106. Allergen Allergen 3. Caliskan M, Bochkov YA, Krein- HRV er-Moller E, Bonnelykke K, Stein Cross-linking of Fc RI MM, Du G et al. Rhinovirus wheez- Expression of Fc RI ing illness and genetic risk of childhood onset asthma. N Engl J Med 2013;368:1398-1407. PBMCs 4. Jackson DJ, Sykes A, Mallia P, John- ston SL. Asthma exacerbations: Ori- gin, effect, and prevention. J Allergy (Durrani et al, JACI 130:489, 2012) Clin Immunol 2011;128:1165-1174. IFN 5. Jackson DJ, Evans MD, Gangnon Type I & Type III IFN Type I & Type III IFN RE, Tisler CJ, Pappas TE, Lee WM et al. Evidence for a causal relationship between allergic sensitization More frequent and severe virus-induced wheezing and rhinovirus wheezing in early Prolonged inflammation life. Am J Respir Crit Care Med 2012; Possible airway remodeling and/or loss of lung function 185:281-285. S ection B Figure 3 The process of allergic sensitization may influence innate immune 6. Durrani SR, Montville DJ, Pratt AS, responses to human rhinovirus (HRV) infection. Incubation of peripheral blood Sahu S, Devries MK, Rajamanickam mononuclear cells (PBMCs) with HRV without cross linking of the high affinity V et al. Innate immune responses

receptor for IgE antibody (FcεRI) (left panel) results in decreased production to rhinovirus are reduced by the - Epidemiology and risk factors of type I and type III interferons (IFN). Following cross-linking of this receptor high-affinity IgE receptor in allergic (right panel) this decrease is further reduced. asthmatic children. J Allergy Clin Im- munol 2012;130:489-495. 7. Wark PA, Johnston SL, Bucch- ieri F, Powell R, Puddicombe S, Laza-Stanca V et al. Asthmatic bronchial epithelial cells have a de- ficient innate immune response to infection with rhinovirus. J Exp Med 2005;201:937-947. 8. Cox DW, Bizzintino J, Ferrari G, Khoo SK, Zhang G, Whelan S et al. Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions. Am J Respir Crit Care Med 2013;188:1358-1364. 9. Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Im- munol 2007;119:1105-1110. 10. Simpson A, Tan VY, Winn J, Sven- sen M, Bishop CM, Heckerman Figure 4 Two distinct mechanistic pathways dependent on antecedent HRV DE et al. Beyond atopy: multiple wheezing illnesses predispose children to asthma. The first pathway, termed patterns of sensitization in rela- 17q21, appears to be dependent on an asthma susceptibility locus and totally tion to asthma in a birth cohort independent of the presence of allergic sensitization. The second pathway, study. Am J Respir Crit Care Med termed FcεRI, is dependent on the development of allergic sensitization. 2010;181:1200-1206.

Risk factors for childhood asthma: viral infection and allergic sensitization 137 Global atlas oF allergy

Environmental risk 4g factors for allergy: helminth infections

Abena Firdaus Hermelijn Maria S. Amoah Hamid H. Smits Yazdanbakhsh Leiden University Medical Center, Leiden, The Netherlands

Over 1 billion people worldwide are infected with parasitic worms. Key messages Most of these individuals are found in tropical regions of the • In developing countries, large differences exist in the prevalence world, where such infections are of allergies between rural and urban areas as well as between linked to poverty and rural living. high and low socioeconomic status (SES) groups within urban Both helminths and allergens are areas potent inducers of T helper 2 (Th2) • Helminth infections, which are ubiquitous in rural areas and responses that lead to high levels among low-SES urban dwellers, drive T-helper 2 (Th2) responses of immunoglobulin (Ig) E, tissue • High levels of total IgE and allergen-specific IgE are seen in eosinophilia, mast cells as well as helminth-infected subjects, but these do not translate into skin the secretion of Th2 cytokines reactivity or clinical symptoms • Regulatory network induced by helminths and helminth-induced

