Get an inside look at how Middleton's Allergy approaches climate change and immune health — from air pollution, wildfires, and pollen to epithelial barrier damage, microbial dysbiosis, and the rising prevalence of allergic diseases and asthma.
The gold standard text in allergy— unparalleled for both reference and study Order your copy today at elsevierhealth.com/9780443249723 From Middleton’s Allergy, 2 volume set, 10th Edition Exclusive preview: Climate Change on Allergic Diseases and Asthma 806 46 Climate Change: Allergic Diseases and Asthma Vanitha Sampath, Ioana Agache, Harald Renz, Marc E. Rothenberg, Cezmi A. Akdis, Kari C. Nadeau C O N T E N T S Introduction, 806 Climate change and immune dysregulation: Allergic diseases, asthma, autoimmune diseases, and cancer, 807 The impact of climate change on allergies and asthma, 808 Conclusion, 818 SUMMARY OF IMPORTANT CONCEPTS • Increased greenhouse gas emissions caused by burning of fossil fuels are increasing surface global temperatures and adversely affecting planetary health and causing climate change. • Climate change is accelerating sea level rise, melting of glaciers, and increasing the frequency and intensity of climate events such as wildfires, sand and dust storms, droughts, and floods. • Climate change extreme weather events are changing the human exposome by increasing air pollution and also the spread of infectious vectors. • The rapidly changing exposome mediates epithelial barrier damage, microbial dysbiosis, and immune dysregulation, leading to increases in the prevalence of immune-mediated diseases, such as allergies and asthma. • Adaptation and mitigation strategies at the individual, local, national, and international levels are needed to stabilize or reverse global temperature increases and prevent further climate change. • A One Health approach, which recognizes the interconnectedness of human, animal, and environmental health, is needed to protect planetary and human health. While air pollution is a major climate change–associated factor which adversely affects health, other climatic factors also play a role. Higher global temperatures increase ground level or tropospheric ozone levels, which is known to affect respiratory health. Other deter- minants of health that are indirectly affecting climate change and which compound and exacerbate its effects include human displacement and migration; food, water, and housing insecurity; decreasing biodiversity and greenspace; and disruption and inequity in health care. These environmental changes have increased the prevalence of immune-mediated diseases such as allergic diseases, respiratory diseases, autoimmune diseases, and cancers with further increases expected. 4 There is an urgent need to increase personal and systems resilience in order to adapt to this accumulating climate change–related health burden while working toward mitigating its impact by decreasing GHGs, promoting sustainable growth and development, increasing biodiversity and green spaces, and decreasing inequities in health care in order to protect human and planetary health. 5,6 In this chapter, we discuss the various ways anthropogenic activ- ity is affecting the human exposome and thus is increasing immune- mediated diseases. We discuss molecular mechanisms by which climate change mediates immune diseases. In particular, we focus on the effect of climate change on allergies and asthma. We suggest ways to adapt to and mitigate climate change and improve planetary and human health as the two are interconnected. Individuals and local, national, and international communities need to have an active role in promoting and maintaining planetary and human health. We discuss current international policies and agreements in place for mitigating climate change. We also discuss the role that health care providers, their patients, and the general population can have in adapting to and mitigating climate change. Anthropogenic Activities, Climate Change, and the Human Exposome Since the start of the Industrial Revolution, increased human activity and population growth have significantly altered the earth’s environ- ment. The human exposome, which encompasses the totality of human environmental exposures, both internal and external, from concep- tion to death, is being subjected to rapid changes. Industrialization, INTRODUCTION Increased anthropogenic activity which started during the Industrial Revolution has been accelerating since 1950, leading to excessive air, land, and water pollution, breaching the planetary health boundar- ies. Greenhouse gases (GHGs), emitted by burning of fossil fuels, by raising global temperatures, have accelerated climate change. Conse- quently, we are witnessing increased frequency and intensity of climate change–related events, such as extreme weather events, wildfires, and sand and dust storms (SDS), which further increase air pollutants, par- ticularly particulate matter (PM). Wildfires also release carbon dioxide (CO2), a potent GHG, adding to the feedback loop fueling further cli- mate change. Other climate change–related events that increase air pol- lution are prolonged summer season and flooding. Prolonged summer season increases the number of days each year that pollen is released into the air as well as its concentration. Flooding increases dampness leading to increases in mold spores. 1 Thunderstorms affect pollen aller- genicity and have been linked to asthma epidemics. 2,3 812 SECTION E Respiratory Tract likelihood of development of new sensitizations and of allergy, and earlier onset of symptoms (Fig. 46.1). Ragweed is a common allergen. Climate change is expected to promote the geographical spread of this invasive weed and increase incidence and exacerbation of allergies and asthma. 190 Vector-Borne Diseases . Climate change has led to the global spread of disease vectors, such as lone star ticks. The lone star tick is a vector for red meat allergy. The tick, by transmitting a sugar called alpha-gal into a person’s bloodstream, sensitizes an individual to red meat. Alpha-gal is present in most mammals, such as cows and pigs. When a sensitized individual consumes meat from these animals or their products, an allergic reaction may occur. Symptoms may include hives, swelling, difficulty breathing, and anaphylaxis. 191 Droughts . Drought adversely affects human health as food and water shortages increase risk of malnutrition and dehydration. Many poten- tially harmful metals, such as cadmium, chromium, copper, nickel, zinc, lead, and mercury are found in our waterways. 192,193 Warmer water temperatures have been correlated with heavy metal concentrations, specifically increased bioaccumulation of mercury in fish. 194 In some communities, heavy metals such as arsenic and cadmium are present in the drinking water. 195–197 Exposure to these metals have been associated with changes in immune cells. 198,199 Nutritional Content of Foods . Climate change is associated with decreased yield and altered nutritional content of foods. It is estimated that a 1°C increase in temperature decreases wheat yield by 6%. 200 Ris- ing CO2 concentrations have been linked to a reduction in the nutri- tional quality of major cereal crops. 201 Soybeans subjected to heat waves during early pod development cause significant yield loss; lentils exposed to heat stress have decreased levels of iron, zinc, and crude protein content. 202,203 The concentrations of other nutrients in plants, such as iron and zinc, are also lowered by increased global warming and increased CO2. 204–206 Synergistic Exposures . About 850 million children live in areas where they are exposed to four or more climate change–related events and environmental hazards, such as wildfires, flooding, air pollution, and resource scarcity. 207 These factors often act synergistically increas- ing adverse asthma- and allergy-related outcomes. Socioeconomic Disparities, Vulnerable Populations, and Climate Justice Climate change is a threat multiplier exacerbating existing socioeco- nomic inequities. Individuals in low-income countries particularly those socioeconomically disadvantaged bear the brunt of the adverse effects of climate change. Even in developed countries, low-income groups are the most affected and more likely to live in more polluted neighborhoods. Certain populations such as children, older adults, pregnant women, disabled, or those with chronic diseases are at even greater risk. GHG emissions vary widely, with developed nations emit- ting the largest carbon footprint. The Group of 20 (Argentina, Aus- tralia, Brazil, Canada, China, France, Germany, India, Indonesia, Italy, Japan, Republic of Korea, Mexico, Russia, Saudi Arabia, South Africa, Turkey, the United Kingdom, the United States, and the European Union) are responsible for about 76% of global GHG emissions. By contrast, least developed countries account for about 3.8% of global emissions, while small island developing states contribute less than 1%. 208 However, many of the world’s poorest nations, who are the least polluting are the most vulnerable. These inequities have led to calls for climate justice. Fig. 46.1 Climate change effects on pollen and increased prevalence of allergic disease. droughts, melting permafrost, sea level rise, and heat will render nearly a fifth of the planet inhabitable by 2070. 180 Estimates range from 150 million to over one billion people may be displaced by 2050. 181,182 Human migration due to wars and social conflicts, economic hard- ships, food and water insecurity will expose individuals to new aller- gens and disease vectors. These migrations also increase exposure to anthropogenic pollutants as migration is generally from rural to urban areas. By 2050, it is estimated that 143 million people in sub-Saharan Africa, South Asia, and Latin America will become displaced due to climate change. Fifty-five percent of the world’s population currently live in urban cities and this is expected to grow by 2050 to seventy percent. 183 These migratory patterns, particularly to urban areas, are expected to increase allergies and asthma. A study conducted in Canada found that asthma rates were higher in urban environments compared with rural areas. 184 Another study in the United Kingdom found that individuals living in urban areas recorded greater hay fever symptoms than in rural environments. 185 A systematic review and meta-analysis found that risk of asthma was higher in urban areas compared with rural areas but not for the risk of AR. 186 Migrants are also exposed to new allergens that they may not have encountered before and therefore may potentially lack immune tolerance to these allergens. 187 This is supported by a study which found increases in the prevalence of allergy in migrants compared with native-born individuals and between second- and first-generation migrants. 188 Migration also changes the mechanisms of the allergic diseases, a new concept in precision medicine called regiotypes. For example, in chronic rhinosinusitis with nasal polyps, the polyps tend to be predominantly neutrophilic in the Chinese population whereas in Western populations, they are mostly eosinophilic. 