1200 word literature review for 15 Articles + Questions

2170  |  wileyonlinelibrary.com/journal/all Allergy. 2020;75:2170–2184.© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Received: 24 July 2019  |  Revised: 20 December 2019  |  Accepted: 27 December 2019

DOI: 10.1111/all.14177

R E V I E W A R T I C L E

The need for clean air: The way air pollution and climate change affect allergic rhinitis and asthma

Ibon Eguiluz-Gracia1  | Alexander G. Mathioudakis2,3  | Sabine Bartel4,5  | Susanne J. H. Vijverberg6  | Elaine Fuertes7  | Pasquale Comberiati8,9 | Yutong Samuel Cai10,11 | Peter Valentin Tomazic12  | Zuzana Diamant13,14  | Jørgen Vestbo2,3  | Carmen Galan15  | Barbara Hoffmann16

1Allergy Unit, IBIMA-Hospital Regional Universitario de Malaga-UMA, Malaga, Spain 2Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, UK 3North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Southmoor Road, Manchester, UK 4Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Member of the German Research Center for Lung Research (DZL), Borstel, Germany 5Department of Pathology and Medical Biology, University Medical Center Groningen, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands 6Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 7National Heart and Lung Institute, Imperial College London, London, UK 8Section of Paediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy 9Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia 10Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK 11The George Institute for Global Health, University of Oxford, Oxford, UK 12Department of General ORL, Head and Neck Surgery, Medical University of Graz, Graz, Austria 13Department of Respiratory Medicine & Allergology, Institute for Clinical Science, Skane University Hospital, Lund University, Lund, Sweden 14Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic 15Department of Botany, Ecology and Plant Physiology, International Campus of Excellence on Agrifood (ceiA3), University of Córdoba, Córdoba, Spain 16Institute for Occupational, Social and Environmental Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany

Eguiluz-Gracia and Mathioudakis are equally contributed to this work.

This review was produced as result of the collaboration between the European Respiratory Society (ERS) Early Career Members Committee (ERS ECMC) and the European Academy of Allergy and Clinical Immunology (EAACI) Junior Members Assembly (EAACI JMA) Board, as part of an Environmental Awareness Initiative. It is not an official document of the ERS or EAACI and the views expressed are those of the authors and not necessarily those of the ERS or EAACI.

Correspondence Ibon Eguiluz-Gracia, Allergy Unit, IBIMA- Hospital Regional Universitario de Malaga- UMA, ARADyAL, Malaga, Spain. Email: [email protected]

Alexander G. Mathioudakis, Division of Infection, Manchester Academic Health Science Centre, Immunity and Respiratory Medicine, School of Biological Sciences, Manchester University NHS Foundation Trust, University of Manchester, Manchester, UK. Email: Alexander.Mathioudakis@ Manchester.ac.uk

Abstract Air pollution and climate change have a significant impact on human health and well- being and contribute to the onset and aggravation of allergic rhinitis and asthma among other chronic respiratory diseases. In Westernized countries, households have experienced a process of increasing insulation and individuals tend to spend most of their time indoors. These sequelae implicate a high exposure to indoor al- lergens (house dust mites, pets, molds, etc), tobacco smoke, and other pollutants, which have an impact on respiratory health. Outdoor air pollution derived from traf- fic and other human activities not only has a direct negative effect on human health but also enhances the allergenicity of some plants and contributes to global warming.

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1  | INTRODUC TION

Since the beginning of the industrial revolution, Western countries expe- rienced an explosive process of urbanization, which dramatically affected environmental exposures. Following this trend, many low-to-middle in- come countries are undergoing similar processes. Consequently, >90% of the population lives in places where air quality does not meet the rec- ommendations of the World Health Organization (WHO).1 The European Environmental Agency reported that most urban dwellers were exposed to concentrations of fine particulate matter (PM2.5) and particulate mat- ter of ≤10 mm in diameter (PM10) above WHO recommendations (74% and 42%, respectively).2 Importantly, air pollution is currently one of the leading causes of premature death in the world.3,4

Allergic rhinitis (AR) and asthma share many pathophysio- logical links5,6 and are among the commonest respiratory con- ditions,7,8 with their increasing prevalence mirroring the rise in Westernized lifestyle worldwide.9 Because the airways represent one of the major boundaries of the body, environmental exposures (collectively termed “the exposome”)10 greatly affect the homeo- stasis of the respiratory mucosae. Importantly, climate and urban dwelling (with its associated decrease in biodiversity) significantly determine the exposome composition.11 Among the exposome components, pollutants, microbes, and allergens have a substan- tial impact on health.12

Several policy changes could help reduce the deleterious com- ponents of the exposome and minimize their effects on respiratory health.2 Of note, some policy measures have already proven effec- tive at decreasing the burden of air pollution–related diseases (e.g., restrictions on tobacco smoking in public places).13

This narrative review summarizes the latest insights regarding the effects of indoor and outdoor pollution and climate change on AR and asthma, and addresses the policy adjustments required to mitigate their effects. To this end, we identified relevant articles published during the period 2014-2019, together with several previ- ous key studies related to the topic.

2  | INDOOR AIR POLLUTION

Most individuals in Westernized countries spend ~80% of their time indoors,14,15 demonstrating the importance of indoor air quality.

