Ann Allergy Asthma Immunol 125 (2020) 528e534

Contents lists available at ScienceDirect

Review

A butterfly flaps its wings

Extinction of biological experience and the origins of allergy
Susan L. Prescott, MD, PhD, FRACP *, y
* The ORIGINS Project, Telethon Kids Institute, University of Western Australia, Perth Children's Hospital, Nedlands, Australia
y
inVIVO Planetary Health of the Worldwide Universities Network, West New York, New Jersey

Key Messages

 The once subtle effects of urbanization have escalated into a large-scale biodiversity loss, which is echoed on the microecologic scale
with changes in personal and environmental microbial ecosystems. This loss is directly implicated in the epidemic of allergy and many
other noncommunicable diseases.
 Modernity has also been associated with human behavioral changes, with considerably more time indoors, progressively less contact
with biodiversity in natural environments, and evidence that reduced early-life experience of biodiversity primes people for immune
dysregulation and a higher propensity of low-grade inflammation.
 Efforts to increase direct, personal contact with biodiversity have clear benefits for multiple aspect of physical and mental health, the
skin and gut microbiome, and immune function. There are also beneficial effects on health behaviors, such as food choices, sleep, and
physical activity, that favorably affect immune function.
 Increasing nature connectedness is also important for promoting environmental responsibility and value systems that are geared to
restoring and preserving biodiversity.

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To explore links between biodiversity on all scales and allergic disease as a measure of immune
Received for publication March 29, 2020. dysregulation.
Received in revised form May 17, 2020. Data Sources: PubMed and Web of Science were searched using the keywords biodiversity, nature related-
Accepted for publication May 21, 2020.
ness, allergic disease, microbiome, noncommunicable diseases, coronavirus disease 2019, and associated terms.
Study Selections: Studies were selected based on relevance to human health and biodiversity.
Results: Contact with natural environments enriches the human microbiome, promotes regulated immune
responses, and protects against allergy and both acute and chronic inflammatory disorders. These important
links to ecopsychological constructs of the extinction of experience, which indicates that loss of direct,
personal contact with biodiversity (wildlife and the more visible elements of the natural world), might lead
to emotional apathy and irresponsible behaviors toward the environment.
Conclusion: The immune system is a useful early barometer of environmental effects and, by means of the
microbiome, is a measure of the way in which our current experiences differ from our ancestral past.
Although we would benefit from further research, efforts to increase direct, personal contact with biodi-
versity have clear benefits for multiple aspects of physical and mental health, the skin and gut microbiome,
immune function, food choices, sleep, and physical activity and promote environmental responsibility.
Ó 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction
Reprints: Susan L. Prescott, MD, PhD, FRACP, Department of Paediatrics, University
Humanity has progressively affected global environments and
of Western Australia, Nedlands 6009, Australia; E-mail: [email protected].
planetary systems to such an extent that our own well-being is now
Disclosures: Dr Prescott reports consultancy activities relevant to the microbiome
with the Swisse Advisory Board, Sanofi (probiotics), and Bayer (probiotics). under threat.1 In the epoch of the Anthropocene, it is abundantly
Funding Sources: The author has no funding sources to report. clear that all the grand challenges are interrelated, including

https://doi.org/10.1016/j.anai.2020.05.025
1081-1206/Ó 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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 S.L. Prescott / Ann Allergy Asthma Immunol 125 (2020) 528e534 529