189 Impact on Pollen Growth and Allergenicity . Climate change is also affecting the growth, phenology, and distribution of grasses and weeds. It is expected to increase allergenicity and production of pollen and prolong duration of pollen season. This will bring about a greater 815 CHAPTER 46 Climate Change: Allergic Diseases and Asthma PM2.5 may also deplete major antioxidant mechanisms of the human body, such as superoxide dismutase, glutathione peroxidase, and non- enzymatic mechanisms, thus affecting the cellular redox balance. 259 Micro- and nanoplastics have been detected in human lungs, stools, placentas, and blood. 8 Orally exposed micro- and nanoplastics, due to their resistance to degradation, cause lysosomal dysfunction acti- vation and IL-1 production in intestinal macrophages. Micro- and nanoparticles induce phosphorylation of MAPK and induction of proinflammatory proteins such as cPLA2 and COX-1 and IL-1β, IL-6, and TNF-α release in kidney cells in animal models. 260,261 Polystyrene nanoplastics cause ROS-induced NLRP3 activation and subsequent neutrophil infiltration and neutrophil extracellular trap formation in mouse liver. 262 Heavy metals are also associated with immune changes. A study found that maternal arsenic and cadmium exposure from contami- nated water was associated with alterations in the T cell population in cord blood of infants. 198 Arsenic exposure was found to increase levels of the Th2 mediators, IL-4, IL-6, and IL-13, which increases suscepti- bility to allergic asthma. 199 Another mechanism by which heat stress has been shown to medi- ate its effects on asthma and allergic disease is via transient receptor potentials (TRPs), which are found in epidermal keratinocytes and are sensitive to temperature. There are several different TRP channels and research into their varying roles is still ongoing. TRPV1 channels have been found to be overexpressed in patients with asthma. 263 In a murine asthma model, TRPV1 antagonist or TRPV1 siRNA led to a reduction of airway hyperresponsiveness and reduction of inflammatory cyto- kines, such as TSLP, IL-25, IL-33, IL-4, IL-5, and IL-13. 264 Microbial Dysbiosis . Microbial dysbiosis has been implicated in allergy, and germ-free mice have elevated IgE. 265 Compositional dif- ferences in the microbiome have been found in atopic individuals. Analysis of the gut microbiota by 16S rRNA sequencing found that individuals with asthma harbored compositional differences from healthy controls in both adults and children. 266 In mice, lung micro- biota has been shown to affect pulmonary inflammation and oxidative stress induced by PM2.5 exposure. Pollutants can also alter microbial composition. When mice were exposed to PM2.5 intranasally for 12 days, microbial diversity decreased by 75.2% with increased abun- dance of Proteobacteria and decreased abundance of Bacteroidota . The altered composition of the microbiota was significantly correlated with pulmonary inflammation and oxidative stress-related indicators. 267 Individuals with allergies have been found to have significantly lower fecal microbial richness and fecal microbiota transplantation may offer Fig. 46.4 Mechanism of tolerance to innocuous environmental substances and Th2 mediated–allergic reac- tion (From Sampath V, Aguilera J, Prunicki M, Nadeau KC. Mechanisms of climate change and related air pollution on the immune system leading to allergic disease and asthma. Semin Immunol . 2023;67:101765. doi:10.1016/j.smim.2023.101765.) 814 SECTION E Respiratory Tract also well elucidated. In tolerance, T naïve cells are transformed into T regulatory cells, rather than Th2 inflammatory cells. T regulatory cells skew B cell class switching to secrete IgA and IgG4. These antibodies block the inflammatory allergic IgE state (Figs. 46.3 and 46.4). 248,249 IgE- mediated activation of mast cells and basophils leads to symptoms of an allergic reaction, which can be mild to severe, or even fatal. 247 Th2-type inflammation is the most important pathological process for asthma, accounting for approximately 50% of mild-to-moderate asthma and a large portion of severe asthma. 250 Our understanding of the immune mechanisms associated with tolerance and allergy has assisted with the development of many monoclonal antibodies, such as dupilumab, an IL-4Rα antibody, which blocks downstream signaling of both IL-4 and IL-13. This has been approved for both asthma, atopic dermatitis, and eosinophilic esophagitis, a type of chronic food allergy. Omalizumab, an anti-IgE molecule is approved for asthma and food allergy. 251 PM has also been shown to affect immune cells. Firefighters exposed to smoke from wildfires show increased pulmonary and systemic inflammation with increases in IL-6 and IL-12 and decreases in IL-10. 252,253 A study by Prunicki et al. 254 found wildfire smoke is associated with increased levels of proinflammatory markers such as C-reactive protein (CRP) and IL-1β. These biomarkers are associ- ated with increased asthma symptoms. Using targeted proteomics and immune cell phenotyping, a study found functional changes in critical immune cells and their proteins during wildfire smoke exposure in a cohort from the San Francisco Bay area during a major wildfire in 2020. 255 PM can also activate the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor and induce CYP1, AKR, NOx and COX-2 genes resulting in excessive generation of ROS. 256 It has been shown that AhR exerts numerous effects on mast cells, B cells, macrophages, antigen-presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells, thus playing a significant role in aller- gen-induced diseases. 257 Primary bronchial epithelial cells exposed to diesel exhaust particles showed upregulation of alarmins, which were abolished by knockdown of AhR by siRNA. 258 Chronic exposure to Fig. 46.2 Environmental factors associated with epithelial barrier damage. Fig. 46.3 Allergic inflammation on loss of epithelial barrier integrity. 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Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 806 46 Climate Change: Allergic Diseases and Asthma Vanitha Sampath, Ioana Agache, Harald Renz, Marc E. Rothenberg, Cezmi A. Akdis, Kari C. Nadeau C O N T E N T S Introduction, 806 Climate change and immune dysregulation: Allergic diseases, asthma, autoimmune diseases, and cancer, 807 The impact of climate change on allergies and asthma, 808 Conclusion, 818 SUMMARY OF IMPORTANT CONCEPTS • Increased greenhouse gas emissions caused by burning of fossil fuels are increasing surface global temperatures and adversely affecting planetary health and causing climate change. • Climate change is accelerating sea level rise, melting of glaciers, and increasing the frequency and intensity of climate events such as wildfires, sand and dust storms, droughts, and floods. • Climate change extreme weather events are changing the human exposome by increasing air pollution and also the spread of infectious vectors. • The rapidly changing exposome mediates epithelial barrier damage, microbial dysbiosis, and immune dysregulation, leading to increases in the prevalence of immune-mediated diseases, such as allergies and asthma. • Adaptation and mitigation strategies at the individual, local, national, and international levels are needed to stabilize or reverse global temperature increases and prevent further climate change. • A One Health approach, which recognizes the interconnectedness of human, animal, and environmental health, is needed to protect planetary and human health. While air pollution is a major climate change–associated factor which adversely affects health, other climatic factors also play a role. Higher global temperatures increase ground level or tropospheric ozone levels, which is known to affect respiratory health. Other deter- minants of health that are indirectly affecting climate change and which compound and exacerbate its effects include human displacement and migration; food, water, and housing insecurity; decreasing biodiversity and greenspace; and disruption and inequity in health care. These environmental changes have increased the prevalence of immune-mediated diseases such as allergic diseases, respiratory diseases, autoimmune diseases, and cancers with further increases expected. 4 There is an urgent need to increase personal and systems resilience in order to adapt to this accumulating climate change–related health burden while working toward mitigating its impact by decreasing GHGs, promoting sustainable growth and development, increasing biodiversity and green spaces, and decreasing inequities in health care in order to protect human and planetary health. 5,6 In this chapter, we discuss the various ways anthropogenic activ- ity is affecting the human exposome and thus is increasing immune- mediated diseases. We discuss molecular mechanisms by which climate change mediates immune diseases. In particular, we focus on the effect of climate change on allergies and asthma. We suggest ways to adapt to and mitigate climate change and improve planetary and human health as the two are interconnected. Individuals and local, national, and international communities need to have an active role in promoting and maintaining planetary and human health. We discuss current international policies and agreements in place for mitigating climate change. We also discuss the role that health care providers, their patients, and the general population can have in adapting to and mitigating climate change. Anthropogenic Activities, Climate Change, and the Human Exposome Since the start of the Industrial Revolution, increased human activity and population growth have significantly altered the earth’s environ- ment. The human exposome, which encompasses the totality of human environmental exposures, both internal and external, from concep- tion to death, is being subjected to rapid changes. Industrialization, INTRODUCTION Increased anthropogenic activity which started during the Industrial Revolution has been accelerating since 1950, leading to excessive air, land, and water pollution, breaching the planetary health boundar- ies. Greenhouse gases (GHGs), emitted by burning of fossil fuels, by raising global temperatures, have accelerated climate change. Conse- quently, we are witnessing increased frequency and intensity of climate change–related events, such as extreme weather events, wildfires, and sand and dust storms (SDS), which further increase air pollutants, par- ticularly particulate matter (PM). Wildfires also release carbon dioxide (CO2), a potent GHG, adding to the feedback loop fueling further cli- mate change. Other climate change–related events that increase air pol- lution are prolonged summer season and flooding. Prolonged summer season increases the number of days each year that pollen is released into the air as well as its concentration. Flooding increases dampness leading to increases in mold spores. 1 Thunderstorms affect pollen aller- genicity and have been linked to asthma epidemics. 