The composition of indoor air is affected by several factors includ- ing outdoor pollutants, the quality/quantity of ventilation, indoor allergens, and activities such as smoking, heating, and cooking.16

2.1 | Second-hand exposure to tobacco smoke

2.1.1 | Epidemiological evidence

Tobacco smoke contains at least 4500 toxic chemical compounds, including PM, oxidative gases, heavy metals, and at least 50 carcino- gens.17 Tobacco smoke poses significant health risks to nonsmokers who inhale the smoke in various microenvironments, such as house- holds or workplaces (second-hand smoke (SHS) exposure). Recently, the pyro-synthesis and cigarette combustion related to domestic smoking were identified as key phenomena increasing the levels of PM and toxic chemical agents in households.18

Second-hand smoke exposure during pregnancy and infancy is as- sociated with asthma onset, poor asthma control, and more severe ex- acerbations during childhood,19-21 among other chronic conditions.22 Prenatal and postnatal SHS exposure was linked to a 21%-85% in- crease in the risk of asthma in children, with the highest effect ob- served among children exposed to tobacco smoke during the first two years of life.20,23 More recently, a study of five European birth cohorts (n = 10 860) showed that maternal smoking during infancy correlated with a 15% (95%CI: 0%-31%) increase in the risk of asthma in chil- dren.24 Interestingly, SHS exposure might induce epigenetic changes with transgenerational repercussions on asthma onset,25 which would imply a very long-term effect of tobacco smoking on respiratory health. The immaturity of the immune and respiratory systems of children and their larger air volume per weight kilogram inhaled as compared to adults might explain the high sensitivity to tobacco smoke during childhood.26 The initial studies conducted by the European Community Respiratory Health Survey (ECRHS) in different European countries did not reach a definitive conclusion regarding the role of SHS exposure on asthma in adults.27 Conversely, later studies suggested a higher risk of adult-onset asthma in patients exposed to tobacco smoke,28,29 to- gether with a slightly lower risk of seasonal AR.29 Similarly, a recent study from the ECRHS found associations between SHS exposure and physician-diagnosed asthma and poorer asthma control in adults, yet no effect was observed on the lung function.30

Funding information Instituto de Salud Carlos III; Spanish Ministry of Science and Innovation through the Rio Hortega; RETICS schemes, Grant/Award Number: CM17/00140 and RD16/0006/0001; National Institute of Health Research Manchester Biomedical Research Centre; Medical Research Council Early Career Research Fellowship awarded through the MRC-PHE Centre for Environment and Health, Grant/Award Number: MR/M501669/1

Climate change modifies the availability and distribution of plant- and fungal-derived allergens and increases the frequency of extreme climate events. This review summa- rizes the effects of indoor air pollution, outdoor air pollution, and subsequent climate change on asthma and allergic rhinitis in children and adults and addresses the policy adjustments and lifestyle changes required to mitigate their deleterious effects.

K E Y W O R D S

allergic rhinitis, asthma, climate change., environment, pollution

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2.1.2 | Tobacco smoke alters airway microbiota

Similar to the gut,31,32 the respiratory tract of healthy humans is colonized by a variety of different bacteria, viruses, and fungi.33 This colonization may shift in response to changes in the local en- vironment (e.g., tobacco smoke), potentially inducing a long-lasting state of bacterial dysbiosis.34 A study reported that the pharyn- geal microbiota of individuals exposed to tobacco smoke was richer in species, such as Porphyromonas, Neisseria, and Gemella, compared to nonexposed subjects, but the authors failed to iden- tify significant changes in the microbiota recovered from bron- choalveolar lavage samples.35 Various tobacco smoke compounds can directly affect the airway microbiota (e.g., enhanced biofilm formation by Staphylococcus aureus36), and cigarettes themselves carry bacteria and fungi, including several human pathogens (Figure 1).37 Furthermore, tobacco smoke upregulates the airway mucus production, impairs the mucociliary clearance, and induces low-grade inflammation within the lungs, collectively changing the micro-environmental conditions of the niche, which might affect the local microbiota.38 These changes might eventually promote airway remodeling.39,40

Many chronic lung diseases, including asthma and bronchiectasis, have been associated with an altered respiratory microbiota.34,41-43 The asthmatic bronchus with chronic inflammation and increased mucus production represents an ecological niche different from that of a healthy bronchus.34 However, it is still unclear whether the bac- terial dysbiosis is a cause or a consequence of the disease.44 In this regard, the diverse compositions of the airway microbiota correlate

with the concentration of inflammatory cytokines in murine lungs, suggesting that changes in the microbiota can also modulate the host's inflammatory status.45

2.2 | Other sources of indoor air pollution

Other agents, such as nitrogen dioxide (NO2), carbon monoxide (CO), or some volatile organic compounds (VOC) (e.g., formaldehyde), are also main indoor pollutants.46,47

Indoor NO2 is mainly generated by gas-fueled cooking and heat- ing appliances, and the levels in European households can be as high as 2500 µg/m3.48 On the other hand, the Towards Healthy Air in Dwellings in Europe (THADE) project reported that the mean con- centration of indoor NO2 in Europe ranged from 10-15 µg/m3 in Scandinavia to 65 µg/m3 in Poland.49 Numerous studies have re- ported positive associations between indoor NO2 and the presence/ aggravation of asthma symptoms in children.16,50 Some VOCs gen- erated from sources like building materials or consumer products (cleaning products, cosmetics, air fresheners, etc) act as indoor air pollutants.51 A systematic review from 2015 reported only weak ev- idence relating exposure to this type of VOCs to the onset of asthma and AR, as well as to the aggravation of asthma/AR symptoms in both children and adults.52

