Environmental Research 216 (2023) 114489

Contents lists available at ScienceDirect

Environmental Research
journal homepage: www.elsevier.com/locate/envres

Review article

Asthma triggered by extreme temperatures: From epidemiological evidence

to biological plausibility
Azhu Han a, Shizhou Deng a, Jiarui Yu b, Yali Zhang a, Bin Jalaludin c, Cunrui Huang d, *
a
School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
b
Shenzhen Health Development Research and Data Management Center, Shenzhen 518028, China, School of Arts and Sciences, Columbia University, New York City,
NY, USA
c
School of Population Health, University of New South Wales, Sydney, Australia
d
Vanke School of Public Health, Tsinghua University, Beijing, 100084, China

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

Keywords: Background: There is rapidly growing evidence indicating that extreme temperature is a crucial trigger and
Asthma potential activator of asthma; however, the effects of extreme temperature on asthma are inconsistently reported
Extreme temperature and the its potential mechanisms remain undefined.
Epidemiology
Objectives: This review aims to estimate the impacts of extreme heat, extreme cold, and temperature variations on
Mechanism
Review
asthma by systematically summarizing the existing studies from epidemiological evidence to biological
plausibility.
Methods: We conducted a systematic search in PubMed, Embase, and Web of Science from inception to June 30,
2022, and we retrieved articles of epidemiology and biological studies which assessed associations between
extreme temperatures and asthma. This protocol was registered with PROSPERO (CRD42021273613).
Results: From 12,435 identified records, 111 eligible studies were included in the qualitative synthesis, and 37
articles were included in the meta-analysis (20 for extreme heat, 16 for extreme cold, and 15 for temperature
variations). For epidemiological evidence, we found that the synergistic effects of extreme temperatures, indoor/
outdoor environments, and individual vulnerabilities are important triggers for asthma attacks, especially when
there is extreme heat or cold. Meta-analysis further confirmed the associations, and the pooled relative risks for
asthma attacks in extreme heat and extreme cold were 1.07 (95%CI: 1.03–1.12) and 1.20 (95%CI: 1.12–1.29),
respectively. Additionally, this review discussed the potential inflammatory mechanisms behind the associations
between extreme temperatures and asthma exacerbation, and highlighted the regulatory role of immunological
pathways and transient receptor potential ion channels in asthma triggered by extreme temperatures.
Conclusions: We concluded that both extreme heat and cold could significantly increase the risk of asthma.
Additionally, we proposed a potential mechanistic framework, which is important for understanding the disease
pathogenesis that uncovers the complex mechanisms of asthma triggered by extreme temperatures and protects
the sensitive individuals from impacts of extreme weather events and climate change.

Abbreviations: CI, confidence interval; CL, cumulative lag; CGRP, calcitonin gene-related peptide; COPD, chronic obstructive pulmonary disease; DC, dendritic
cell; DTR, diurnal temperature range; EOS, eosinophil; GDP, gross domestic product; FEV1, forced expiratory volume in 1 s; HI, high income; HSP, heat shock protein;
IAQ, indoor air quality; ICD, International Classification of Disease; IPCC AR6, Intergovernmental Panel on Climate Change Sixth Assessment Report; LMI, lower
middle income; MC, mast cell; MMPs, matrix metalloproteinases; NE, neutrophil endopeptidase; NEU, neutrophil; O3, Ozone; ORs, odds ratios; NKA, neurokinin A;
PEFR, peak expiratory flow rate; PGs, prostaglandins; PM, particulate matter; ROS, reactive oxygen species; RR, relative risks; RSV, respiratory syncytial virus; SES,
socioeconomic status; SL, single lag; TCN, temperature changes between neighbouring days; TRP, transient receptor potential; TVN, temperature variation between
neighbouring days.
* Corresponding author. Vanke School of Public Health, Tsinghua University, Haidian District, Beijing, 100084, China.
E-mail address: huangcunrui@tsinghua.edu.cn (C. Huang).