2,3 46 Climate Change: Allergic Diseases and Asthma Vanitha Sampath, Ioana Agache, Harald Renz, Marc E. Rothenberg, Cezmi A. Akdis, Kari C. Nadeau C O N T E N T S Introduction, 806 Climate change and immune dysregulation: Allergic diseases, asthma, autoimmune diseases, and cancer, 807 The impact of climate change on allergies and asthma, 808 Conclusion, 818 SUMMARY OF IMPORTANT CONCEPTS • Increased greenhouse gas emissions caused by burning of fossil fuels are increasing surface global temperatures and adversely affecting planetary health and causing climate change. • Climate change is accelerating sea level rise, melting of glaciers, and increasing the frequency and intensity of climate events such as wildfires, sand and dust storms, droughts, and floods. • Climate change extreme weather events are changing the human exposome by increasing air pollution and also the spread of infectious vectors. • The rapidly changing exposome mediates epithelial barrier damage, microbial dysbiosis, and immune dysregulation, leading to increases in the prevalence of immune-mediated diseases, such as allergies and asthma. • Adaptation and mitigation strategies at the individual, local, national, and international levels are needed to stabilize or reverse global temperature increases and prevent further climate change. • A One Health approach, which recognizes the interconnectedness of human, animal, and environmental health, is needed to protect planetary and human health. While air pollution is a major climate change–associated factor which adversely affects health, other climatic factors also play a role. Higher global temperatures increase ground level or tropospheric ozone levels, which is known to affect respiratory health. Other deter- minants of health that are indirectly affecting climate change and which compound and exacerbate its effects include human displacement and migration; food, water, and housing insecurity; decreasing biodiversity and greenspace; and disruption and inequity in health care. These environmental changes have increased the prevalence of immune-mediated diseases such as allergic diseases, respiratory diseases, autoimmune diseases, and cancers with further increases expected. 4 There is an urgent need to increase personal and systems resilience in order to adapt to this accumulating climate change–related health burden while working toward mitigating its impact by decreasing GHGs, promoting sustainable growth and development, increasing biodiversity and green spaces, and decreasing inequities in health care in order to protect human and planetary health. 5,6 In this chapter, we discuss the various ways anthropogenic activ- ity is affecting the human exposome and thus is increasing immune- mediated diseases. We discuss molecular mechanisms by which climate change mediates immune diseases. In particular, we focus on the effect of climate change on allergies and asthma. We suggest ways to adapt to and mitigate climate change and improve planetary and human health as the two are interconnected. Individuals and local, national, and international communities need to have an active role in promoting and maintaining planetary and human health. We discuss current international policies and agreements in place for mitigating climate change. We also discuss the role that health care providers, their patients, and the general population can have in adapting to and mitigating climate change. Anthropogenic Activities, Climate Change, and the Human Exposome Since the start of the Industrial Revolution, increased human activity and population growth have significantly altered the earth’s environ- ment. The human exposome, which encompasses the totality of human environmental exposures, both internal and external, from concep- tion to death, is being subjected to rapid changes. Industrialization, INTRODUCTION Increased anthropogenic activity which started during the Industrial Revolution has been accelerating since 1950, leading to excessive air, land, and water pollution, breaching the planetary health boundar- ies. Greenhouse gases (GHGs), emitted by burning of fossil fuels, by raising global temperatures, have accelerated climate change. Conse- quently, we are witnessing increased frequency and intensity of climate change–related events, such as extreme weather events, wildfires, and sand and dust storms (SDS), which further increase air pollutants, par- ticularly particulate matter (PM). Wildfires also release carbon dioxide (CO2), a potent GHG, adding to the feedback loop fueling further cli- mate change. Other climate change–related events that increase air pol- lution are prolonged summer season and flooding. Prolonged summer season increases the number of days each year that pollen is released into the air as well as its concentration. Flooding increases dampness leading to increases in mold spores. 1 Thunderstorms affect pollen aller- genicity and have been linked to asthma epidemics. 2,3
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 807 CHAPTER 46 Climate Change: Allergic Diseases and Asthma urbanization, and population growth have led to deforestation, clear- ing of land for agriculture and grazing, and reef destruction, all leading to loss of biodiversity. In addition, increased energy utilization (pri- marily from burning of fossil fuels), mining, use of synthetic fertilizers and pesticides in agriculture, and manufacture of synthetic chemicals have increased chemical pollution exponentially. Runoff from syn- thetic fertilizers, pesticides, and other toxins pollutes our waterways, soil, and food. More than 350,000 synthetic chemicals introduced for use in the last 50 years, all toxic to human health at very low concentra- tions, continuously pollute our air, water, soil, and food. 7 The number of newly generated forever chemicals, which are those that persist in the environment for hundreds to thousands of years, are increasing and accumulating in our environment. The volume of discarded plastics and microplastics is so large that the current era has been nicknamed the Plasticene era. 8 We have also altered our lifestyles with increased urbanization; improved hygiene; use of antibiotics, detergents, and soaps; consumption of processed foods; decreased outdoor activ- ity; and reduced exposure to pets, farm animals, and green space. All these factors are altering the human exposome physically, chemically, and biologically with consequences to the normal functioning of the immune system. By polluting our air, water, and soil and destroying natural resources, increased human activity is increasing global surface temperatures and ocean acidity, which are leading to fundamental changes in Earth’s cli- mate. The burning of fossil fuels is the major contributor to climate change. Fossil fuels are hydrocarbons of biological origin (fossilized plant and animal remnants) formed millions of years ago and primarily include coal, petroleum, and natural gas. These nonrenewable fuels are extracted from the Earth’s crust and have been increasingly used for the production of heat, electricity, transportation, and for manufacturing. Currently, they supply more than 80% of all the energy consumed by the industrially developed countries of the world. 9 Their consumption has increased around eightfold since 1950. 10 Fossil fuels powered the industrial revolution and ushered many regions of the world into the modern era; however, they also increased the concentration of pollut- ants that adversely affect planetary and human health. Burning of fossil fuels primarily releases oxides of carbon, sulfur, and nitrogen; hydrocarbons; and volatile organic compounds. They also release PM, which is a mixture of solid particles and liquid drop- lets suspended in the air. Of the emitted gases, CO2, methane, and nitrous oxides are GHGs, which trap heat in the Earth’s atmosphere, similar to insulating glass walls of a greenhouse. By trapping heat, they raise global temperatures. Fossil fuels account for over 76% of global GHG emissions. 11 The predominant GHG is CO2, accounting for 76% of all GHGs, followed by methane (16%), nitrous oxide (6%), and fluo- rinated gases (2%). 12 The effect of each gas on global warming depends on their abundance, how long they stay in the atmosphere, and their global warming potential. 13 For example, methane has 28 times greater global warming potential than CO2. 14 However, methane has a rela- tively short life span of 7 to 12 years in the atmosphere, while CO2 can persist for hundreds of years or more. 15 While fossil fuels are primarily responsible for the release of GHGs, other anthropogenic activities also release GHGs. Large amounts of methane are released by cattle farm- ing, landfill waste dumps, and the production of oil and gas. Nitrous oxides are also released through fertilizers, nitric-acid production, and biomass burning. Fluorinated gases are synthetic gases produced in smaller amounts; however, they are long-lasting and highly potent GHGs. CO2 levels have been increasing since the start of the Industrial Revolution (roughly around the 1770s) and in January 2024 was 422 ppm, much higher than at any point in human history. Prior to the Industrial Revolution, CO2 levels were consistently around 280 ppm for almost 6000 years of human civilization. Current levels are now comparable to those seen between 4.1 and 4.5 million years ago, when they were close to, or above 400 ppm. 16 Additionally, the concentra- tion of methane in the atmosphere has more than doubled over the past 200 years. 15 Another GHG of importance is ground-level or tro- pospheric ozone, which is not directly emitted by fossil fuels, but is formed through chemical reactions between nitrogen oxides and vola- tile organic compounds in the presence of sunlight. It is a short-lived pollutant with an atmospheric lifetime ranging from a few hours to a few weeks, primarily in polluted urban regions. 17 Currently it is estimated that the health care sector contributes to more than 4% of net GHG emissions. Hospitals and research labs also use high amounts of consumables, which require large amounts of raw materials and energy to produce. They are further responsible for pol- luting the environment via disposal of plastics, drug products such as asthma inhalers, and other chemicals. 18 With increases in GHGs, there have been increases in global surface temperatures. Earth was about 1.4°C warmer in 2023 than the average temperature in the late 19th century (1850 to 1900). The 10 most recent years are the warmest on record with 2023 19 being the warmest year on record since global records began in 1850. 20 Sea surface temperature also increased during the 20th century. From 1901 to 2020, sea surface temperature rose at an average rate of 0.14°F per decade and continues to rise. 21 CO2, in addition to increasing global surface temperatures, increases ocean acidity. The ocean absorbs some of the CO2 that is released into the atmosphere. In the last 200 years, the pH of surface ocean waters has fallen by 0.1 pH units, a change of approximately 30% increase in acidity. 