climate change, environmental degradation, biodiversity losses, species during the same period.9 It is time to understand the direct
ecosystems collapse, new infectious contagions, economic insta- links between these phenomena, namely the links between
bility, social unrest, and obscene inequality. For decades, human biodiversity losses, on all scales, and the current rates of allergic
health has been under threat from a mounting pandemic of non- diseases and immune dysregulation.
communicable diseases (NCDs).2,3 Although this crisis in slow
motion has been responsible for vastly more deaths and disease
A Butterfly Flaps Its Wings
than infectious disease, it has unfortunately not galvanized the
same coordinated global efforts for prevention, as we are currently
[Butterfly] disappearance indicates loss of life. When the
seeing with more imminent acute infectious threats, such as
coronavirus disease 2019 (COVID-19). However, given that infec-
last tiger is killed in India, it may hit the headlines,
tious outbreaks are also interrelated with the same disruptions in however, shrinkage of biodiversity also takes place in the
planetary health and that individuals with preexisting NCDs are far micro-world close to us, but without notice. Preserving
more susceptible to infections such as COVID-19, it is imperative to biodiverse life might have a preventive effect on allergy
take a more integrated, cross-sectoral approach to health, recog- and other diseases of modern civilization. e Tari Haah-
nizing that immune resilience is a common factor. Ultimately, this tela, MD, PhD10
means directing resources to remediating the underlying causes of The butterfly effect is another oft-used metaphor to explain how
these connected challenges in ways that have cobenefits for the the most minute change in local conditions can lead to massive
health of people, place, and planet in the broadest sensedas also differences in the state of wider systemsdthrough ripple effects
articulated recently by the Lancet One Health Commission.4 across a complex interconnected web. As first postulated by
Among all NCDs, the marked increase in allergic diseases during Edward Lorenz as part of chaos theory, if a butterfly flaps its wings
the past half century has arguably been one of the most striking in one location, this tiny change in the atmosphere could, at least
measures of the effect of urbanization and adoption of a western- theoretically, influence weather at distant, future sites. It is rare for
ized lifestyle on immune health.5,6 The fact that asthma and allergic mathematical theories to penetrate the discourse of popular cul-
diseases develop so early in life provides a unique opportunity to ture, but the butterfly effect has captured the imagination of the
understand how the interconnectivity between changing envi- public. Perhaps because humans love both metaphors and
ronments (at macro-, meso-, and microlevels) affects the human butterflies.
immune system from the first moments of development. Finnish physician-scientist Tari Haahtela has dedicated his
Indeed, it has been suggested that the allergy disease epidemic career to the study of allergic diseases and allergy. He also happens
is a “canary in the coalmine” that exposes the effect of modern to love butterflies and as a side passion has traveled the globe
environmental change and, in particular, the specific vulnerability examining these flying flowers and their habitats (Fig 1). In 2009,
of the immune system, which has wider significance for other as- Allergy published a Commentary from Dr Haahtela entitled “Allergy
pects of health. The early-life experience of the immune system Is Rare Where Butterflies Flourish in a Biodiverse Environment”10;
now appears to prime the propensity for low-grade inflammation for many readers, it may have seemed a strange and curious outlier
and immune dysregulation, increasing the risk of many other later- among critically important articles on omalizumab treatment,
onset NCDs. In effect, the immune system is a useful early barom- filaggrin mutations, gene variants, dietary carotenoids, and lipoxin
eter of environmental effects and, via the microbiome (microor- A4 generation in patients with asthma and/or allergic diseases.
ganisms, their genetic material, and theater of activity), a measure Research conducted by Dr Haatela's group and others has indi-
of the way in which our current experiences in the Anthropocene cated that westernized urban environments seem to lack essential
differ from our ancestral past.7 We are also reminded that the elements, which otherwise provide necessary exposures for the
smallest elements in our ecosystems, microorganisms, are critical optimal development of tolerance against foreign proteins. Notably,
to large-scale systems, including climate change biology, as high- these observations came to light with striking differences in
lighted in a recent warning by environmental scientists in Nature immune disease between Finland and neighboring Russian Karelia.
Reviews.8 Although Finland and Russian Karelia are geographically close, Dr
Whatever label we use for the current global burden of allergic Haatela's group had discovered strikingly different allergy
diseases and asthmadepidemic, crisis, scourgedwe can all agree
that the rates are intolerably excessive. Moreover, there is
consensus that genetics cannot explain the rapid shift in the burden
of disease and that environmental change has played a primary
role, interacting with genetic susceptibilities over time. With good
reason, the initial scientific search for causation has largely focused
on environmental toxinsdthe increasing presence of detrimental
exposures. However, it is equally important to consider that the
lack of protective factors could have commensurate effects on
health.
In this context, this Review focuses on the consequences of the
biological extinction of experience, considering the evidence that
the current burden of allergic disease may be, at least partially,
driven by the absence of immune system experience with biodi-
versity. The “canary in the coalmine” was a useful metaphor for
illuminating the once subtle concept that the increase in allergic
diseases 50 years ago was a forewarning of a larger crisis of NCDsd
that allergy may be an indicator species for the effects of ill-defined
toxins on the risk of inflammatory disease.7 However, now there is
Figure 1. Every ecosystem depends on the health of its smaller parts: “A swallowtail
nothing subtle about environmental change or the effect on human butterfly wondering where to go” inspired by a photograph taken by Dr Tari
health. Indeed, the avian metaphor has become a terrible reality, Haahtela in Portugal on the Atlantic coast (Tari Haahtela, MD, PhD, written
with concomitant stunning real-world losses of a multitude of bird communication, June 2018). Copyright 2020: Susan L. Prescott.