- Epidemiology and risk factors such as interleukin (IL)-4, IL-5, IL-9 and IL-13. IgE cross-reactivity prevent the translation of Th2 responses into allergic disorders Despite the similar immunologi- • Allergen-specific IgE has limited diagnostic value for allergic cal profiles associated with both disease in helminth-endemic areas S ection B helminths and allergies, there is little overlap in the geographical distribution of these two health regulatory T and B cells, alterna- explain the inverse association problems. Moreover, in develop- tively activated macrophages and between helminth infection and ing countries, among urban popu- modified dendritic cells (Figure 2). allergy may involve helminth-in- lations of high socioeconomic sta- This leads to an anti-inflammato- duced IgE cross-reactivity. Cur- tus (SES), improved hygiene and ry environment that prevents the rent helminth infections are as- fewer infections have been linked down-stream effector phase of sociated with increased levels to an increase in allergic disor- Th2 responses associated with al- of allergen-specific IgE that do ders. Indeed, a number of studies lergic disorders. However, the tim- not translate into skin reactivity have found a negative association ing and duration of helminth infec- or clinical symptoms (Figure 3). between helminth infections and tion are key, since infections early Moreover, this helminth-induced allergic disorders among rural and in life and/or chronic infections are IgE appears to be of low affinity low SES urban populations within more effective in down-modulat- and does not lead to mast cell de- these countries (Figure 1). ing allergic disease. In addition, granulation. the species of helminth is also Mechanistically, chronic helminth In fact, in developing countries, an important determinant in the infections have been shown to in- strong correlations are observed modulation of allergic disorders. duce an immune regulatory net- between allergen-specific IgE and work in the host characterized by Another mechanism that might symptoms of allergy among urban

138 Environmental risk factors for allergy: helminth infections Global atlas oF allergy

populations of high SES. However, in rural populations as well as urban low SES groups, helminth-induced IgE cross-reactivity and regulatory networks may prevent the translation of allergen-specific IgE into skin reactivity or allergic symptoms (Figure 4). Therefore, allergen-specific IgE has limited diagnostic value for allergic disease in helminth-endemic areas. Future studies taking an interna- tional perspective will be essential Figure 1 Allergy field research in a helminth-endemic area on Flores Island, for our understanding of environ- Indonesia. The study showed an inverse association between current helminth mental risk factors and underlying infection and skin prick test positivity to house dust mite in a semi-urban mechanisms to develop new treat- population. (From Hamid F, Wiria AE, Wammes LJ, Kaisar MM, Djuardi Y, ments that can halt the allergy ep- Versteeg SA, Wahyuni S, van Ree R, Sartono E, Supali T, Yazdanbakhsh M. Risk idemic worldwide. Factors Associated with the Development of Atopic Sensitization in Indonesia. S ection B PLoS One. 2013 19;8(6) :e67064). KEY REFERENCES 1. Cooper PJ, Vaca M, Rodriguez A, Chico ME, Santos DN, Rodri- gues LC, et al. Hygiene, atopy and - Epidemiology and risk factors wheeze-eczema-rhinitis symptoms in schoolchildren from urban and rural Ecuador. 2014;69:232- CD1d Thorax 239. IL-10 TGFβ 2. Smits HH, Everts B, Hartgers FC, Yazdanbakhsh M. Chronic hel- Breg minth infections protect against al- cells lergic diseases by active regulatory processes. Curr Allergy Asthma Rep Effector 2010;10:3-12. T cells 3. Amoah AS, Obeng BB, Larbi IA, Ver- Glycoconjugates steeg SA, Aryeetey Y, Akkerdaas JH et al. Peanut-specific IgE antibodies in asymptomatic Ghanaian children possibly caused by carbohydrate determinant cross-reactivity. J Al- lergy Clin Immunol 2013;132:639- 647. 4. Mpairwe H, Webb EL, Muhangi L, Ndibazza J, Akishule D, Nampijja M et al. Anthelminthic treatment Figure 2 Helminths and their products induce an immune regulatory network during pregnancy is associated in the host characterized by regulatory T (Tregs), regulatory B cells (Bregs), with increased risk of infantile ec- alternatively activated macrophages (AAMΦ) and modified dendritic cells zema: randomised-controlled trial (immature dendritic cells [iDC] and regulatory dendritic cells [DCreg]). results. Pediatr Allergy Immunol. 2011;22:305-312.