https://doi.org/10.1016/j.envres.2022.114489
Received 15 August 2022; Received in revised form 25 September 2022; Accepted 1 October 2022
Available online 5 October 2022
0013-9351/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A. Han et al.
1. Introduction
In the context of global climate change, the frequency and intensity
of extreme weather events are increasing rapidly with a significant
impact on human health and potential long-term consequences (Field
and Barros, 2014; Hoegh-Guldberg et al., 2019). In 2022, the Inter­
governmental Panel on Climate Change Sixth Assessment Report (IPCC
AR6) confirms that several non-communicable respiratory diseases are
climate sensitive based on their exposure pathways (Pӧrtner, 2022).
Accumulating evidence indicate that heatwaves, cold spells, and tem­
perature drops could increase the risk of morbidity and mortality of
respiratory diseases, particularly asthma and chronic obstructive pul­
monary disease (COPD) (Isaksen et al., 2015; Wang and Lin, 2015; Zhao
et al., 2019; Zhou et al., 2022). Knowledge of the synergistic health ef­
fects of extreme temperatures, environments, and individual vulnera­
bilities as well as the underlying pathophysiological pathways, is
important to protect vulnerable individuals from extreme weather
events associated with climate change.
Asthma, a respiratory disease characterized by shortness of breath
and wheezing (Papi et al., 2018), remains a significant global health
issue which caused an estimated 495, 100 deaths and 22.8 million
disability-adjusted life-years in 2017 (Kyu et al., 2018; Roth et al.,
2018). Since asthma is the product of genetics and environments, the
mechanisms behind this interaction are complex and contradictory
(Tang et al., 2021). At present, factors that impact asthma attacks
include individual vulnerabilities (genetic predisposition, age, obesity,
etc.) and environmental factors (allergens, infections, air pollution,
climate change, etc.) (Altzibar et al., 2015; D’Amato et al., 2020; Tzi­
vian, 2011). Over the past decades, research has also demonstrated as­
sociations between exposure to extreme temperatures and asthma
exacerbation. Extreme temperatures not only directly increase the risk
of asthma hospital admissions, respiratory symptoms, deterioration of
lung function, and airway inflammation (da Silva et al., 2019; Deng
et al., 2020; Du et al., 2019; Hyrkas-Palmu et al., 2022; Hyrkäs et al.,
2016; Hyrkäs et al., 2014; Lei et al., 2022; Li et al., 2014), but also
indirectly affect the interaction of environmental factors and thereby
increasing the risk of asthma attacks (Choi et al., 2021; Hu et al., 2020b;
Zhang et al., 2020). However, recent studies have also shown that after
controlling for air pollution or exposure to pollens, there is a persistent
relationship between extreme temperature and asthma exacerbation
(Fang et al., 2021; Sohail et al., 2020; Zhang et al., 2020). This dem­
onstrates that extreme temperature is an independent predictor of
asthma exacerbation.
The temperature-asthma relationships exhibit a U- or J-shaped
curve, that is, both extreme heat and extreme cold could increase the
risk of asthma attacks (Cong et al., 2017; Fang et al., 2021; Lam et al.,
2016). Numerous studies, using different study designs including
cross-sectional, case-control, case-crossover, time-series and cohort
studies, have examined temperature-asthma associations and the results
are inconsistent. Specifically, the risk of asthma is defined as incidence
rate of asthma according to self-reported asthma or hospital/national
records. Additionally, the definition of extreme temperatures in the
literature is not consistent (Lam et al., 2019; Lei et al., 2021; Sangkharat
et al., 2020; Son et al., 2014; Wei et al., 2020). Extreme temperatures are
often defined by the relative or absolute threshold of different ambient
temperature metrics and duration. In recent years, an increasing amount
of literatures have shown that environmental factors are potential effect
modifiers for the relationships between extreme temperatures and
asthma (Bergmann et al., 2020; Tischer et al., 2017; Ziska et al., 2019),
and have further explored the potential inflammatory mechanisms
behind the complex relationships (Deng et al., 2020; Du et al., 2019).
Previous studies have focused on either estimating the relative risks
of extreme temperature or characterizing the potential effect modifiers
of the exposure-response relationships. For instance, multiple exposure
pathways contribute to asthma attacks, some of which are temperature-
related, including changes in concentrations of air pollutants such as
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Environmental Research 216 (2023) 114489
suspended particulate matter (PM) and ozone formed by photochemical
reactions that are sensitive to temperature (Entwistle et al., 2019; Gri­
gorieva and Lukyanets, 2021); and modification of aeroallergen pro­
duction and duration of exposure etc. (Anenberg et al., 2020; Witonsky
et al., 2019). Indeed, inconsistencies in epidemiologic evidence have
been found for associations differ by study characteristics (e.g., de­
mographic, geographic regions). In addition, experimental evidence
suggest that extreme temperature exposures can trigger asthma attacks
via airway inflammation (Deng et al., 2020; Du et al., 2019; Millqvist,
2015). However, there is still a lack of comprehensive frameworks to
explain the effect of extreme temperatures on asthma attacks, and this