The use of solid fuel (e.g., coal) for cooking and heating does not only remain a source of indoor pollution in developing countries, but is still a common practice for residential heating in many Western households.53 Exposure to the smoke generated by this biomass has

F I G U R E 1   Tobacco smoke as driver of microbial dysbiosis in the airways: A, During homeostasis, there is a symbiosis between the airway microbiota and the stromal and immune cells of the respiratory epithelium; B, Tobacco smoke carries different microbes that can colonize the airways, and also promotes several changes in the resident microbiota such as the formation of biofilms by Staphylococcus aureus; C, Tobacco smoke upregulates mucus production, impairs the mucociliary clearance, and induces low-grade inflammation in the airway mucosa; C, The interaction between the effects of tobacco smoke on airway microbiota and respiratory epithelium further alters the ecological niche, promotes the outgrowth of certain species, and ultimately affects the microbial balance

(B)

(B)

(C) (A)

Inflamma�on

Inflamma�on

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been linked to several respiratory conditions in both adults and chil- dren,54 but robust evidence is still lacking to support a causative role in the case of adult or pediatric asthma.

Indoor allergens from furry pets, molds, and house dust mites (HDM) also influence the quality of indoor air. Sensitization to furry animals is detected in up to 15% of the population55 with a high degree of cross-reactivity among the different species. Moreover, HDM are the most common triggers of airway allergy, as up to 50% of asthmat- ics are sensitized to them.56 Recent data suggest that in children with wheezing episodes, sensitization to HDM is associated with greater bronchial inflammation and reduced lung function.57 Importantly, in- door allergens induce more severe phenotypes of airway allergy than outdoor seasonal allergens.58-60 Additionally, dampness is present in 10%-15% of households, which can lead to mold or cockroach col- onization and subsequent allergic sensitization of the residents.61,62 Beyond allergic mechanisms, molds can promote inflammation of the upper and lower airways through several metabolites like glucans or mycotoxins.63

In addition to residential environments, indoor air quality in nonresidential buildings (e.g., schools) plays an important role in respiratory health.64-66 The Schools Indoor Pollution and Health: Observatory Network in Europe (SINPHONIE) project, funded by the European Parliament, assessed indoor air exposure in schools in 23 countries.67 The study found that PM2.5, some VOCs (e.g., form- aldehyde), radon, and allergens (especially molds) were commonly

present.67 Moreover, the Health Effects of School Environment (HESE) project 68 reported that 78% and 66% of children attend- ing schools in Norway, Sweden, Denmark, France, and Italy were exposed to PM10 over 50 μg/m3 and to carbon dioxide (CO2) over 1000 ppm, respectively. Another study from the HESE project in- vestigating the burden of fungi showed that the number of viable molds in indoor air exceeded the maximum standard of 300 cfu/ m3 in 33% of participating classrooms.69 Very recently, these find- ings were confirmed in a study conducted in Southern Italy.70 Importantly, this work observed that the concentration of elements from industrial emission was significantly higher in schools located in urban/industrial areas as compared to rural areas,70 implying that the penetration of outdoor pollutants further deteriorates the quality of indoor air.

Table 1 summarizes the main effects of indoor pollution on AR and asthma.

3  | OUTDOOR AIR POLLUTION

3.1 | Epidemiological evidence

Various epidemiological studies have demonstrated that long- term exposure to outdoor air pollution (e.g., from traffic, indus- try) negatively affects respiratory health.71 A multicenter study in

Indoor Air Pollution (effects amplified by the amount of time spent indoors and the isolation of buildings)

Environmental factors Health outcomes

Second-hand tobacco smoke

During perinatal period 1. Higher prevalence of asthma, poorer asthma control, and more severe asthma exacerbations during childhood19-24

2. Potential epigenetic changes with transgenerational repercussions25

During adulthood 1. Possibly higher asthma prevalence28-30

2. Possibly lower prevalence of allergic rhinitis29

Lifelong Alteration of airway microbiota/bacterial dysbiosis34

NO2 from gas-fueled cooking and heating

Higher prevalence and exacerbation rate of asthma during childhood (16. 50)

Volatile organic compounds from building materials and consumer products

Possibly higher prevalence and exacerbation rate of allergic rhinitis and asthma in both children and adults52

Indoor allergens

Lifelong 1. Increased sensitization rates to house dust mites, molds, and allergens from furry animals 55,56

2. More severe phenotypes of allergic rhinitis and asthma, as compared to those induced by outdoor allergens 58-60

During childhood Higher bronchial inflammation and reduced lung function in sensitized children with wheezing episodes57

Colonization of the households by molds and cockroaches due to dampness

1. Higher sensitization rate to dampness-related allergens61,62

2. Airway inflammation due to allergy-independent mechanisms (glucans, mycotoxins, etc)63

TA B L E 1   Consequences of indoor air pollution over allergic rhinitis and asthma