Environmental risk factors for allergy: helminth infections 139 Global atlas oF allergy

Figure 3 Differences in the prevalence of mite sensitization when measured as IgE or as SPT among 5-16 year olds from three populations living in Ghana (urban and more rural areas of the Greater Accra region which is undergoing rapid urbanization) and on two Islands in Indonesia (semi-urban and rural parts of Flores Island as well as among high SES and low SES subjects living in an urban centre of Sulawesi Island). The data presented are from Hamid F, Wiria AE, Wammes LJ, Kaisar MM, Djuardi Y, Versteeg SA, Wahyuni S,van Ree R, Sartono E, Supali T, Yazdanbakhsh M. Risk Factors - Epidemiology and risk factors Associated with the Development of Atopic Sensitization in Indonesia. PLoS One. 2013 19;8(6) :e67064 as well as unpublished data from field studies in Ghana and Sulawesi, Indonesia.

S ection B Developing countries i. Groups with chronic helminth infection ii. Groups with no helminth infections

Cross-reactive High affinity biologically weak CD1d IgE IgE IgE IgE Strong IL-10 Weak Regulatory TGFβ Regulatory Network Network SPT SPT

Allergy Allergy Symptoms Symptoms

Figure 4 (i) In developing countries, the regulatory network induced by helminths and helminth-induced IgE cross- reactivity prevent the translation of Th2 responses into allergic disorders among groups with chronic helminth infections. (ii) In the same countries, among groups with no helminth infections, specific IgE translates into skin prick test positivity and allergy symptoms from field studies in Ghana and Sulawesi, Indonesia).

140 Environmental risk factors for allergy: helminth infections Global atlas oF allergy

Perinatal immune 5 development and its role in atopy development

Patrick G. Holt Telethon Kids Institute, The University of Western Australia and Queensland Children’s Medical Research Institute, The University of Queensland Queensland, Australia

Interest in the role of immune development as a risk factor for ato- Key messages

py was first stimulated by exper- S ection B imental studies on the sequelae • programming of long-term sensitization versus tolerance to of de novo exposure of immuno- allergens occurs in early life against a background of functional logically naïve animals to aeroal- immaturity within the immune system lergen. Such exposure triggered • slow postnatal maturation of immune functions increases - Epidemiology and risk factors an initial “default” response com- sensitization risk prising low-level Th2-immunity, • multiple cell types within the innate and adaptive immune system exhibit slow maturation kinetics in children, who subsequently including specific IgE production, develop atopy which was eventually terminated • postnatal maturation is driven by microbial signals, particularly by emergence of specific T-regu- from gut commensals latory cells (Tregs) that induced a • the trajectory for postnatal immune development is partially state of long-lived immunological present in utero, driven via signals present in the maternal tolerance, protecting the animals environment, including microbial exposures against sensitization at subsequent re-exposures. These findings served to focus human stud- (ii) the rate of postnatal matu- Following the advent of the Hy- ies on the etiology of atopy on the ration of Th-cell functional giene Hypothesis in the late life period (infancy), during which competence (as measured 1980s, interest has progressively the naïve immune system first en- by capacity to generate “bal- increased in the role of the gut mi- counters allergens. A number of anced” Th1/Th2 cytokine re- crobiome as the “driver” of postna- resultant observations attest to sponses) is slower in children tal development of immunocom- the validity of this approach: at high risk for allergy devel- petence. Recent findings suggest a link between postnatal devel- (i) data from birth cohorts (Fig 1) opment; demonstrate an initial induc- opment of immunity to organisms tion of aeroallergen-specific (iii) subsequent studies have ex- within the respiratory microbiome IgE in both atopic and non at- tended the range of cell types and risk for atopic asthma. opic children during infancy, manifesting atopic risk-asso- Since many of these functional preceding subsequent stabi- ciated developmental defi- deficiencies are already evident in lization of “tolerized” versus ciencies to additional popu- cord blood the trajectory for post- “sensitized” immunopheno- lations within the innate and natal immune maturation seems at types, as the immune system adaptive immune system in- least partially preset before birth. progressively programs alter- cluding monocytes, dendritic Observations stemming from nate forms of T-cell memory; cells and Tregs. the “farm barn” studies in Europe