22 Ocean acidification reduces the amount of car- bonate, which are building blocks for the skeletons and shells of many marine organisms. CLIMATE CHANGE AND IMMUNE DYSREGULATION: ALLERGIC DISEASES, ASTHMA, AUTOIMMUNE DISEASES, AND CANCER The rapidly changing human exposome is adversely affecting immune health. The immune system is the major organ system that responds to substances in the environment to either build tolerance to self and innocuous substances that we encounter or mount an attack against harmful substances such as viruses, parasitic worms, or toxins. It is also the key pillar of resilience to the harmful impacts of the exposome, together with the microbiome, the epithelial barrier, and diet. 6,23–26 The immune system is constantly learning and adapting to envi- ronmental changes but can be overwhelmed by rapid changes. It can also become hyperactive and react to innocuous substances, such as foods, pollen, and molds in allergic disease. In other cases, the immune system attacks one’s own cells as in autoimmune diseases. The role of immune dysregulation in cancer is also being increasingly recognized. The immune system plays a critical role in identifying and eliminat- ing tumors (immune surveillance) and dysregulation of the immune system can increase the risk of developing cancer. Several autoimmune conditions are associated with an increased risk of cancer. In autoim- mune diseases, when immune cells attack and damage one’s own tis- sues, it leads to a proinflammatory state, which increases susceptibility to cancer. Similarly, viral infections create a persistent inflammatory state and increase risk of tumorigenesis. 27 Moreover, the cross-talk between the immune and the metabolic systems is pivotal in promot- ing “metabolic health” throughout the life of an organism and plays fundamental roles in its adaptation to ever-changing environmental landscape and nutritional availability. 28 Allergic diseases and allergic asthma affect millions of people worldwide and pose a huge global health and socioeconomic burden. 29
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 808 SECTION E Respiratory Tract The mechanism underlying allergic hypersensitivity diseases vary and include types 1 to 4 immune responses together with tissue-mediated mechanisms, metabolic- and microbiome-induced immune dysregu- lation, and direct cellular and inflammatory responses to chemicals. 30 Although prevalence data vary with type of allergy, geographical loca- tion, methodology, and population, allergic diseases have been steadily increasing. 31 Reported rates of asthma range from 1% to 20%, allergic rhinitis (AR) from 1% to 18%, and skin allergies from 2% to 10% in var- ious populations. 31 Although genetics has been shown to have a role in the etiology of allergic diseases, the rate of increase in allergic diseases is too rapid to be explained by genetics alone and is currently consid- ered one of the best examples of environmentally driven immune dys- regulation leading to chronic inflammation. Allergic diseases are often chronic needing long-term treatment and individuals with one allergic condition often develop other allergic diseases. The so-called allergic march starts in early infancy or childhood with atopic dermatitis and food allergies, followed later in life by AR and asthma. 32,33 In the United States, direct costs are reported to be $57.9 billion for asthma (2013 estimate of total medical costs); between $252 and $314 million for atopic dermatitis (2013 estimate of direct health care costs), $225 million for food allergy (2007 direct medical costs), and more than $4.6 billion dollars for AR (annual direct medical costs). 29,34 Approximately 4.4% of adults and up to 18.6% of children/adolescents have AD in Europe, with 20% of all cases accounting for moderate- to-severe forms. This form of the condition in adults results in annual societal costs across Europe of an estimated €30 billion; €15.2 billion related to missed workdays or reduced work productivity, €10.1 bil- lion related to direct medical costs, and €4.7 billion related to personal expenditure of patients/families. 35 The costs of allergic diseases increase with severity and with lack of control, which is strongly dependent on the environmental aggression. 36 The prevalence of autoimmune diseases is estimated to be about 4.5%. The risk of most autoimmune diseases is higher in women than in men (6.4% versus 2.7%, respectively). 37 Studies suggest that preva- lence of autoimmune diseases is increasing. NHANES data show that antinuclear antibodies (ANA), which are a group of diverse autoanti- bodies that are used to screen for autoimmune diseases, have increased from 11.0% in 1988–1991 to 16.1% in 2011–2012. 38 Some studies have associated long-term exposure to polluted air with higher risk of developing autoimmune diseases, in particular rheumatoid arthritis, connective tissue diseases, and inflammatory bowel diseases. 39 A ret- rospective observational study found every 10 μg/m 3 increase in PM10 was associated with an incremental 7% risk of having autoimmune disease. Exposure to PM10 above 30 μg/m 3 and PM2.5 above 20 μg/m 3 was associated with a 12% and 13% higher risk of autoimmune dis- ease, respectively. 40 Air pollution has also been found to be potentially involved in autoimmune diseases of the musculoskeletal system via oxidative stress and local and systemic inflammation, epigenetic modi- fications, as well as the mitochondrial dysfunction. 41 According to the World Health Organization (WHO), cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one in six deaths. 42 A meta-analysis of cohort studies indicated that long-term exposure to ambient air pollutants is associated with increased mortality from all cancers. 43 The global bur- den of disease study reported that cancer deaths attributable to ambient PM pollution increased by more than 300% from 1990 to 2017. 44 The carcinogenic potential of PM2.5 extends beyond respiratory implica- tions, affecting various organs, including the digestive tract, breast, and prostate. Polycyclic aromatic hydrocarbons attached to PM2.5 are rec- ognized as endocrine-disrupting chemicals with specific implications for breast and prostate cancer. 45 A large US cohort with historical air pollutant exposure estimated that PM2.5 increased the risk of estrogen receptor–positive breast cancer. 46 A study evaluated the association between wildfire-related PM2.5 and site-specific cancer mortality in Brazil, from 2010 to 2016, and found that exposure to wildfire-related PM2.5 increases the risks of cancer mortality for many cancer sites, and the effect for wildfire-related PM2.5 was higher than for PM2.5 from non- wildfire sources. 47 The International Agency for Research on Cancer in 2013 classified both outdoor air pollution and PM in outdoor air pollu- tion as Group 1 human carcinogens. 48 THE IMPACT OF CLIMATE CHANGE ON ALLERGIES AND ASTHMA Climate change–related events (wildfires, SDS, thunderstorms, pro- longed pollen season, mold proliferation, and others) add to existing air pollution from industrial and vehicular emissions. Other anthro- pogenic activities that increase air pollution, particularly in indoor spaces, include open fires or stoves for cooking fueled by biomass or coal, tobacco smoke, and volatile organic compounds from consumer products such as cleaning supplies. The WHO estimates that 99% of the global population lives in areas with air that exceeds the WHO guide- line limits for air pollutants, especially in low- and middle-income communities. 49 There are many thousands of air pollutants. While the toxicity of many is known, the toxicity of other compounds has not been evaluated. Currently, the US Environmental Protection Agency (EPA) regulates six air pollutants for which it sets permissible levels. These six pollutants include carbon monoxide, lead, nitrogen oxides, ground-level ozone, PM, and sulfur oxides. 50 Of these, PM has been most studied for its respiratory health effects. Another air pollutant that has been associated with respiratory health is ground-level ozone. PM consists of a mixture of solid particles and liquid droplets with varying chemical composi- tion, depending on the source. Those that are smaller than 10 microns (PM10) can enter the lungs, which on deposition on the lung surface can induce tissue damage and lung inflammation. Of particular concern is PM with an aerodynamic diameter of 2.5 micrometers or less (PM2.5). They are able to travel deep into the bronchioles and alveoli of the lungs and enter the bloodstream, potentially causing the most harm. 51,52 Many studies have found associations between air pollutants and respiratory diseases 53,54 such as COPD, 55 asthma, 4,56–60 and AR. 61–63 Poor air quality is associated with both new-onset asthma and adverse asthma-related outcomes, including increased rates of emergency room visits and hospitalizations for acute exacerbations and loss of asthma control. 64 Air pollutants damage the epithelial barrier and thus can increase allergen contact with the submucosal antigen presenting cells and promote sensitization. 65 Analysis of data from 3687 participants of the prospective Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort found a higher incidence of new-onset asthma through the age of 20 years with higher exposure to nitrogen dioxide and PM lesser than 10 μm. 66 A systematic review and meta- analysis found that the odds ratio associated with a 10 μg/m 3 increase in exposure to PM10 and PM2.5 and risk of AR was 1.13 and 1.12, respec- tively. 67 A meta-analysis and systematic review found that increased longitudinal childhood exposure to PM2.5 increased risk of new-onset asthma (odds ratio 1.14). 68 A meta-analysis of 35 studies across 12 countries showed a positive association between air pollution (PM10, PM2.5, SO2, ozone, nitrogen dioxide [NO2]) and the prevalence of AR. 69 Air pollution also increases risk for respiratory infections and impaired lung growth and function in children. 70 Air pollutants are thought to increase risk for and exacerbate respiratory disease by epithelial barrier damage, local epithelitis with release of epithelial derived cytokines, enhancement of sensitization to aeroallergens, various immunological and inflammatory pathways, including neuroinflammation, increased