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five European birth cohorts (conducted as part of the European Study of Cohorts for Air Pollution Effects, ESCAPE project) showed that exposure to PM and nitrogen oxides was associated with poor lung function in school-age children.72 An early analysis of the ESCAPE project did not find a statistically significant associa- tion between air pollution and the development of asthma up to the school age.73 However, the re-analysis of these cohorts when the study individuals were 14-16 years old revealed associations between asthma incidence and NO2 (OR 1.13, 95% CI: 1.02-1.25) and PM2.5 (OR 1.29, 95% CI: 1.00-1.66) exposure. The associations were particularly strong in the case of asthma diagnosed after the school age.74 A recent meta-analysis of observational epide- miological studies published between 1999 and 2016 showed an association between traffic pollution and childhood asthma, with an OR ranging from 1.03 (95%CI: 1.01-1.05) to 1.08 (95%CI: 1.03- 1.14) depending on the type of pollutant analyzed.75 Other large studies have also reported similar links between outdoor pollution and childhood asthma.76,77

The ESCAPE project also analyzed five European adult cohorts (overall ~7500 participants) and found that higher exposure to nitrogen monoxide (NO), NO2, and PM10 from traffic was asso- ciated with decreased lung function during adulthood.78 A very recent study within the ESCAPE framework also found associa- tions between decreased lung function and PM2.5 exposure in adults, with stronger effects observed for males.79 Another work

within the ESCAPE project found suggestive (but nonsignificant) evidence that long-term exposure to NO2, PM10, and PM2.5 was associated with higher asthma incidence in adults.80 Interestingly, a recent analysis of data from three large European cohort stud- ies (with > 600 000 participants) showed that long-term PM10 exposure was significantly associated with a 12.8% increase in lifetime asthma prevalence.81 Furthermore, several studies have confirmed the association between outdoor pollution and asthma exacerbations.82 Notably, a study from the Improving Knowledge and Communication for Decision Making on Air Pollution and Health in Europe (APHEKOM) network, which analyzed data from 10 European cities, showed that air pollution was accountable for up to 15% of all asthma exacerbations.83

Regarding rhinitis, the urban dwelling has been related to a higher risk of AR as compared to the suburban dwelling.84 Nevertheless, studies assessing the effect of air pollution on rhinitis onset have yielded inconsistent results in both children 85 and 86 adults, which contrasts with the large body of evidence relating air pollution to asthma.

Besides outdoor pollution from traffic, industry, energy pro- duction, heating, etc, emissions from livestock farming include spe- cific pollutants such as organic dust, toxins from microorganisms, and gases like ammonia or methane.87 These agents also influence the respiratory system either directly or through their role as pre- cursors of other polluting particles. A large-scale population-based

F I G U R E 2   Innate and adaptive immune effects of outdoor pollution on respiratory epithelium: A, PM10 upregulates the expression of NLRP3 by airway epithelial cells (AEC). AECs in turn release CXCL1, which contributes to the recruitment of neutrophils from the bloodstream. AECs also release IL-6, which promotes mucus secretion: B, Black carbon induces the methylation and the expression of the IL-4 gene in different immune cells in the respiratory epithelium. Increased levels of IL-4 promote both mucosal Th2 cell priming and local IgE production by IgE + B cells. NRLP3: nucleotide-binding domain, leucine-rich repeat protein 3

CXCL1 IL-6 Increased

mucus produc�on

(A)

IL-4

(B)

Black Carbon

Demethyla�on

IgE

PM10 PM10

IL4

IL4

NLRP3 NLRP3

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study including ~2000 Dutch rural dwellers recently showed that increased levels of livestock-related air pollution were associated with decreased lung function, even in nonfarming individuals.87

3.2 | Environmental-human interactions

The respiratory epithelium is composed of a pseudostratified layer of ciliated airway epithelial cells (AECs) intermingled with mucus- producing goblet cells.88,89 A recent study compared the response of primary murine and human AECs to either traffic-derived or ambient (collected in Sidney metropolitan area) PM2.5 and PM10.90 Noteworthy, ambient PM10 induced a stronger secretion of IL-6 and CXCL1 by AECs, an effect attributed to the higher content of iron- rich particles from geological origin, as compared to traffic-derived PM10. Importantly, PM10-mediated secretion of cytokines is depend- ent on the nucleotide-binding domain, leucine-rich repeat protein 3 (NLRP-3), a component of the inflammasome.91 The PM10-mediated activation of the inflammasome induced profound innate immune effects in mouse models of allergic asthma, but was dispensable for PM10-facilitated allergen sensitization.91 This finding indicates that PM10 activates distinct inflammatory pathways, which might inde- pendently contribute to asthma pathogenesis.

Primary AECs from patients with severe asthma released more cytokines when exposed to PM or diesel exhaust (DE) compared to those from healthy subjects 92 or patients with less severe asthma phenotypes.89 This observation might explain how pollutant-in- duced epithelial insults93,94 can trigger asthma exacerbations.83 Nevertheless, segmental allergen challenges in atopic subjects ex- posed to either DE or filtered air did not induce a different release of inflammatory mediators.89,95 This finding suggests that the ad- juvant effect might rely on repetitive exposures. A recent mouse study96 compared the effects of a two-hour exposure to DE or to the allegedly less toxic biodiesel (BD). Both exhaust products in- duced cardiovascular and pulmonary inflammation, while only BD generated an increase of neutrophils in bronchoalveolar lavage.