Perinatal immune development and its role in atopy development 141 Global atlas oF allergy

have identified TLR-dependent microbial signaling to innate immune cells in the maternal decidua as the potential mechanism: this may result in stabiliza- tion of the immunological milieu in the placenta, contributing to protection of the integrity of the local vasculature responsible for Figure 1 Postnatal development of sensitization versus tolerance to house delivering nutrients to the fetus, dust mite (HDM). Fluctuations in HDM-specific IgE titers in individual children thus optimizing in utero growth who were not (left) or were (right) sensitized at age 5 years. The dotted line and development (Figure 2). indicates the 0.35 kU/L sensitization threshold. Note “cycling” of IgE production, particularly in non atopics, reflecting underlying competitive interactions between regulatory and helper T-cell populations. ( Holt et al 2010 originally KEY REFERENCES published in J Allergy Clin Immunol 125(3), 645-651. Reprinted under Rightslink Lic 1. Holt PG, Clough JB, Holt BJ, No 3346780104940.) Baron-Hay MJ, Rose AH, Robin- son BWS et al. Genetic risk for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy 1992;22:1093-1099. 2. Holt PG, Strickland DH, Bosco A, Jahnsen FL. Pathogenic mechanisms of allergic inflammation: atopic asthma as a paradigm. In: Advances in Immunology. Eds: FW Alt. 2009;51-113. 3. Holt PG, Rowe J, Kusel M, Par- - Epidemiology and risk factors sons F, Hollams E, Bosco A, et al. Towards improved predic- tion of risk for atopy and asthma amongst preschoolers: a pro- S ection B spective cohort study. J Allergy Clin Immunol 2010;125:645-651. 4. Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009;123:774-782. 5. Holt PG, Strickland DH. Sooth- Figure 2 Proposed mechanisms by which maternal exposure to bacteria ing signals: transplacental protects against allergies in offspring. A multi-step process may be involved: (i) transmission of resistance to initial mild-to-moderate inflammation in the lungs induced by aerosol exposure asthma and allergy. J Exp Med to microbe-containing dust; (ii) resultant cytokine signals translocate from lung 2009;206:2861-2864. to placenta via the bloodstream, where they attenuate local TLR expression and modulate resident myeloid cell functions; (iii) circulating cytokines enter the 6. Holt PG, Strickland DH, Hales BJ, maternal bone marrow, where they “program” myeloid precursors that subse- Sly PD. Defective “immune sur- quently traffic to the decidua to replenish resident myeloid populations and veillance” of respiratory mucosal influence the local inflammatory milieu.Reproduced ( with permission from Patrick surfaces: a primary causal factor G. Holt, et al. Soothing signals: transplacental transmission of resistance to asthma in asthma onset and progression. and allergy. J Exp Med. 2009;206(13):2861-2864.) Chest 2014;145:370-378.