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 809 CHAPTER 46 Climate Change: Allergic Diseases and Asthma oxidative stress, and airway remodeling. 58,71,72 In 1970, the Clean Air Act was passed, which was a federal law regulating air emissions that authorizes the EPA to establish National Ambient Air Quality Stan- dards to protect public health and public welfare and to regulate emis- sions of hazardous air pollutants. 73 In 2024, the US EPA limits for PM2.5 were lowered to 9 mg/m 3 (previously 12 mg/m 3 ). 50 The WHO guideline for PM2.5 is currently at 5 mg/m 3 . 74 Pollutants act synergistically with pollen on the airways, increasing the odds of asthma exacerbations, thus climate change–linked longer pollen season and increased pollution create a vicious cycle deeply impacting patients with asthma or AR. 75 Wildfire . Climate change is increasing the frequency and intensity of wildfires and prolonging the length of the wildfire season. Wildfires are uncontrolled fires usually in a forest, grassland, brushland, or peatland involving combustible vegetation. They can adversely affect human lives, health, infrastructure, or the environment. The nature and intensity of the wildfire depends on the fuel source (dried out organic materials or built structures), weather conditions (wind, temperatures, lightning, and humidity), and topography (uphill versus downhill). Humans also have an important role in wildfires with more people living in wildland-urban interfaces and accidentally or intentionally starting fires. Increased fuel accumulation in forests combined with fire suppression has also had significant impacts on fire scale and intensity. Wildland fire events are getting more extreme in terms of acres burned, duration, intensity, loss of life and property, and downwind air pollu- tion impacts. A study looked at forest loss and found increasing trends from 2001 to 2019, which was driven by increases across the tropics, subtropical, and temperate Australia, and boreal Eurasia. 76 Recent years have seen increasingly severe wildfires, including in the Amazon rainforest (2019), Australia (2019 to 2020), Siberia and other parts of Russia (2020, 2021), California, USA (2020), Canada (2019 to 2023), and Greece, Italy, and Spain (2015 to 2023). Since 2000, wildfires have burned an annual average of 7.0 million acres. The figure is more than double that burned in the 1990s. 77 Wildfire smoke can travel hundreds to thousands of miles from the source. 78,79 The 2021 fires that burned large swathes of the West Coast resulted in air quality warnings as far east as Philadelphia and New York. 80 Wildfire smoke is a complex mix of gases and PM, the composi- tion depending on the components that are burning. These may include CO2, carbon monoxide, PM, complex hydrocarbons, nitrogen oxides, trace minerals, heavy metals and many other toxic and carci- nogenic compounds. In 2020 after the start of a wildfire in California, USA, PM2.5, ozone, and carbon monoxide concentrations increased by approximately 220%, 20%, and 151%, respectively. 81 In addition, when wildfires burn down built structures, synthetic materials such as plastics, metals, and other household chemicals, toxins from these materials are also released. 82 Preliminary evidence also suggests that wildfire smoke may grow more toxic over time as it travels through the atmosphere and gets further oxidized into free radicals. 83 Wildfires are themselves a significant source of carbon emissions. In 2021 wild- fires caused the release of 1.8 billion tons of carbon worldwide. 84 By releasing CO2, forest fires create a vicious feedback loop accelerating climate change. 85 Further, by destroying trees and other vegetation, wildfires decrease carbon sinks and hamper the environment’s capacity to absorb CO2. Wildfire smoke affects a large number of individuals. A study esti- mated that in the United States, nearly 10% (about 30.5 million) of the population live in areas where the contribution of fires to annual ambi- ent PM2.5 is high (>1.5 μg/m 3 ) and 10.3 million individuals experience unhealthy air quality levels (daily fire-PM2.5 >35 μg/m 3 ) for more than 10 days per year due to smoke. 86 Many studies have found increased rates of respiratory diseases such as asthma following exposure to wildfires. During the 2003 California wildfires, average increases of 70 μg/m 3 PM2.5 during heavy smoke conditions compared with PM2.5 in the pre-wildfire period were associated with a 34% increase in asthma admissions. 87 An analysis of emergency department visits and hospitalizations in Colorado, USA, between May-August of 2011 and 2014 found an increase for asthma and combined respiratory disease for every 1 μg/m 3 increase in wildfire PM2.5. 88 In Oregon, USA, a study found that a 10 μg/m 3 increase in wildfire smoke PM2.5 exposure was associated with increased asthma diagnosis and increased prescrip- tions for asthma rescue inhaler medication. 89 Increase in asthma con- sultations were found among firefighters involved in fighting the 2016 Fort McMurray fire in Alberta, Canada. The study found FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) were positively associated with increasing exposure; a fifth of the firefighters had a positive methacholine challenge test and bronchial wall thicken- ing. 90 In Thailand, decreased FEV1/FVC ratio was observed in those exposed long-term to wildfire smoke exposure, suggesting obstructive lung abnormality. Patients in the study also reported watery and itchy nasal symptoms, cough, phlegm, and chest pain. 91 Many studies have also looked at the effect of wildfire smoke on children as they are more susceptible to harm from inhaling pollutants because they inhale more air per pound of body weight than adults. They also spend more time outdoors. In addition, children’s immature immune systems may cause them to be more susceptible to PM than healthy adults. 92 In Canada, PM2.5 exposure in children during and after wildfires led to increased respiratory condition–related outpatient phy- sician visits during and after wildfires. Risk of respiratory symptoms per 10 μg/m 3 increase in PM2.5 during and after wildfire was increased by 33% and 55%, respectively. Respiratory symptoms included asthma, acute bronchitis and acute respiratory infection. 93 A retrospective cohort study in Calgary, Canada showed a clear increase in asthma exacerbations over the baseline (incidence rate ratio: 1.13; 95% CI: 1.02 to 1.24) directly related to wildfire smoke days that was not seen with air pollution in general. 94 It is suggested that smoke from wildfires is more harmful than exposure to environmental tobacco smoke as it has more organic polar compounds with greater potential for oxidative stress and systemic inflammation. This is supported by a study which found increases in respiratory hospitalizations ranging from 1.3 to up to 10% with a 10 μg m −3 increase in wildfire-specific PM2.5, compared to 0.67 to 1.3% associated with non-wildfire PM25. 95 These findings highlight the need for measures to prevent wild- fires and protect individuals from their harmful effects. A study used a modeling approach and estimated that smoke-related asthma events in 2050 could increase at a rate of 15.1 hospital visits per 10,000 per- sons in the Western United States with health care costs due to asthma exacerbation to be over $1.5 billion during a single future fire season. 96 Sand and Dust Storms . Sand and dust particles are classified into large particles (60 μm or larger) and small particles (less than 60 μm in diameter). SDS have become more frequent and severe in recent decades due to increased global temperature, heat waves, droughts, and deforestation. The areas with high dust storm activity are located in desert areas primarily in a broad dust belt that extends from West Africa across the Middle East, to South, Central, and Northeast Asia. 97 SDS contain large amounts of PM2.5, 98 which contains a variety of minerals and their oxides (e.g., silicon, magnesium, iron, or calcium oxides), organic content, pathogens (bacteria, fungi, and viruses), aller- gens (dust mites, pollen, and fungal spores), and anthropogenic pol- lutants in its matrix or on its surface. A report by the United Nations estimated that 2 billion tons of dust are emitted into the atmosphere each year, with the Asia-Pacific region contributing to 27% of those
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 810 SECTION E Respiratory Tract emissions. 99 SDS carry particles thousands of miles from their source crossing national and international boundaries. Dust from East Asia is transported not only to North China but also South Korea and Japan, and can even reach extensive areas of the Pacific Ocean and North America, Greenland, Alaska, and the Alps in Europe. 100 A nationwide multicenter time-series study analyzed around 1.5 million deaths and 2024 SDS events from 214 Chinese counties and found that excess mortality risks for respiratory disease associated with SDS were 8.90%. 101 SDS have a significant impact on hospital admissions for respiratory diseases such as asthma. 102,103 A study found that over a 5-year period in Kuwait, on days with dust storms, same day asthma and respiratory admission at hospitals increased significantly. 104 A sys- tematic review found that most studies found harmful effects of SDS on respiratory diseases, including increase in the number and duration of hospitalizations, as well as increases in mortality and exacerbation of these diseases; however, not all these results were statistically signifi- cant. 105 As SDS contains pathogens and microorganisms such as bacte- ria, fungi, and spores, they can affect respiratory health. These particles can travel long distances leading to respiratory infections, asthma, and allergies. 106,107 In the southwestern United States, increased incidence of Coccidioidomycosis infections have been observed. These airborne fungal spores can be inhaled leading to valley fever, a respiratory infec- tion similar to pneumonia. The incidence of infection has been seen to increase during the dry summer months and natural events, such as earthquakes, dust storms, and fires. It is hypothesized that global warming may increase the geographic range of the fungus northwards. Experts predict that, due to climatic and other environmental changes, the incidence of coccidioidomycosis may increase by 164% by 2050. 108 Changing Season Temperatures and Duration: Effects on Ozone and Pollen . Climate change has prolonged the duration of the sum- mer season and shortened the duration of the spring and autumn seasons. It has also led to warmer winters. Over the period of 1952 to 2011, the length of summer in the Northern Hemisphere midlatitude increased from 78 to 95 days and that of spring, autumn, and winter decreased from 124 to 115, 87 to 82, and 76 to 73 days, respectively. Climate change in North America has been estimated to contribute to about 50% of the prolonged pollen season. 109 It is projected that by 2100, summer might last nearly half a year, but winter less than 2 months. 110 Longer summer seasons lead to increased formation of another GHG, ozone, which is formed more readily in warmer climates. Ground level ozone is a major constituent of smog and formed when volatile organic compounds and oxides of nitrogen react in sunlight. Major sources of volatile organic compounds and oxides of nitrogen include motor vehicle exhaust, gasoline vapors, and chemical sol- vents. Increased ground-level ozone is associated with increased risk of asthma exacerbations. It is one of the air pollutants whose standards are set by the EPA, 50 European Environment Agency (EEA), 112 and WHO. 113 It is thought to cause an inflammatory cascade in the airways through an increase in proinflammatory mediators, chemokines, and neutrophils. 