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Figure 2. Time is of the essence in addressing dysbiotic drift. Decades of macroscale biodiversity loss reflected in microscale ecology with a direct effect on physical and mental
well-being (many mediated via effects on immune health). The longer we delay addressing this, the more we risk irreversible loss of ecosystems. Copyright 2020: Susan L.
Prescott.

prevalence in the borderlands of these areas. The higher microbial wings. In the realm of asthma and allergic diseases, Dr Haahtela
quantity and diversity in the drinking water and house dust were was provoking our profession to consider the answer to that
among the implicated factors associated with a reduced risk of question. It was not his contention that butterflies have unique
allergic disease in Russian Karelia.11,12 antiallergic properties but rather that this colorful, flamboyant
From his broader vantage, Dr Haahtela also noted that allergic species might be informing us about the relationship between
diseases appeared to be rarer in regions where butterfly pop- biodiversity in general and allergic diseases in particular.
ulations enjoy rich diversity. It was a generalized observation, and Dr Haahtela's original Commentary in Allergy has since spawned
although it lacked detailed investigation on butterfly populations a larger biodiversity hypothesis, which states that contact with
per se, the plausibility matched evolving knowledge derived from natural environments enriches the human microbiome, promotes
the hygiene hypothesis: the overarching idea of the original hy- immune balance, and protects against allergy and inflammatory
pothesis13 and its related variants14 that the global increase in disorders. It argues that there are nested layers of biodiversity: an
allergic disease could be related to diminished opportunity for outer mantle that includes soil, water, plant, and animal-associated
early-life exposure to microbial diversity via antibiotic overuse, microbiota and an inner layer that includes the microbiota of the
smaller family sizes, excessive use of personal and household skin, lungs, and alimentary canal. The outer layer plays a large role
cleaning products (including detergents), and lower exposure to in the colonization of the inner layer and, by extension, the oper-
nonpathogenic bacteria in foods (eg, lowered consumption of fer- ations of the immune system21,22; given the recent discoveries on
mented foods). According to the hypothesis, the mediator between the immune-nervous system interface, the natural environment
these environmental changes and immune system training was and its outer mantle of biodiversity can potentially extend its reach
proposed to be an abnormally stable microflora.14 A new-normal to the brain through microbe-mediated nonsensory pathways.15,23
microbiome may characterize the lived experience in urbanized,
western industrial nations, reflecting a more generalized decrease Extinction of Experience
in biodiversity. In essence, a manifestation of wider dysbiotic drift15
(Fig 2).
“What is the extinction of the Condor to a child who has
Dr Haatela's Commentary served to underscore the potential
never seen a wren?” e Robert Pyle, PhD24
relevancy of biodiversity at all scales to the work of practitioners
and scientists working in the field of allergy and immunology. More As experts in the field of allergy explored lifestyle factors that
than 10 years on, the global collapse of insect species is far more might contribute to the increase in allergic diseases (coincident
devastating than even imagined. In 2019, Australian researchers with global urbanization), our colleagues in ecology and psychol-
reported shocking decreases in flying insect populations and pro- ogy expressed concern about the transgenerational loss of
jections that indicated extinction of as many as 40% of the world's cognitive-emotional experience with the natural environment. Dr
insect species during the next few decades.16 Butterflies are among Robert Pyle, an ecologist who specialized in the study of butterflies,
the species experiencing devastating decreases.17,18 Although some coined the term extinction of experience.24 He and others worried
insect species are resilient, urbanization is detrimental to both that loss of direct, personal contact with biodiversitydwildlife and
abundance and species richness.19 If these decreases continue, the the more visible elements of the natural worlddmight lead to
implications are catastrophic; insects are integral in freshwater emotional apathy and irresponsible behaviors toward the
ecosystems and the entire food web; they are food for countless environment.25
larger species and perform vital roles, such as pollination, pest Although more research is needed on the topic of emotional
control, and nutrient recycling.20 disconnection from nature, several studies support the idea that
Perhaps the more relevant question for humanity now pertains adults and children in westernized, industrial, and technologically
to what might happen in a system if a butterfly does not flap its mature nations are spending more time indoors26-28 and less time