142 Perinatal immune development and its role in atopy development Global atlas oF allergy

Perinatal risk and 6 protective factors for allergic diseases

Arne Høst Hans Christian Andersen Children’s Hospital Odense, Denmark

The development and phenotypic expression of allergic disease de- Key messages

pends on the interaction between S ection B genetic and environmental factors • The development and phenotypic expression of allergic disease such as exposure to allergens to- depends on a complex interaction between genetic factors, gether with risk and/or protective environmental factors (food or inhalant allergen exposure) and factors (Table 1). Over the last risk/protective factors - Epidemiology and risk factors decades an increase in the preva- • The concept of the hygiene hypothesis has been extensively lence of allergic diseases has been investigated and has influenced our understanding of early-life events reported worldwide. From pro- • Some susceptible/predisposed individuals may benefit from spective birth cohort studies, pos- reduction of allergen exposure sible protective and risk factors • Exposure to food or inhalant allergens cannot be totally avoided, have been identified (Table 2, 3). and observational and interventional studies on avoidance/ A family history of allergic disease reduction of exposure have not shown convincing results (asthma, allergic rhinoconjunctivi- • Multifaceted allergy avoidance during infancy with avoidance of tis, atopic eczema or food allergy) both foods and airborne indoor allergens have shown a persisting in first degree relatives, is strongly reduction of asthma associated with an increased risk for allergic disease. Considering that the increase in gic diseases. Such associations can effect. The hygiene hypothesis the prevalence of allergic diseas- only be used for generation of hy- may in part explain the increase in es cannot be ascribed solely to potheses. the incidence of allergic diseases . However, multifactorial environ- genetic factors, most studies on Many hypotheses on causes of mental factors may play a role and development of allergic diseases the increase in allergic diseases interact (Table 3). have focused on the influence of have been suggested, most often in environmental factors, e.g. ear- without convincing and consist- A strong association between ex- ly feeding (breastfeeding vs. cow’s ent results (Table 4). The concept posure to allergens and IgE sensiti- milk formula), diets/nutrients, of the hygiene hypothesis has been zation has been documented and exposure to allergens, tobacco extensively investigated and has also a strong association between smoking, pollution, farm vs. urban influenced our understanding of sensitization and development of environment, and infectious load. early-life events. According to allergic disease, such as allergic Many hypotheses have been pro- this hypothesis, early exposure to asthma and rhinoconjunctivitis. posed based on observed asso- common bacterial triggers such Sensitization to foods appears ciations between environmental as endotoxins, LPS or helminths first, followed by sensitisation to factors and development of aller- might have an allergy preventive indoor allergens (e.g. house dust

Perinatal risk and protective factors for allergic diseases 143 Global atlas oF allergy

TABLE 1 TABLE 4 Development of allergic disease Hypotheses on causes of increase in allergic diseases The development and phenotypic expression of allergic disease depends on a complex interaction between: • Changes in dietary factors • Genetic factors • Changes in allergen exposure • Environmental factors food allergen exposure • Modified infectious load – inhalant allergen exposure hygiene hypothesis • Risk/protective factors e.g. • Pollutants/irritants tobacco smoke microbials, endotoxins, LPS • Obesity infections • Life style factors diet (nutrients/foods) other Age, dose and duration of exposure are important Synergistic effects mites, pets) and later by sensitisation to outdoor allergens (e.g. TABLE 2 pollen, mould). However, sensitization may be a transient normal Predictors for sensitisation and persistent allergic disease phenomena followed by develop- Predictors for sensitization and allergic disease ment of tolerance. • Atopic heredity The concept of avoidance • Elevated cord blood IgE For decades, primary prevention • Early sensitization to foods and aeroallergens addressing prevention of sensitization and development of clini- • Persistent sensitization cal allergic disease has mostly fo- Predictors for persistent allergic airway disease into adolescence/adulthood cused on avoidance of exposure to

- Epidemiology and risk factors • Persistent sensitization allergens (e.g. foods, indoor aller- • High degree sensitization and polysensitization gens). Over the last decade, a new concept of primary prevention has • Early onset of persistent asthma emerged. Earlier it was believed

S ection B • Severe disease that breastfeeding and avoidance • Reduced lung function of cow’s milk proteins could prevent development of cow’s milk • Presence of another atopic disease protein allergy. However, human milk contains cow’s milk proteins, TABLE 3 if the mother has an intake of cow’s Possible environmental factors influencing development of allergic diseases milk. Other food proteins are also present in human milk. Thus, for- Risk factors Protective factors eign proteins cannot be avoided Allergen exposure Exclusive breastfeeding 4-6 months by exclusive breastfeeding. The Early exposure to endotoxins, LPS, concept of avoidance of foods dur- Tobacco smoke? helminths? ing breastfeeding is wrong. Infants are exposed to small amounts of Lack of breastfeeding? Infections? foreign proteins (reduced expo- Diets/nutrients? Early introduction of solid foods? sure), which may rather lead to Antioxidants, lipids, probiotics, vitamins tolerance than to clinical allergic Mode of delivery (Caesarean section) disease. Furthermore, breast milk contains many immune-modulat- Infections? ing factors that may influence the Early treatment with antibiotics? development of allergy (Table 5).