114 It has been linked to respiratory tract irritation, inflam- mation, oxidative stress, decreased function, and increased epithelial barrier permeability. A study used published survey data on national and regional emergency room visits among people with asthma and estimated that in 2015, 9 to 23 million (8% to 20% of total) asthma- related emergency room visits globally were attributable to ozone. 115 A systematic review found that increases in long-term ozone exposure in children was associated with a decrease in FEV1. 116 Using allergy symp- tom, pollen, weather, and air quality data, a study found that ozone affects symptom severity of pollen allergy. 117 Changes in pollen season, pollen concentration, and geographical distribution of pollens have led to increased duration and severity of seasonal AR and allergic asthma. 118,119 Higher temperatures and CO2 levels increase photosynthesis in plants, leading to increased produc- tion of pollen. 120–122 Timothy grass pollen doubled when CO2 in the atmosphere (under controlled laboratory conditions) doubled from 400 to 800 ppm. 123 NO2 and ozone have also been shown to dam- age pollen cell membranes and increase the concentration of pollen released into the atmosphere. Further, they were found to alter the pollen protein structure via nitrification and oxidation increasing its immunogenicity and stability. 124 Pollen season varies with the source of the pollen. A study found that tree pollen is more common in the spring while weed pollen is more common in the fall. 125 Pollen concen- trations are on the rise and are estimated to increase by 200% by the end of the century. 121 The increase in pollen concentration has signifi- cant consequences for public health outcomes, especially for respira- tory diseases such as allergy and asthma. Pollen exposure is associated with increased rates of asthma and allergies, specifically AR. 121 A sys- temic review and meta-analysis found a statistically significant increase in the number of asthma emergency department visits with increases of 10 grass pollen grains per cubic meter of exposure. 126 Thunderstorms and Floods . As global temperatures rise, the risk of severe storms and thunderstorms increases as warmer air holds more moisture. 127 Extreme flooding can occur in coastal areas particularly when storm surge coincides with normal high tide, resulting in storm tides reaching up to 20 feet or more in some cases. Thunderstorms are formed when warm, moist air rises into cold air and condenses. They are associated with lightning, which occurs as the negative charges (electrons) in the bottom of the cloud are attracted to the positive charges (protons) on the ground. 128 Estimates indicate that the likeli- hood of a tropical storm developing into a category 3 or higher hur- ricane is increasing by 8% per decade due to climate change. 129 Areas damaged by wildfires are particularly susceptible to flash floods. Rainfall that is normally absorbed by soil and vegetation can run off almost instantly, causing creeks and drainage areas to flood much earlier and with higher magnitude than normal. Urban areas with limited areas for water runoff are also more likely to be affected by flash floods. Flash floods, storm surges, and inland flooding increase moisture in dwellings, thus increasing mold spores, which affect aller- gies and asthma. 130 Molds affect 10% to 30% of households in moderate and warm climates. 131 They release spores that can induce airway irrita- tion and inflammation on inhalation. An association between thunderstorms and asthma, termed thun- derstorm asthma (TA), has been observed. TA refers to observed increases in asthma incidence following the occurrence of thunder- storms when pollen counts are high, generally in late spring and early summer. 132 They can result in significant morbidity and mortality and have been linked to increased asthma exacerbations and emergency room visits. 133,134 During thunderstorms, pollen and/or mold spores are swept up into the clouds, where they are fractured either by electric charge or by osmotic shock into smaller, more allergenic fragments resulting in each grain releasing hundreds of small (<5 μm) allergenic granules, which are capable of reaching the lower airways. 135,136 In November 2016, a catastrophic and deadly TA epidemic struck Mel- bourne, Australia and overwhelmed health services, leading to loss of many lives. 137 During that time, grass pollen concentrations were extremely high (>100 grains/m³) and within 30 hours, there was a 672% increase in respiratory issues at the emergency department, a 992% increase in asthma-related admissions, and the death of 10 individuals. 138 TA events are rare with slightly over 20 reported cases. They have occurred in several countries around the world, including the United States, United Kingdom, Canada, and Australia. A study estimated change in the risk of asthma-emergency room visits related
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 811 CHAPTER 46 Climate Change: Allergic Diseases and Asthma to TA events in the Minneapolis–St. Paul metropolitan area over the years 2007 to 2018 and found a 1.05 times higher risk of asthma- related emergency department visits on the day of TA event. 139 They are sporadic and infrequent and difficult to predict. However, they primarily occur when circulating aeroallergen counts are high. 136 Flooding is also associated with increased asthma and other respi- ratory disorders. After major floods, there is proliferation of mold spores due to increased dampness exposing residents to indoor aero- allergen exposure. 135,140 In the aftermath of Hurricane Harvey, flood- exposed individuals were at increased risk of upper respiratory tract allergic symptoms on exposures to mold. 141 In the aftermath of hur- ricane Katrina and Rita in New Orleans, USA, high concentrations of molds were found; those homes with greater flood damage had higher levels of mold growth compared with homes with little or no flood- ing triggering asthma attacks. 142 Analysis of data from a cross-sectional National Survey of Children’s Health (2017 to 2018) found that among over 41,000 US children, the prevalence of asthma in children who were exposed to homes with mold was greater than those in homes without mold. 143 Molds are characterized by the presence of multicel- lular filaments called hyphae. Multiple studies suggest that exposures to molds such as Alternaria , Aspergillus , Cladosporium , and Penicillium may contribute to the development of asthma. 144 Extreme Temperatures: Heat Waves and Cold Spells . Cold spells, heatwaves, and droughts are examples of long-lasting high- impact weather events directly related to climate change. These types of persistent weather events have a huge social and economic impact on our lives, from our food and water supply to our health. Heat waves are increasing and affecting planetary health. 145 Although the definition of a heatwave has not been standardized, in general, heat waves are defined as persistent periods of ambient tem- perature higher than the average. 146,147 The EPA defines heat waves as a period of two or more consecutive days when the daily minimum apparent temperature exceeds the 85th percentile of historical July and August temperatures (1981 to 2010). With increasing global tempera- tures, heat waves are becoming more frequent and severe. In the United States, incidence of heat waves has been steadily increasing from about two per year (1960s) to six per year (2010s and 2020s). 148 Cold spells like the Beast from the East in winter 2018, 149 the Arctic air that reached as far South as Texas in February 2021, 150 or the storm that left Madrid, 151 and Athens 152 unusually covered in snow for days in early 2021 are becoming more common. Some of the mechanisms that lead to these cold spells are linked to global warming through exchanges of energy and air masses between different altitude ranges in the stratosphere. Heatwaves and cold spells may increase the risk of asthma-related emergency department visits, hospital admissions and asthma mor- tality. 153 Another meta-analysis found the pooled relative risks for asthma attacks on exposure to extreme heat was 1.07. 154 Analysis of data (between 2016 and 2020) from asthma hospital visits in Shen- zhen, China found the cumulative relative risk of asthma during heat waves compared to other days was 1.06. 155 A 2009 study found that adolescent emergency room visits at similar levels of air pollution were 9.45% higher in the summer than in the winter. 156 A study of Medicare patients between 1999 and 2008 found that each 5.6°C increase in tem- perature increased same-day emergency hospitalizations for respira- tory diseases by 4.3%. 157 There is evidence of a synergistic interaction between heat and air pollution on asthma hospitalizations. Short-term exposure to extreme heat and air pollution alone were individually associated with increased risk of mortality, but their coexposure had larger effects beyond the sum of their individual effects. Increased risk of respiratory mortality on extreme coexposure days was 38.0% and was more than the sum of individual effects of extreme temperature and PM2.5 only. 158 It is hypothesized that the high temperature may facilitate chemical transformation of PM2.5 while also increasing levels of ozone. 159 Green Space and Biodiversity . Deforestation and clearing of grassland for agricultural use, industrialization, and human habitat has decreased the amount of green space. Plants act as carbon sinks that absorb CO2 through photosynthesis. The destruction of forests and greenspaces leads to habitat loss and severely reduced biodiver- sity, which refers to the variability among living organisms and the ecosystems in which they live. 160 Globally, since 1970, there has been around a 68% decrease in biodiversity as estimated by monitored wild- life populations (amphibians, birds, fish, mammals, and reptiles). 161,162 A recent report found that over a third of species and ecosystems in the United States are at risk of extinction, including 34% of plant species, 40% of animal species and 41% of ecosystems. 163 Climate change is also decreasing soil microbial diversity, which is essential for a healthy soil and food security. 164 One study analyzed soil samples and found that experimental warming decreased richness of bacteria by 9.6%, fungi by 14.5% and protists by 7.5%. 165 A study showed that the interaction between indices of historical climate warming and intensive agricul- tural land use is associated with reductions of almost 50% in the abun- dance and 27% in the number of species within insect assemblages relative to those in less-disturbed habitats with lower rates of historical climate warming. 166 It is estimated that a third of the world’s farmland is degraded and a third of commercial fish species are overexploited due to industrialized farming practices and increased consumption. 