The environment acts on the genome inducing epigenetic changes, which function as important effectors of external insults. Epigenetic modification induces alterations in the DNA structure leading to changes in gene expression and inducing downstream dis- ease.97 Two recent studies analyzing pediatric populations from New York city showed a relationship between black carbon exposure and relevant epigenetic changes in immune genes.98,99 In a study ana- lyzing samples from the oral mucosa, individuals with higher black carbon exposure had lower DNA methylation levels in the IL-4 gene, possibly leading to higher expression.99 This effect was even more significant in IgE-sensitized children99 (Figure 2).

Importantly, most experimental studies apply pollutants in water solutions. This approach specifically selects for water-soluble com- ponents and modifies their chemical properties and interaction with AECs. This fact partly hampers the translation of the results from experimental settings to naturally occurring diseases. Moreover, in many studies, AECs are cultured submerged and in monolayers,

which does not reflect their natural physiology. Therefore, experi- mental designs using primary AECs grown at the air-liquid interface are required to investigate the real effect of PM or DE exposures on AEC responses in health and disease.

3.3 | Environment-environment interactions

Some air pollutants do not only have a direct effect on the res- piratory system but also interact with plants and fungi to en- hance the production and allergenicity of pollen, like ragweed or cypress,100,101 and of fungal spores.102 For example, ragweed in an urban area with high CO2 concentrations grew faster and flowered earlier and more intensely, which leaded to the pro- duction of more pollen, as compared to ragweed grown in rural areas.103 Recently, it has been shown that pollutants can also promote the release of allergens via direct cell damage.104 Pollen grains and fungal spores contain several bioactive compounds, which may exert pro-inflammatory and pro-allergic effects.105,106 Recent data suggest that several pollen-associated lipid mediators (PALMs) activate Th2 cells to promote IgE synthesis in vitro.107 Importantly, the pollen collected next to roads with heavy traffic released higher amounts of PALMs.104 Similarly, a study carried out in Germany showed that birch trees exposed to higher con- centrations of ozone produced more birch allergen (Bet v1) and PALMs per pollen grain than ozone-free trees.108 Importantly, the skin prick test performed with an allergenic extract obtained from the highly exposed trees induced a significantly larger wheal diameter in birch pollen-AR patients as compared to the less ex- posed trees108 (Figure 3).

Pollutants can also induce the oxidation or nitration of allergens, leading to changes in their conformation or stability. These chemical modifications enhance their immunogenicity and affect their inter- action with receptors on immune cells.11,104 Several studies have shown that nitrated fungal spores109 and nitrated pollen from birch, ragweed, and hornbeam108,110-112 have increased T cell–stimulatory and IgE-inducing capacity. Therefore, it is tempting to speculate that nitration by air pollutants plays a role in the IgE sensitization to allergens.105

However, the clinical significance of these phenomena remains unclear.113 Epidemiological studies are largely limited by their inabil- ity to quantify individual exposure to air pollutants and allergens on a population scale. A French study including 36 397 AR patients found no effect of air pollution on the association between airborne pollen concentrations and rhinitis severity.114 Conversely, a study in eleven Canadian cities showed an interaction effect of air pollution on the risk of asthma-related hospitalizations and the burden of pol- len grains and fungal spores.115 These findings have been recently confirmed in a study conducted in Belgium, which reported a syner- gistic effect of ozone, PM10 and pollen exposure on the risk of asth- ma-related hospitalizations.116

Table 2 summarizes the main effects of outdoor pollution on AR and asthma.

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4  | CLIMATE CHANGE

4.1 | Climate change and aeroallergens

Air pollution and climate change are closely interlinked. Nowadays, the vast majority of global energy is derived from fossil fuels whose burning generates huge amounts of CO2, methane, black carbon, nitrogen oxides, and sulfate aerosols.117 Some of these pollutants (e.g., CO2) are naturally occurring greenhouse gases, which persist for long periods in the atmosphere. Other agents (e.g., methane or black carbon) have shorter lifetimes but also contribute to climate change.118 Greenhouse gases help keep the earth warm by absorb- ing the sun's energy and by redirecting it back to the earth's sur- face.117 However, an overabundance of greenhouse gases traps an excessive amount of heat in the atmosphere and ultimately accounts for global warming.119

Global warming alters local vegetation patterns and speeds up the growth rate and phenology of plants, leading to increases in airborne pollen concentrations100,120 and changes in the geo- graphical spread of plants.121,122 In this regard, climate change

was associated with increased duration of the ragweed pollen season in different studies conducted in North America and Europe.123-125 Changes in atmospheric humidity and precipitation also very likely affect the growth and distribution of fungi, yet this aspect remains uninvestigated.126 The interactions of these changes with the photoperiod will modify the migration pat- tern of some plants and fungi.127 Unlike air pollution,108 global warming has not been related to date to enhanced allergenicity of plants.100

The effects of climate change on allergenic plants and fungi128-130 are likely to continue in the future. A long-term prediction of these changes is challenging given the many variable factors, although computation efforts are currently ongoing.121,131,132 A process-based model of weed growth, plant competition, and population dynam- ics predicted that ragweed might spread to Northern European countries.121 Ragweed is a native species in North America, but is now rapidly invading several European areas.121 The colonization of geographical areas by new species will likely induce respiratory symptoms by both de novo sensitizations and cross-reactivity with pre-existing species.133,134