144 Perinatal risk and protective factors for allergic diseases Global atlas oF allergy

TABLE 5 ble/predisposed individuals may benefit from reduction of allergen Factors in human milk influencing development of allergy exposure. Further studies on the Factors Inducing Protective influence of both genetic and environmental factors are warranted. Antigens (e.g. food proteins) Sensitising allergens Tolerising allergens The present recommendations for IL-4 TGF-beta primary prevention of allergic dis- Cytokines IL-5 sCD 14 eases are shown in Table 6 and 7. IL-13 KEY REFERENCES Immunoglobulins s-IgA 1. Halken S. Prevention of allergic Arachidonic acid N3-PUFA disease in childhood: clinical and PUFA epidemiological aspects of primary N-6 PUFA Other and secondary allergy prevention. Pediatr Allergy Immunol 2004;15:4- 5, 9-32. TABLE 6 2. Lau S, Illi S, Platts-Mills TA, Riposo D, Nickel R, Grüber C et al. Longitu- Evidence-based recommendations for primary prevention of food allergy

dinal study on the relationship be- S ection B For all infants: tween cat allergen and endotoxin exposure, sensitization, cat-specif- • No special diet during pregnancy or for the lactating mother ic IgG and development of asthma in childhood – report of the German • Exclusively breastfeeding for 4-6 months - Epidemiology and risk factors Multicentre Allergy Study (MAS Further recommendations for infants with atopic predisposition: 90). Allergy 2005;60:766-773. • If supplement is needed during the first 4 months a documented hypoaller- 3. Scott M, Roberts G, Kuruku- genic formula is recommended laaratchy RJ, Matthews S, Nove A, Introduction of complementary foods after the age 4 months according to nor- Arshad SH. Multifaceted allergen mal standard weaning practices and nutrition recommendations for all children avoidance during infancy reduces irrespective of atopic heredity asthma during childhood with the effect persisting until age 18 years. Thorax 2012;67:1046-1051. TABLE 7 4. Karvonen AM, Hyvärinen A, Evidence-based recommendations for prevention of allergy to inhalant al- Gehring U, Korppi M, Doekes G, lergens Riedler J et al. Exposure to microbial agents in house dust and wheez- • Avoid exposure to tobacco smoke ing, atopic dermatitis and atopic sensitization in early childhood: a • Avoid pets at home if parents or siblings are allergic to pets birth cohort study in rural areas. Common sense: Clin Exp Allergy 2012;42:1246- • Restrict exposure to house dust mites and pets for children with atopic dis- 1256. position 5. Illi S, Weber J, Zutavern A, Genu- neit J, Schierl R, Strunz-Lehner C, et al Perinatal influences on the Other routes of exposure occur via sults. However, multifaceted aller- development of asthma in atopy in inhalation (proteins in house dust), gy avoidance during infancy with childhood. Ann Allergy Asthma Im- munol 2014;112:132-139. or via the skin. Likewise, exposure avoidance of both foods and air to inhalant allergens cannot be born indoor allergens have shown 6. de Silva D, Geromi M, Halken S Host A, Panesar SS, Muraro A, et al on totally avoided, and observation- a persisting reduction of asthma. behalf of the EAACI Food Allergy al and interventional studies on Importantly, the development of and Anaphylaxis Guidelines Group. avoidance/reduction of indoor al- allergy to environmental allergens Primary prevention of food allergy lergen exposure (house dust mite, is a complex gene-environment in children and adults: systematic cat) have not shown convincing re- interaction and some suscepti- review. Allergy 2014;69:581-589.