167 Biodiversity (including microbial diversity) is critical for pollina- tion, the maintenance of healthy microbiome and the normal function- ing of the immune system. The loss of biodiversity has been linked to allergies and asthma. 168 The “biodiversity hypothesis” states that con- tact with a natural and biodiverse environment enriches the human microbiome, promotes immune balance, and protects from allergy and inflammatory disorders. 169 Studies have linked a decrease in the gut and lung microbiome to allergic, autoimmune diseases and cancer. A study found that lower microbial richness and imbalances in specific gut bacteria in infants was significantly associated with allergic sensiti- zation. 170 The gut microbiome plays an important role in food allergy. 171 Bunyavanich et al. found that higher microbial diversity in infancy was associated with a resolution of milk allergy by age 8. 172 Children living on farms and exposed to greater microbial diversity were significantly less likely to develop asthma compared to those who did not live on farms, 173 consistent with a recent proposal that climate change interacts with the hygiene hypothesis to promote the allergy epidemic. 174 In addition to microbial diversity, an inverse relationship between the amount of forest cover close to children’s home and the develop- ment of allergic disease has been observed. 175,176 In one study, proxim- ity to a green environment at birth decreased the risk of developing allergic diseases and asthma by age 7. 177 Living in an biodiverse envi- ronment or green space can enhance immunological resilience and prevent allergic diseases and asthma. 178 However, a recent systematic review and meta-analysis found that greenspace exposure on asthma and AR was not significant. Further research is needed. 179 Indirect Effects of Climate Change on Allergies and Asthma Human Migration and Displacement . In addition to the direct effects of climate change events, climate change also mediates its effects in indirect ways by adversely affecting immune health and increasing susceptibility to allergies and asthma. Extreme storms, floods, wildfires,
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 812 SECTION E Respiratory Tract likelihood of development of new sensitizations and of allergy, and earlier onset of symptoms (Fig. 46.1). Ragweed is a common allergen. Climate change is expected to promote the geographical spread of this invasive weed and increase incidence and exacerbation of allergies and asthma. 190 Vector-Borne Diseases . Climate change has led to the global spread of disease vectors, such as lone star ticks. The lone star tick is a vector for red meat allergy. The tick, by transmitting a sugar called alpha-gal into a person’s bloodstream, sensitizes an individual to red meat. Alpha-gal is present in most mammals, such as cows and pigs. When a sensitized individual consumes meat from these animals or their products, an allergic reaction may occur. Symptoms may include hives, swelling, difficulty breathing, and anaphylaxis. 191 Droughts . Drought adversely affects human health as food and water shortages increase risk of malnutrition and dehydration. Many poten- tially harmful metals, such as cadmium, chromium, copper, nickel, zinc, lead, and mercury are found in our waterways. 192,193 Warmer water temperatures have been correlated with heavy metal concentrations, specifically increased bioaccumulation of mercury in fish. 194 In some communities, heavy metals such as arsenic and cadmium are present in the drinking water. 195–197 Exposure to these metals have been associated with changes in immune cells. 198,199 Nutritional Content of Foods . Climate change is associated with decreased yield and altered nutritional content of foods. It is estimated that a 1°C increase in temperature decreases wheat yield by 6%. 200 Ris- ing CO2 concentrations have been linked to a reduction in the nutri- tional quality of major cereal crops. 201 Soybeans subjected to heat waves during early pod development cause significant yield loss; lentils exposed to heat stress have decreased levels of iron, zinc, and crude protein content. 202,203 The concentrations of other nutrients in plants, such as iron and zinc, are also lowered by increased global warming and increased CO2. 204–206 Synergistic Exposures . About 850 million children live in areas where they are exposed to four or more climate change–related events and environmental hazards, such as wildfires, flooding, air pollution, and resource scarcity. 207 These factors often act synergistically increas- ing adverse asthma- and allergy-related outcomes. Socioeconomic Disparities, Vulnerable Populations, and Climate Justice Climate change is a threat multiplier exacerbating existing socioeco- nomic inequities. Individuals in low-income countries particularly those socioeconomically disadvantaged bear the brunt of the adverse effects of climate change. Even in developed countries, low-income groups are the most affected and more likely to live in more polluted neighborhoods. Certain populations such as children, older adults, pregnant women, disabled, or those with chronic diseases are at even greater risk. GHG emissions vary widely, with developed nations emit- ting the largest carbon footprint. The Group of 20 (Argentina, Aus- tralia, Brazil, Canada, China, France, Germany, India, Indonesia, Italy, Japan, Republic of Korea, Mexico, Russia, Saudi Arabia, South Africa, Turkey, the United Kingdom, the United States, and the European Union) are responsible for about 76% of global GHG emissions. By contrast, least developed countries account for about 3.8% of global emissions, while small island developing states contribute less than 1%. 208 However, many of the world’s poorest nations, who are the least polluting are the most vulnerable. These inequities have led to calls for climate justice. Fig. 46.1 Climate change effects on pollen and increased prevalence of allergic disease. droughts, melting permafrost, sea level rise, and heat will render nearly a fifth of the planet inhabitable by 2070. 180 Estimates range from 150 million to over one billion people may be displaced by 2050. 181,182 Human migration due to wars and social conflicts, economic hard- ships, food and water insecurity will expose individuals to new aller- gens and disease vectors. These migrations also increase exposure to anthropogenic pollutants as migration is generally from rural to urban areas. By 2050, it is estimated that 143 million people in sub-Saharan Africa, South Asia, and Latin America will become displaced due to climate change. Fifty-five percent of the world’s population currently live in urban cities and this is expected to grow by 2050 to seventy percent. 183 These migratory patterns, particularly to urban areas, are expected to increase allergies and asthma. A study conducted in Canada found that asthma rates were higher in urban environments compared with rural areas. 184 Another study in the United Kingdom found that individuals living in urban areas recorded greater hay fever symptoms than in rural environments. 185 A systematic review and meta-analysis found that risk of asthma was higher in urban areas compared with rural areas but not for the risk of AR. 186 Migrants are also exposed to new allergens that they may not have encountered before and therefore may potentially lack immune tolerance to these allergens. 187 This is supported by a study which found increases in the prevalence of allergy in migrants compared with native-born individuals and between second- and first-generation migrants. 188 Migration also changes the mechanisms of the allergic diseases, a new concept in precision medicine called regiotypes. For example, in chronic rhinosinusitis with nasal polyps, the polyps tend to be predominantly neutrophilic in the Chinese population whereas in Western populations, they are mostly eosinophilic. 189 Impact on Pollen Growth and Allergenicity . Climate change is also affecting the growth, phenology, and distribution of grasses and weeds. It is expected to increase allergenicity and production of pollen and prolong duration of pollen season. This will bring about a greater
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 813 CHAPTER 46 Climate Change: Allergic Diseases and Asthma An analysis of 108 urban areas in the United States found elevated temperatures in formerly redlined areas (regions mapped by race resulting in less economic investment) relative to their non–redlined neighbors by as much as 7°C. Redlining was a discriminatory practice where those who resided in certain “hazardous” neighborhoods were disqualified for credit or insurance. Redlining resulted in homes in these neighborhoods being in close proximity to hazardous waste sites, urban heat islands, or major highways and the segregation of Blacks from White communities. 209–211 Seventy-one percent of historically redlined neighborhoods are now considered low- or middle-income areas and 64% are predominantly populated by Black and Hispanic people. 212 They are also more likely to live in counties within flood zones or high risk flood areas and live in homes with poor infrastruc- ture. 213–216 Urban heat islands are characterized by asphalt, dense build- ings, and heavy vehicular traffic. 217,218 These communities also often lack adequate nutrition, health care, education, access to air-condition- ing and social support. In California, USA, neighborhoods with more subsidized housing were more vulnerable to extreme heat than other neighborhoods. 219 On average, low-income blocks in the United States have between 15% and 30% less tree cover and are between 1.5⁰C and 4.0⁰C hotter than high-income blocks. 220 These disparities have resulted in worsening asthma and allergy outcomes as shown by numerous studies. 221 The EPA’s 2021 Climate Change and Social Vulnerability reports that minority communities are 53% to 58% more likely to reside in neighborhoods with the high- est predicted increases in asthma-related emergency room visits. 222 Children who live just above, at, or below the poverty line have been shown to be more likely to have increased asthma morbidity. 223 A study found that low-income children have a 15% higher projected increase in asthma diagnoses relative to non–low-income children. 224 In the United States, the rate of childhood asthma is more than double for Black compared to White children. 225 Increased exposures to potential allergens caused by damp indoor areas result in underserved popula- tions disproportionately experiencing an exacerbation of symptoms associated with chronic respiratory diseases. 214,226 Children in low- income communities and in certain racial and ethnic groups, such as African-American and Hispanic children, have disproportionate expo- sure to air pollution 227 and to impacts of climate change, such as from Hurricanes Katrina and Harvey in Louisiana and Texas. 