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 S.L. Prescott / Ann Allergy Asthma Immunol 125 (2020) 528e534 531

in natural environments, untethered to screen-based devices.29,30 markers of inflammation, immune parameters (eg, natural killer
There are also indications that losses in local biodiversity and cells), blood pressure, and heart rate variability44 (Fig 3).
environmental degradation are associated with greater time spent These shinrin-yoku studies are limited by small sample sizes
indoors31; in Japan, researchers have found an age-related, cross- and short duration; moreover, given that potential allergens are
generational decrease in childhood experiences with indicators of among the components emitted from trees and flowering plants,
biodiversity.32 they cannot be used to make arbitrary decisions about public policy
Psychologists have developed scales to assess individual levels (eg, planting certain trees or flowers) that might otherwise influ-
of awareness of, and fascination with, the natural world; for ence millions of people with allergy. Immense planting of new
example, the Nature Relatedness Scale (or separate Nature Con- growth cedar (sugi) trees in postwar Japan is still considered to be a
nectivity or Nature Connectedness scales) capture the degree to factor in sugi-pollinosis, considered now to be a national
which participants in research studies have an interest in making affliction.45
contact with nature. Higher scores on nature relatedness have been However, the emerging research on psychological extinction of
linked with general health and mental well-being33,34 and with experience and nature relatedness is of importance to the biodi-
higher concern for the sustainability of the natural environ- versity hypothesis; in particular, inclusion of validated nature
ment.35,36 Intervention research that involves children exposed to relatedness scores (identifying personal connection to nature or
biodiversity-rich environments indicates that psychological well- lack thereof) might provide further insight into existing epidemi-
being and nature relatedness can improve in tandem.37 Recently, ologic work. For example, early-life familial pet ownership has been
psychologists have argued that available evidence supports that the linked to reduction in allergic disease,46,47 yet we know little about
humans have a basic psychological need for nature relatedness.38 the psychological underpinnings that might drive pet ownership
For the most part, the work of professionals in allergic diseases (such as nature relatedness) in the first place. These psychological
has yet to intersect with the burgeoning nature relatedness and constructs might be associated with several differing lifestyle var-
psychological extinction of experience research. But perhaps it is iables, differences that might explain the conflicting findings on pet
time for the twain to meet. The microbiome revolution may yet ownership and allergic diseases.48-50
deliver on its many therapeutic promises,39,40 but in the meantime, Consider also the several large-scale studies using satellite
it has already transformed how we view the human self and helped technology and land use data to link geographic greenness (as a
erase the imaginary dividing line between the biological and surrogate of trees, shrubs, and plant-based biodiversity) with lower
psychological.41,42 rates of wheezing, asthma, respiratory disorders, and allergic dis-
Also sitting at the periphery of mainstream immunology and the eases.51,52 Similar to pet ownership, the results are conflicting, with
study of allergic diseases is an increasing body of in vivo research some research indicating that living near coniferous forests (and
typically housed within environmental psychology or physiological unspecified green space) is associated with worse outcomes in
anthropology. The study of shinrin-yoku (now generally referred to asthma and allergic diseases.53,54 Several studies have found re-
in Japanese studies as simply forest medicine or forest therapy) lationships between residential proximity to farms and arable
exemplifies an intriguing line of preliminary evidence that may be lands, exposure to farm-associated microbiota, and protection
of interest to our field. Loosely translated, shinrin-yoku means against allergic diseases and asthma.55,56 However, all farms cannot
forest-air bathing or absorbing the forest air and places an be painted with the same brush, and efforts to bring protective soil
emphasis on the entire forest experience.43 Several small, short- and farm-associated microbiota to practitioners and patients
term intervention studies (under the shinrin-yoku rubric) have awaits lengthy translation.57 In the meantime, it may be helpful to
found that spending time in a forest environment vs an urban built know more about the psychological antecedents (beyond the oft-
environment can influence stress physiology, cytokines, and other discussed term stress) that might influence risk, and the
cognitive-emotional drivers of the behavior that might place one in
contact with biodiversity.
Loss of contact with biodiversity can also be imagined in the
form of wholesale changes to dietary patterns; it has been argued
that for children in westernized nations the loss of whole plant
foods (relatively unprocessed and high in fiber and phytochemi-
cals) from the diet, coincident with the massive encroachment of
the “invasive species” known as ultraprocessed foods58,59 (which
now dominate the nutritional landscape, such as weeds, displacing
nutrient-dense foods), is also an extinction of experience.60
Displacement of relatively unprocessed foods with ultraprocessed
foods is another contemporary disconnection from nature and the
products of biodiversity with direct implications for the gut
microbiome.61 Ironically, it appears that animal studies exploring
environmental determinants of immune resilience may more
accurately resemble human immune responses if they are reared in
more natural environments.62
Ongoing research is currently evaluating strategies to promote
nature relatedness in preschool children and how this may improve
Figure 3. Multidimensional health benefits of nature-based solutions (green pre- dietary habits and exercise among parents and children in the same
scriptions). Decades of research show health benefits across all domains, including household,63 as well as affect microbiome and immune function.
improved mental health (improved mood and sleep, reduce depression, anxiety, and Green prescriptions, also known as nature-based solutions, may
posttraumatic stress disorder), improved performance (improved concentration and have considerable cobenefits for individuals, community, and the
cognitive performance), reduced inflammation, reduced cortisol and stress re-
wider environment64 (Fig 3). Similarly, microbiome-inspired green
sponses, reduced asthma and allergies, lower blood pressure, lower heart rate, lower
oxidative stress, and reduction and buffering of noncommunicable disease. There is infrastructure provides ecologic solutions that promote personal
also evidence that increasing urban greenspaces can reduce health inequalities biodiversity through healthier, more biodiverse cities and urban
because of social disadvantage. Copyright 2020: Susan L. Prescott. environments.65 These place-based environmental strategies will