hampers the understanding local environmental divers of symptoms in
people with asthma and the current research priorities and increases the
potential challenges for the future.
Although previous systematic reviews have summarized the evi­
dence of temperature-asthma associations (Bodaghkhani et al., 2019;
Cong et al., 2017; Xu et al., 2018), the effects of extreme temperatures,
such as extreme heat, extreme cold, and temperature variations, on
asthma are not consistent. Hence, a systematic search of evidence on the
associations between extreme temperatures and asthma is important.
This review aims to review the epidemiological evidence for the syn­
ergistic effects of extreme temperatures, indoor/outdoor environments,
and individual vulnerabilities on asthma attacks, and quantify the as­
sociations between extreme temperature and asthma attacks. Addi­
tionally, we aimed to clarify the underlying biological plausibility
between extreme temperature and asthma, and make recommendations
for future research directions.
2. Methods
Due to the complexity of this topic, we summarize the relevant
studies by systematically retrieving all evidence that included various
explorations of the extreme temperature-related asthma from epidemi­
ologic evidence to biological plausibility. Firstly, the epidemiologic
evidence included current studies for the associations between extreme
temperatures and asthma, and the synergistic effects of extreme tem­
peratures, indoor/outdoor environments, and individual vulnerability
on asthma attacks. Secondly, we use meta-analysis to further quantify
the associations between extreme temperatures and asthma attacks.
Finally, regarding biological plausibility, we systematically evaluated
the clinical and experimental evidence for the potential mechanisms
behind the association between extreme temperatures and asthma.
2.1. Search strategy
All relevant literatures published in English up to June 30, 2021 from
PubMed, Embase, and Web of Science were searched. The following
terms: (asthma) and (temperature* or cold* or heat*) (Supplementary
Table 1) were used as our search strategies. This systematic review was
performed according to the PRISMA 2020 statement (Page et al., 2021)
and the protocol was registered in PROSPERO (CRD42021273613). The
PRISMA checklist can be found in Supplementary Table 2.
Titles and abstracts were screened to include all eligible articles, and
the references of the retrieved articles were independently assessed by
two researchers (A.H., S.D.). All studies were classified as extreme
temperatures (i.e., including extreme heat, extreme cold, and tempera­
ture variations) studies after screening to identify papers that reported
the associations between extreme temperatures and asthma. We also
manually searched the references from the primary studies for addi­
tional publications, and all identified citations were merged in Endnote
version 20 and duplicates were removed.
2.2. Selection criteria
All relevant studies were extracted after screening the titles and
abstracts that were related to the temperature-asthma associations. The
A. Han et al.
selection process was shown in Fig. 1. As for the epidemiological evi­
dence, descriptive epidemiological studies and studies without full data
were included. Studies that report the modifications (e.g., indoor/out­
door environments and individual vulnerabilities) of temperature-
related asthma were also included. For the meta-analysis, the inclu­
sion criteria were: (1) the outcome in the study was diagnosed asthma
defined according to the International Classification of Disease (ICD) or
local hospital/national records; (2) the extreme temperatures in the
study include extreme heat (defined as 99th, 90th or 75th etc. percentile
or with temperatures above), extreme cold (defined as 1st, 10th or 25th
etc. percentile or with temperatures below), and temperature variations
(intra- or inter-day temperature variability); (3) original epidemiolog­
ical studies; and (4) the reported risk estimates. Exclusion criteria were:
(1) reviews/commentaries/letters; (2) duplicate data; (3) non-English
studies; and (3) other focuses (i.e., full text articles without presenting
data on review outcomes or temperature exposure). For the biological
plausibility, papers that focused on the mechanisms of asthma triggered
by temperatures were included in the review. Data from animal models,
human tissues and vitro studies that explored the potential mechanisms
for temperature-related asthma were also included.
Fig. 1. Flowchart of study selection.
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2.3. Data extraction
Data from the eligible studies were independently extracted by two
investigators (A.H. and S.D.). The extracted information included: first
author, publication year, study location, duration of study, participant
age, sample size, outcomes, exposure measurement methods, lag pe­
riods, relative risks (RRs)/odds ratios (ORs) and 95% confidence in­
tervals (CIs). Details about effect estimates were extracted and recorded
in Supplementary Table 3. Two investigators (A.H. and S.D.) completed
the critical appraisal checklist for analytical cross-sectional studies
developed by the Joanna Briggs Institute to assess the risk of bias (Moola
et al., 2017) (Supplementary Table 4). Furthermore, the relationships
between extreme temperatures and asthma attacks are characterized by
the time lag (in days) between exposure and health events, and the in­