228 These disparities are seen globally. Climate change has so far cost the global economy trillions of dollars, but low-income countries in tropical regions have borne the brunt of these losses. A study estimated that the global economy lost between US$5 trillion and $29 trillion from 1992 to 2013, as a result of human-driven global warming. But the effect was worst in low-income tropical nations, leading to a 6.7% reduction in their national income on average, whereas high-income countries experienced only a 1.5% average decrease. Low-income com- munities face increased risk of loss of livelihood, becoming climate ref- ugees, and decreased access to clean water and nutritious foods. Mechanisms by Which the Exposome Mediates Epithelial Barrier Damage, Microbial Dysbiosis, Inflammation, and Immune Dysregulation Climate change leading to increased exposure to pollutants and decreased exposure to a biodiverse environment, increased urbaniza- tion, improved hygiene, antibiotic use, and lack of physical activity has led to microbial dysbiosis and epithelial barrier dysfunction, factors which modulate both innate and adaptive immune systems leading to immune dysregulation and a proinflammatory state. 230,231 Epithelial Cell Activation and Disrupted Barriers . The epithe- lial barriers of the skin, gut, and lungs form a physical and chemical barrier against environmental pollutants and act as the body’s first line of defense. Immune cells embedded in the epithelial layer act as senti- nels monitoring the environment and are poised to combat threats in the environment. One of the hypotheses proposed for the increased incidence of immunological diseases is the epithelial barrier hypoth- esis, which proposes that damage to the epithelial barrier increases penetration of allergens, microbes, and other substances, thus increas- ing proinflammatory reactions. Tight junctions, which are composed of transmembrane proteins (occludin, claudins, and junctional adhe- sion molecules) and adaptor proteins (Zonula occludens and cingulin) are essential for maintaining the integrity of the epithelial barrier and maintaining health. 23,232–234 Numerous allergens, infectious agents, and environmental sub- stances can damage the epithelial barriers. These include air pollut- ants such as cigarette smoke, PM, diesel exhaust, ozone, micro- and nano-plastics, certain bacteria, fungi, and viruses, as well as surfactants and enzymes included in laundry, dishwashing, and household clean- ing products. Surfactants, enzymes, and emulsifiers present in pro- cessed foods have also been shown to damage the epithelial barrier 235 (Fig. 46.2). Detergents disrupt the epithelial barriers of the skin and respiratory tract, even at very high dilutions and increase epithelial permeabil- ity contributing to the development of allergic diseases. 236–240 Sodium dodecyl sulfate (SDS) or sodium lauryl sulfate (SLS) cause damage to epithelial cells. They were introduced to powder detergents in the 1960s and are one of the main constituents of laundry detergents, toothpastes, and household cleaners. 241,242 Airborne allergens such as mold spores, pollens, and insect dander from cockroaches and house dust mites have protease activities which detrimentally affect the tight junction molecules in the airway epithelium, increase permeability, and initiate a proinflammatory cascade that accelerates the onset of the IgE-mediated sensitization and of allergy. 238 Heat stress can also disrupt claudins, occludins, and junctional adhesion molecules, lead- ing to an increase in epithelial permeability. 243 A study found that mice exposed to ozone experienced increased airway inflammatory cell infiltration and bronchial hyper-responsiveness compared to control mice. Increases in reactive oxygen species (ROS) and decreases in lung claudin protein expression were found in mice exposed to ozone sug- gesting that ozone affects tight junction proteins through oxidative mechanisms. 244 Within the airways, ROS react with lipids resulting in the formation of isoprostanes and ethane. These biomarkers of lipid peroxidation can be measured in either exhaled breath condensate or urine in asthmatics. 245 Immunological Mechanisms . Pollen, PM, ozone, and other pol- lutants, which have increased with climate change, are associated with immunological changes. Those associated with allergy and tolerance on exposure to allergens are best understood. Allergens disrupt the epithe- lial layer and induce release of proinflammatory epidermal cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. 246 These cyto- kines, termed alarmins , activate dendritic cells and drive differentiation of naïve CD4 + T cells to Th2 cells leading to the production of proin- flammatory Th2 type cytokines IL-4, IL-5, IL-9, and IL-13. Another cell that is activated by alarmins is the group 2 innate lymphoid cell (ILC2), which also releases IL-5 and IL-13. IL-4 and IL-13 are proinflamma- tory cytokines that skew B cells toward IgE production. 54,247 In food allergy and AR or allergic asthma, allergen-specific IgE antibodies bind to FcεRI receptors on mast cells or basophils, leading to sensitization to the specific allergen. Cross-linking of FcεRI-bound IgE antibodies on subsequent allergen exposure leads to degranulation of inflammatory mediators such as histamine, prostaglandins D2, leukotrienes, and trypt- ase. The mechanism underlying tolerance in nonallergic individuals is
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 814 SECTION E Respiratory Tract also well elucidated. In tolerance, T naïve cells are transformed into T regulatory cells, rather than Th2 inflammatory cells. T regulatory cells skew B cell class switching to secrete IgA and IgG4. These antibodies block the inflammatory allergic IgE state (Figs. 46.3 and 46.4). 248,249 IgE- mediated activation of mast cells and basophils leads to symptoms of an allergic reaction, which can be mild to severe, or even fatal. 247 Th2-type inflammation is the most important pathological process for asthma, accounting for approximately 50% of mild-to-moderate asthma and a large portion of severe asthma. 250 Our understanding of the immune mechanisms associated with tolerance and allergy has assisted with the development of many monoclonal antibodies, such as dupilumab, an IL-4Rα antibody, which blocks downstream signaling of both IL-4 and IL-13. This has been approved for both asthma, atopic dermatitis, and eosinophilic esophagitis, a type of chronic food allergy. Omalizumab, an anti-IgE molecule is approved for asthma and food allergy. 251 PM has also been shown to affect immune cells. Firefighters exposed to smoke from wildfires show increased pulmonary and systemic inflammation with increases in IL-6 and IL-12 and decreases in IL-10. 252,253 A study by Prunicki et al. 254 found wildfire smoke is associated with increased levels of proinflammatory markers such as C-reactive protein (CRP) and IL-1β. These biomarkers are associ- ated with increased asthma symptoms. Using targeted proteomics and immune cell phenotyping, a study found functional changes in critical immune cells and their proteins during wildfire smoke exposure in a cohort from the San Francisco Bay area during a major wildfire in 2020. 255 PM can also activate the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor and induce CYP1, AKR, NOx and COX-2 genes resulting in excessive generation of ROS. 256 It has been shown that AhR exerts numerous effects on mast cells, B cells, macrophages, antigen-presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells, thus playing a significant role in aller- gen-induced diseases. 257 Primary bronchial epithelial cells exposed to diesel exhaust particles showed upregulation of alarmins, which were abolished by knockdown of AhR by siRNA. 258 Chronic exposure to Fig. 46.2 Environmental factors associated with epithelial barrier damage. Fig. 46.3 Allergic inflammation on loss of epithelial barrier integrity.
Order your copy of Middleton’s Allergy, 2 volume Set, 10th Edition at elsevierhealth.com/9780443249723 815 CHAPTER 46 Climate Change: Allergic Diseases and Asthma PM2.5 may also deplete major antioxidant mechanisms of the human body, such as superoxide dismutase, glutathione peroxidase, and non- enzymatic mechanisms, thus affecting the cellular redox balance. 259 Micro- and nanoplastics have been detected in human lungs, stools, placentas, and blood. 8 Orally exposed micro- and nanoplastics, due to their resistance to degradation, cause lysosomal dysfunction acti- vation and IL-1 production in intestinal macrophages. Micro- and nanoparticles induce phosphorylation of MAPK and induction of proinflammatory proteins such as cPLA2 and COX-1 and IL-1β, IL-6, and TNF-α release in kidney cells in animal models. 260,261 Polystyrene nanoplastics cause ROS-induced NLRP3 activation and subsequent neutrophil infiltration and neutrophil extracellular trap formation in mouse liver. 262 Heavy metals are also associated with immune changes. A study found that maternal arsenic and cadmium exposure from contami- nated water was associated with alterations in the T cell population in cord blood of infants. 198 Arsenic exposure was found to increase levels of the Th2 mediators, IL-4, IL-6, and IL-13, which increases suscepti- bility to allergic asthma. 199 Another mechanism by which heat stress has been shown to medi- ate its effects on asthma and allergic disease is via transient receptor potentials (TRPs), which are found in epidermal keratinocytes and are sensitive to temperature. There are several different TRP channels and research into their varying roles is still ongoing. TRPV1 channels have been found to be overexpressed in patients with asthma. 263 In a murine asthma model, TRPV1 antagonist or TRPV1 siRNA led to a reduction of airway hyperresponsiveness and reduction of inflammatory cyto- kines, such as TSLP, IL-25, IL-33, IL-4, IL-5, and IL-13. 264 Microbial Dysbiosis . Microbial dysbiosis has been implicated in allergy, and germ-free mice have elevated IgE. 265 Compositional dif- ferences in the microbiome have been found in atopic individuals. Analysis of the gut microbiota by 16S rRNA sequencing found that individuals with asthma harbored compositional differences from healthy controls in both adults and children. 266 In mice, lung micro- biota has been shown to affect pulmonary inflammation and oxidative stress induced by PM2.5 exposure. Pollutants can also alter microbial composition. When mice were exposed to PM2.5 intranasally for 12 days, microbial diversity decreased by 75.2% with increased abun- dance of Proteobacteria and decreased abundance of Bacteroidota . The altered composition of the microbiota was significantly correlated with pulmonary inflammation and oxidative stress-related indicators. 267 Individuals with allergies have been found to have significantly lower fecal microbial richness and fecal microbiota transplantation may offer Fig. 46.4 Mechanism of tolerance to innocuous environmental substances and Th2 mediated–allergic reac- tion (From Sampath V, Aguilera J, Prunicki M, Nadeau KC. Mechanisms of climate change and related air pollution on the immune system leading to allergic disease and asthma. Semin Immunol . 2023;67:101765. doi:10.1016/j.smim.2023.101765.)