F I G U R E 3   Effect of outdoor pollution and climate change over allergenic plant species: Outdoor pollution increases the amount of pollen grains produced by plants (A), and the amount of both allergens (B) and PALMs (C) per pollen grain. Moreover, aeroallergens can become chemically modified by outdoor pollutants like nitrogen oxides (D). The global warming induces prolonged vegetation periods of allergenic plants (E), and extreme climate events like thunderstorms, which provoke the sudden release of massive amounts of allergens to the atmosphere (F). All these effects result on a higher availability of aeroallergens, and they increase the chances of interaction between the allergens and the stromal and immune cells of the airway mucosa. The interaction of native and nitrated allergens with airway epithelial cells can result on the release of pro-inflammatory mediators (G), whereas allergen interaction with dendritic cells can result on IgE sensitizations (H). The chances of sensitization are further increased by the higher availability of PALMs and nitrated allergens (G). Moreover, allergen interaction with sensitized mast cells can induce the release of inflammatory mediators (I), ultimately inducing the onset of asthma attacks in pollen-allergic patients (J). PALM: pollen-associated lipid mediator

January March May July September

Histamine, tryptase, lipid mediators,

cytokines

Asthma a�ack

(A) (B)

(C) (D)

(E) (F)

Outdoor pollu�on

Increased produc�on of pollen grains

More PALMs per pollen grain

More allergens per pollen grain

Nitra�on of allergens

Global warming Extreme climate events

Prolonged vegeta�on periods

Sudden release of massive amounts of allergens

Pollen grain

Allergen

PALM

Nitrogen oxide

(J)

High-affinity IgE

IL-4

(H)

(G) (I)

Epithelium-derived mediators

Aeroallergen(G)

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4.2 | Climate change as an inducer of respiratory and allergic diseases

There is no doubt that climate change causes or exacerbates res- piratory diseases.135-139 The most important effects of climate change on respiratory health are described below (also summa- rized in Table 3):

1. The higher temperatures and increased frequency of heatwaves amplify the exacerbation rate, morbidity, and mortality of re- spiratory diseases.140-143 The extent of this association usually parallels the pollution levels of local air.144

2. The seasonality and severity of AR and asthma are affected by the growth patterns of allergenic species,145-148 which can act syner- gistically with air pollutants.149 Global warming might also alter the species dominating distinct ecological niches.150

3. Climate change is expected to alter the pattern of respiratory tract infections.151,152

4. Intensive rain and flooding induce dampness and mold prolifera- tion in affected households,61,153 thus influencing the quality of indoor air.

5. Extreme climate events are the cause of specific phenomena like thunderstorm-related asthma episodes.153,154 During these episodes, a large number of patients experience asthmatic symp- toms during the initial 20-30 minutes of a large-scale thunder- storm, providing that it occurs during the allergen season and induces a cold outflow.155 This phenomenon arises from a sudden release of massive amounts of aeroallergens,154 and a causative role for pollen allergy is suspected.156 Numerous case studies of thunderstorm-related asthma have been documented,61 the larg- est of which took place in Melbourne (Australia) on November 21, 2016 (~4000 patients presented at hospitals with respiratory symptoms).156,157

Besides the direct effects of global warming on the airways, the altered levels of aeroallergens account from many of the effects of climate change on respiratory health. As climate change will also in- fluence the amount and type of pollutants in the air, which them- selves interact with aeroallergens,138 the individual and/or combined effects of these environmental parameters on respiratory health are very difficult to predict.

5  | INTERVENTIONS TO MODIF Y AIR POLLUTION AND CLIMATE CHANGE

5.1 | Policy changes

Policy changes are the most effective measures to decrease pol- lution.158,159 While actions of individual citizens can mitigate air pollution only to a small extent,160 larger lifestyle changes at the population level mainly result from policy interventions. For ex- ample, many countries have implemented smoke-free legislation to protect the population, particularly children in public places. A recent meta-analysis of 35 pediatric studies showed that enforce- ment of smoke-free policies was significantly associated with a 9.8% (95%CI: 3%-16%) and 18.5% (95%CI: 4.2%-32.8%) reduction of hospital admissions due to asthma attacks and lower respira- tory tract infections, respectively.13 These associations tended to be stronger in regions with more comprehensive smoke-free laws, indicating that stringent smoke-free policies are necessary to gain maximum health benefits.

The replacement of fossil fuels by renewable energy sources and commitment to a complete phaseout of coal power by the in- dustry represent necessary milestones in the roadmap for a more environmentally friendly economy.161,162 Over the past decade, the implementation of the European Union (EU) environmental policy framework contributed substantially to decreasing the emissions of many air pollutants and improving air quality across Europe.163 The EU recently released an updated version of the environmental performance standards for large combustion plants, which set stricter emission ranges for NO, NO2, sulfur dioxide, PM, and mercury from power plants.164 A recent National Emission Ceiling Directive was also released as a measure to reduce emissions from different sectors.165

TA B L E 2   Consequences of outdoor air pollution over allergic rhinitis and asthma

Outdoor Air Pollution

Environmental factors Health outcomes

Pollution from traffic and industry (PM10, PM2.5, NO, NO2, etc)

During childhood Higher asthma prevalence after the school age74-77

During adulthood Possibly higher asthma prevalence80,81

Lifelong 1. Poorer lung function72,78,79

2. Higher rate of asthma exacerbations (82. 83)

3. Conflicting results on AR onset85,86

Livestock farming (organic dust, toxins form microorganisms, gases like ammonia and methane, etc)

Decreased lung function87

Black carbon Possibly epigenetic changes leading to increased type two inflammation in children99

Interaction between air pollutants (PM10, nitrogen oxides) and allergens (pollen, fungal spores, etc)

Production of more pollen, more allergens per pollen grain, and more PALMs per pollen grain100-104,108

1. Potentially, facilitation of IgE sensitization against aeroallergens104,107

2. Higher rate of asthma-related hospitalizations115,116

Release of allergens via direct cell damage104

Nitration of allergens109-112

Abbreviation: PALM, pollen-associated lipid mediator.