Perinatal risk and protective factors for allergic diseases 145 Global atlas oF allergy

7 The role of microbiome

Erika von Mutius Dr. von Hauner Children's Hospital Munich, Germany

All plants, animals and humans live in close association with mi- Key messages crobial organisms. Historically, microbiologists have isolated and • The number of microorganisms living in and on our body surfaces grown microorganisms to identi- outnumbers human cells by a factor of 10 fy pathogens causing disease. The • The microbiome is essential for a healthy immune response advent of DNA based sequencing • The gut microbiome plays an important role in protecting from methods has allowed amplifica- the development of allergic airway disease in mice tion of DNA from microorganisms • Exposure to a rich and diverse microbial environment such as seen on traditional farms protects from allergic diseases and thereby identification of a large variety of microorganisms that have never been cultured biome has a role for the develop- such as on traditional farms (Fig- - Epidemiology and risk factors before. The Human Microbiome ment of allergic diseases. Germ ure 2) have a much lower prev- Project has shown that the hu- free mice develop more easily al- alence of asthma, hay fever and man body contains trillions of mi- lergic asthma than conventionally allergic sensitization as children croorganisms, which outnumber raised mice. Reconstitution of ne- S ection B grown up in urban settings. The di- human cells by 10 to 1 (Figure 1). onates—but not adult—germ free versity of the microbial exposure Their genes encode products es- mice with a conventional micro- has been shown to account for sential for human survival. In the biota protected the animals from the asthma-protective farm effect gastro-intestinal tract microbes allergic disease. This protective (Figure 3). In urban areas high ex- break down many of the proteins, effect may be mediated by activa- posure to environmental microbes lipids and carbohydrates from our tion of immune responses by mi- (e.g. by keeping dogs indoors) also diet into nutrients so that we can crobial compounds. Alternatively relates to a lower prevalence of absorb them. Moreover, microbes or additionally metabolites secret- allergic disease. A recent mouse produce beneficial compounds ed by microbes such as short- study has demonstrated the piv- such as vitamins. The microbiome chain fatty acids may mediate otal role of the gut microbiome in also profoundly affects the host’s these beneficial effects. Changes mediating this protective environ- immune response. Mice raised in the microbiome will occur with mental exposure. Some birth co- under germ-free conditions have diet and antibiotics as long as they hort studies also suggest that the profound deficits in innate and are ingested. But also microbial composition of the gut microbiota adaptive immunity suggesting exposures in the environment will may be a predictor for the onset of that the microbiome educates a affect the microbiome and there- atopic eczema in young children, child’s immune system. by the risk of allergic diseases. but these observations are not Experimental studies in mice, fur- Children being raised in environ- consistent and need further con- thermore suggest that the micro- ments rich in microbial exposures firmation.

146 The role of microbiome Global atlas oF allergy S ection B - Epidemiology and risk factors

Figure 1 The diversity of the skin microbiome at different anatomical areas. (Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Microbiol, Grice EA1, Segre JA, The skin microbiome, 9,244-253, copyright 2011.)

Key References microbial colonization. Am J Respir 4. Ege MJ, Mayer M, Normand AC, 1. http://genome.cshlp.org/con- Crit Care Med. 2011;184:198-205. Genuneit J, Cookson WO, Braun- tent/19/12/2317.full.html Fahrländer C et al; GABRIELA 3. von Mutius E, Vercelli D. Farm 2. Herbst T, Sichelstiel A, Schär C, Transregio 22 Study Group. Expo- living: effects on childhood asth- Yadava K, Bürki K, Cahenzli J et sure to environmental microorgan- al. Dysregulation of allergic airway ma and allergy. Nat Rev Immunol isms and childhood asthma. N Engl J inflammation in the absence of 2010;10:861-868. Med 2011;364:701-709.

The role of microbiome 147 Global atlas oF allergy

Figure 2 Protection from childhood asthma and allergies has been shown for young children growing up on traditional farms rich in microbial exposures in the environment. - Epidemiology and risk factors S ection B

Figure 3 The diversity of bacterial and fungal exposure in the environment protects from childhood asthma. (From New Engl J Med, Ege MJ, Mayer M, Normand AC, et al. Exposure to environmental microorganisms and childhood asthma,364,701-9, Copyright  2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

148 The role of microbiome