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532 S.L. Prescott / Ann Allergy Asthma Immunol 125 (2020) 528e534

also provide opportunities to study the effect on immune function, promote resilience to inflammation across the life course, particu-
especially in children. larly when the foundations of health are laid.78 Indeed, for decades
In summary, the psychological constructs of extinction of the field of allergic disease has been at the forefront of efforts to
experience and nature relatedness are highly relevant to the work underscore the importance of early-life ecology for life-long
of professionals in our field of allergic diseases; it can be argued immune health.
that up to now, work within the biodiversity hypothesis rubric has Although the desire for such an approach has been advocated by
involved searching for clues in the immunologic extinction of experts in allergic diseases for decades,79 the new era of omics
experience (eg, missing microbes) and that such work will be technologies (the ability to simultaneously measure large numbers
bolstered by looking more deeply at the upstream drivers of be- of biomolecules that represent genes, genes expressions, proteins,
haviors that otherwise put us in contact with biodiversity. and metabolites) provides optimism that researchers can identify
biological markers of relevance to the total lived experience of in-
An Exposome Perspective dividuals (including experiences of parents and grandparents) and
entire populations.80-82 Such technologies, leveraged by the
[The physician] must master a new science focused on microbiome revolution, can help us pick apart the influences of
the effects that the total environment exerts on the hu- dietary choices, stress, sleep, exercise, and psychological drivers of
biological outcomes over time. It may finally be possible to recon-
man condition...knowledge of environmental biology
cile various aspects of total lifestyle, vis à vis disease risk, and place
must therefore become one of the essential bases of
them into the context of larger mediators of Anthropocene-
medical science and practice. e Rene Dubos66
associated disease.83 This understanding cannot be achieved
The complexity of the biodiversity hypothesis underscores the without also addressing the value systems that drive the attitudes
need to evaluate intertwined temporal exposures, including those and actions of individuals and whole societies.84,85
that at first glance may seem unrelated to the microbiome-immune There is little doubt that in the Anthropocene, conversations
system interface. For this reason, many in our field are adopting an about medicine, science, and health (at all scales) are political
exposome perspective. The exposome refers to the study of accu- discussions. There is ample evidence that authoritarianism is
mulated exposures (ie, physical, sensory, and positive or negative detrimental to health at all scales. Hence, experts in planetary
emotional experiences) and their interaction with genes over time. health have advocated for a broad introduction of political science
The exposome vantage takes the position that genes alone cannot into medical and health-related graduate programs. These con-
explain disparities in allergic diseases and asthma and underscores versations are described in detail elsewhere, but a part of this must
that individual exposures we have been measuring during the be in understanding the corporate and commercial determinants of
previous decades (eg, airborne particulate matter, farm-associated health.86-88
microbes, and pollen allergenicity) do not occur independently of In addition to numerous important, well-established top-down
the total environment.67 public health and environmental initiatives, solutions will
The dysbiotic effects of gray space in urban environments are increasingly depend on grassroots strategies that improve the
multidimensional, from the displacement of greenspace and health of people and places. These strategies empower commu-
biodiversity on all scales to the aggregate effects of inequalities in nities, engender optimism, and encourage collaboration among