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Nevertheless, a recent report from the European Economic Area showed that a large proportion of European citizens and ecosys- tems are still exposed to concentrations of air pollutants exceeding the legal limit values of the EU and the guideline values of the WHO (Table 4).2 Renewable energy sources currently account for 24% of total electricity generated,166 illustrating the long way to go before fossil fuels can be replaced. Government investment in clean en- ergy should come together with policies incenting suppliers into a timely transition out of existing fossil-based infrastructure.166

At a local level, greenhouse-gas emissions can be reduced by shifting from private motorized transport to more sustainable mo- dalities, such as public transport, cycling, and walking. There is evi- dence that having good cycling infrastructure integrated with public transport, training of both cyclists and motorists, and making driving costly can promote cycling.166 Local authorities could also incentiv- ize the population to shift to sustainable electric vehicles by intro- ducing ownership tax exemptions and additional advantages such as waivers on fees (e.g., plug-in charging station or parking spots). Studies evaluating the effect of nearby green areas on respiratory health have yielded inconsistent results,167 possibly due to the com- plex interactions between global warming, vegetation, and air pol- lution. Recent studies using the methodology recommended by the Coordination of Information on the Environment (CORINE) program have yielded conflicting results, indicating either a beneficial impact of greenness on general health,168 or an increased risk of wheez- ing, asthma, and AR in children exposed to green spaces, especially coniferous forests.169 Until future studies shed more light on this issue, it seems reasonable that city development plans include green spaces with diverse and nonallergenic species.170,171

The European Academy of Allergy and Clinical Immunology (EAACI)/European Federation for Allergy and Airways Diseases Patients’ Associations (EFA) Interest Group on Allergy and Asthma at the European Parliament recently launched a call to increase the awareness about asthma and promote the legal changes required to decrease the burden of air pollution.172,173

5.2 | Lifestyle adjustments

Various lifestyle adjustments can mitigate air pollution and climate change and indirectly decrease the onset and progression of respira- tory diseases. The avoidance of individual motorized transportation constitutes a simple and basic approach. Exercising outdoors is also recommended, as its benefits are expected to exceed the negative impacts of exposure to outdoor allergens and pollutants, at least in most European cities.174,175 However, limiting the time spent out- doors during the pollen season (for pollen-allergic patients)176 and during high traffic hours or warm days is a reasonable approach. Air quality alerts, pollen calendars, and allergy diaries, among other mo- bile health tools, can help plan outdoor activities, and control and monitor symptoms.177,178 Besides mobility, livestock to provide meat for human consumption is among the main causes of CO2 produc- tion. Therefore, reduction of meat consumption, together with lim- iting trips made by air traffic, and increasing the use of recyclable materials, are also meaningful measures to reduce CO2 emissions.

Adequate and regular ventilation of the living spaces and the filtration of indoor air can prevent mold growth and reduce indoor NO2 concentrations. Moreover, preventing dampness

Environmental changes Health outcomes

More frequent extreme climate events

Heatwaves, wildfires, higher temperatures, etc

Amplification of exacerbation rate, morbidity, and mortality of respiratory diseases.140-143

Intensive rain and flooding Dampness in affected households with subsequent proliferation of molds and cockroaches.61,153 See the consequences of the deterioration of indoor air quality in Table 1.

Thunderstorms Increase in asthma exacerbations and hospitalizations following thunderstorm- related asthma episodes153-157

More intense and more prolonged pollen seasons.100,120,123-125 Possibly similar changes for other allergens (e.g., fungi).

Increase in the severity and alteration of the seasonality of symptoms of allergic rhinitis and asthma 145-148

Alteration of the local vegetation patterns with changes in the geographical spread122 and migration of plants127 Colonization of geographical areas by new species 121 with alteration of the species dominating distinct ecological niches.150

Possibly, similar changes for fungi.126

Increased prevalence and severity of allergic rhinitis and asthma due to both de novo sensitizations and cross-reactivity with pre-existing species133,134

Possibly changes in the growth pattern and distribution of pathogenic microorganisms.151

Possibly changes in the pattern of respiratory tract infections

TA B L E 3   Consequences of climate change and global warming over allergic rhinitis and asthma

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and limiting the number of carpets can decrease the burden of HDMs and molds.179 Nevertheless, in areas with a high burden of HDMs, these strategies are often insufficient, as emphasized by international guidelines and consensus documents on AR and asthma.180-182 Moreover, individuals with an atopic predisposition should carefully consider the choice of keeping a pet.179,183 In this regard, a large epidemiological survey identified exposure to cat during the first year of life as an independent risk factor for AR and asthma presence during school age.184

6  | CONCLUSION

Given the explosive global rise in urbanization, industrial produc- tion, aviation, road traffic, etc, the preservation of good air qual- ity will become increasingly challenging. This narrative review summarizes the current literature about the potential effects of air pollution and climate change on AR and asthma. Although a formal meta-analysis was outside the scope of this review, and there were several difficulties for direct comparisons of the stud- ies due to methodological differences, several conclusions could be made.