income, education, and social cohesion, which differentially affect different sectors of government, industry, science, and the public89
choices and behaviors that contribute to NCDs.68 Living in west- and increase opportunities for people to engage in changed
ernized urban environments has been clearly associated with lower personally and collectively.
biodiversity in the human gut microbiome.69,70 Moreover, migra- Research indicates that most people have clear preference for a
tion to more urbanized regions, such as the United States, is asso- more caring and responsible society in which progress does not
ciated with immediate loss of microbiome diversity and function, erode warmth and social cohesion, with opportunities to partici-
with displacement of native strains (such as Prevotella strains) with pate and make a difference.90,91 Optimism promotes engagement,
US-associated strains (such as Bacteroides strains).71 These effects and change is more likely and more meaningful when there are
increase over time and across generations and are compounded by tangible pathways for people to engage and when we believe that
obesity. our actions can make a meaningful difference.89 At the community
Again, there are direct implications for immune resilience and level, researchers have found that the mere greening of vacant lots
the predisposition for inflammationdnot only for the chronic can improve mental health92; when the topic of environmental
inflammation of NCDs but also acutely as seen with adverse out- factors and a healthy diet is approached from a food justice and
comes with inflammatory responses to the severe acute respiratory power inequity issue, young adults are more engaged and moti-
system coronarvirus 2 (SARS-Cov-2), causing COVID-19.72 vated for nutritional change.93 Thus, finding solutions to complex,
Approximately 79% of people requiring intensive care for COVID- interconnected problems will require research-based collaboration
19 in the United States and 86% of deaths in New York State, as between academia and the communities they serve.
elsewhere around the world, have occurred in those with comorbid Recent events with COVID-19 have shown how a subcellular
NCDs.73 There is also speculation that perturbations in the gut molecular event on one side of the planet can have rapid and far-
microbiome, which are well characterized in many NCDs, may be reaching cascading effects across the entire globe. This finding
implicated in the susceptibility to COVID-19.74 Indeed, even in has heightened the awareness of the connections between personal
healthy individuals, there is preliminary evidence that difference in and planetary health and has demonstrated the capacity for a
the gut microbiome may be associated with proteomic biomarkers galvanizing coordinated response to an acute threat, with rapid
and inflammatory cytokines that predict the progression to severe changes to personal and collective behavior for mutual benefit. The
COVID-19.75 There are now calls to consider the role of lifestyle, same level of effort is now needed to address the NCD pandemic in
diet, and the microbiome and the wider exposome in susceptibility the posteCOVID-19 world, from the first moments of life, when
and resilience to COVID-19,76 notably because expression of many of these conditions have their origins.78 Although the NCD
angiotensin-converting enzyme 2, the receptor for entry of the pandemic has occurred on a much slower time frame and is
SARS-CoV-2 spike protein, is modulated by environmental and seemingly more insidious, the devastating large-scale personal,
lifestyle factors.77 This finding underscores the importance of economic, and societal effect of these chronic diseases is arguably
ecologic approaches to environmental and lifestyle health that far more significant and long-lastingdand no less important.

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 S.L. Prescott / Ann Allergy Asthma Immunol 125 (2020) 528e534 533

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