1. The evidence relating passive smoking and exposure to traf- fic-related pollution (including NO2 and PM2.5) to childhood asthma is currently robust, whereas the link with exposure to smoke from biomass and deleterious VOCs seems weaker.

2. Although the relationship between air pollution and adult-onset asthma has been uncertain for years, recent data suggest that passive smoking and traffic pollutants might be related to asthma development in adults.

3. The relationship between air pollution and AR onset seems less conclusive as compared to asthma in both children and adults.

4. The mechanisms for how pollutants induce respiratory disease are varied. Recent evidence indicates that epigenetic changes in the respiratory epithelium and the alteration of airway micro- biota might account for some of the effects of PM2.5 and tobacco smoke, respectively.

5. Exposure to indoor and outdoor allergens is a well-established risk factor for the development of AR and asthma in both adults and children, with indoor allergens inducing more severe pheno- types of airway allergy.

6. The capacity of outdoor pollutants to increase the allergenicity and immunogenicity of aeroallergens has been shown in vitro, but the clinical implications of these phenomena require further analysis.

7. Unlike pollutants, climate change affects pollen grains and fun- gal spores by increasing their availability rather than altering their chemical structure. Some of the deleterious effects of climate change on respiratory health are likely to arise from this increased availability.

As a key message, we can conclude that the detrimental effects of air pollution and climate change on human health are greatly pre- ventable through timely implementation of adequate legislations. Governments need to adopt effective and evidence-based regula- tions, as political interventions are the only way to achieve large im- provements at the population level. All these efforts are crucial steps in the pathway to clean air, and ultimately, to the prevention and reduction of AR, asthma, and other chronic respiratory conditions.

ACKNOWLEDG MENT

IEG receives funding from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation through the Rio Hortega and

TA B L E 4   Percentage of the urban population in the EU-28 exposed to air pollutant concentrations above the EU limit or target values and above the WHO air quality guidelines (AQGs)

Pollutant EU reference value Exposure estimate (%) WHO AQG Exposure estimate (%)

PM2.5 Year (25) 7-8 Year (10) 82-85

PM10 Day (50) 16-20 Year (20) 50-62

O2 8-h (120) 7-30 8-h (100) 95-98

NO2 Year (40) 7-9 Year (40) 7-9

BaP Year (1) 20-25 Year (0.12) RL 85-91

SO2 Day (125) <1 Day (20) 20-38

Key <5% 5%-50% 50%-75% >75%

Note: Minimum and maximum values observed between 2013 and 2015. The comparison is made for the most stringent EU limit or target values set for the protection of human health. As the WHO has not set AQGs for benzo(a)pyrene (BaP), the reference level in the table was estimated assuming WHO unit risk for lung cancer for PAH mixtures and an acceptable risk of additional lifetime cancer risk of approximately 1 in 100 000. Estimated reference levels are given between parentheses and in μg/m3, except for BaP, which is given in ng/m3. This table was modified and reproduced with permission from the European Environmental Agency Report No 13/2017. Air quality in Europe—2017 report. Available from: https://www.eea. europa.eu/publi catio ns/air-quali ty-in-europe-2017 (assessed: July 2018).

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RETICS schemes (CM17/00140 and RD16/0006/0001). AGM and JV are supported by the National Institute of Health Research Manchester Biomedical Research Centre (NIHR Manchester BRC). Y.C is supported by a Medical Research Council Early Career Research Fellowship awarded through the MRC-PHE Centre for Environment and Health (grant number MR/M501669/1).

CONFLIC TS OF INTERE S T

Apart from academic affiliations, ZD acts as Executive and Scientific Medical Director at a phase I/II pharmacological unit (QPS-NL), which performs clinical studies for pharmaceutical companies. In the past 3 years, ZD received honoraria, consultancy and speaker fees from Astrazeneca, ALK, Aquilon, Boehringer Ingelheim, CSL, HAL Allergy, MSD, Sanofi-Genzyme. The remaining authors have no con- flicts of interest to declare.

AUTHOR CONTRIBUTIONS IEG and AM coordinated the work and designed the structure of the review. SB, SJHV, EF, PC, YSC, and PVT reviewed the literature, wrote the manuscript, and prepared the figures and tables. IEG, AM, ZD, JV, CG, and BH critically reviewed and finalized the manuscript.

ORCID Ibon Eguiluz-Gracia https://orcid.org/0000-0002-3774-931X Alexander G. Mathioudakis https://orcid.org/0000-0002-4675-9616 Sabine Bartel https://orcid.org/0000-0002-9163-795X Susanne J. H. Vijverberg https://orcid.org/0000-0002-4579-4081 Elaine Fuertes https://orcid.org/0000-0003-0205-9025 Peter Valentin Tomazic https://orcid.org/0000-0001-6445-4800 Zuzana Diamant https://orcid.org/0000-0003-0133-0100 Jørgen Vestbo https://orcid.org/0000-0001-6355-6362 Carmen Galan https://orcid.org/0000-0002-6849-1219

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How to cite this article: Eguiluz-Gracia I, Mathioudakis AG, Bartel S, et al. The need for clean air: The way air pollution and climate change affect allergic rhinitis and asthma. Allergy. 2020;75:2170–2184. https ://doi.org/10.1111/all.14177

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