vestigators vary the lags which they study and report. Therefore, based
on most previous studies (Atkinson et al., 2014; Sangkharat et al., 2019),
the effect estimate for the meta-analysis was selected by following pri­
orities: (1) the lag that the investigators focused on or stated as a pri­
ority; (2) the lag that was statistically significant; and (3) the lag with the
largest estimate.
A. Han et al.
2.4. Data synthesis and statistical analysis
In the qualitative systematic review, we classified the associations in
two themes: epidemiological evidence and biological plausibility. Since
a great number of studies were included in the review and with their
different approaches, a critical appraisal for the quality of each study
was deemed to be beyond the scope of a qualitative review. In the meta-
analysis, we retrieved effect estimates RRs and 95%CI for associations
between extreme temperatures and asthma attacks. Given the ORs was
equivalent to RRs under the “rare-disease assumption” (Pace and Mul­
tani, 2018), we therefore used RRs values as measures of associations in
the meta-analysis. Forest plots were used to graphically display the in­
dividual RRs as well as the pooled RRs. We also conducted a number of
subgroup analyses, as followings: (1) gender (female, male); (2) age
(children aged ≤18 years, adults aged from 19 to 64 years, elderly aged
≥65 years); (3) regions (Australia, Asia, Europe, North America); (4)
latitudes (low latitude of 0◦ –30◦ , middle latitude of 30◦ –60◦ ); (5) lag
days (single lag 0 days (SL0), SL1, SL2 days, and cumulative lag 1–2 days
(CL1-2), CL3-6, CL7-14, CL15-30 days); (6) patient visit types (Emer­
gency visits; inpatient admissions; outpatient visits); and (7) extreme
heat (heat, heatwaves) and extreme cold (cold, cold spells). The sub­
group of extreme heat was divided into heat (defined as temperature
above 99th, 90th or 75th percentile etc., in a single day) and heatwaves
for consecutive two or more days with extreme heat. Similarly, the
subgroup of extreme cold was divided into cold (defined as temperatures
below 1st, 10th or 25th percentile etc., in a single day) and cold spells for
consecutive two or more days with extreme cold temperatures.
In the meta-analysis, the effect estimates (RRs/ORs and 95%CI) of
the included studies were quantitatively pooled. Heterogeneity between
studies was evaluated with Cochran’s Q and I2 statistics. P < 0.10 was
considered significant for the Cochran’s Q statistic, and the values I2
greater than 50% were regarded as an indication of moderate-to high-
heterogeneity (Higgins and Thompson, 2002). Fix-effects models were
used if P > 0.1 and I2 < 50%, otherwise a random-effect model was used.
Additionally, subgroup analyses were conducted to explore the source of
heterogeneity and robustness of those findings. Publication bias was
evaluated using funnel plots, Egger’s tests (Egger et al., 1997), and “trim
and fill” analysis (Duval and Tweedie, 2000). A leave-one-out sensitivity
analysis was performed to assess the stability of the pooled estimates. All
statistical analyses were conducted using R (version 4.0.3) with the
“meta” packages (Balduzzi et al., 2019).
3. Results
The search resulted in 12,435 citations (Fig. 1). After removing the
duplicates, 9583 titles and abstract were screened, and 9355 articles
were excluded. From 221 full-text articles assessed for eligibility, 111
eligible studies were included in the qualitative synthesis (80 for
epidemiological evidence and 31 for biological plausibility) (Supple­
mentary Table 3). Due to 43 studies that did not assess associations
between extreme temperatures and asthma from epidemiological
studies, 37 articles were included in the meta-analysis, including 20
studies for extreme heat, 16 studies for extreme cold, and 15 studies for
temperature variations. Approximately half of the included studies were
conducted in Asia and most of the studies had focused on asthma
morbidity in hospitals (Supplementary Fig. 1).
3.1. Epidemiological evidence for extreme temperatures and asthma
The relationship of temperature and asthma exhibits a U- or J-shaped
curve (Cong et al., 2017; Fang et al., 2021; Lam et al., 2016). Initially, it
has been well recognized that acute asthma attacks are often induced by
exposing the body to cold, and such attacks can be prevented by
breathing warm and humidified air (Chen and Chai, 1982; Farley et al.,
1988; Sandsund et al., 1997). Recent studies found that extreme heat
also increased the risk of asthma attacks (Lam et al., 2016; Sangkharat
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et al., 2020; Xu et al., 2020), whereas many studies have shown that the
effects of extreme heat were statistically insignificant (Fang et al., 2021;
Lei et al., 2021). However, numerous studies have shown that extreme
cold has a significantly greater effect on asthma attacks than extreme
heat (Fang et al., 2021; Lam et al., 2016), particularly in people whose
asthma is poorly controlled and are more prone to experiencing
cold-related respiratory symptoms (Hyrkäs et al., 2016). Additionally,
recent studies have also explored the relationships of asthma and tem­
perature variations, including intra-day and inter-day temperature
variability. For example, a previous study identified that an increment of
1 ◦ C in diurnal temperature range (DTR) is significantly associated with
a 2.49% increase in asthma-related emergency department visits (Qiu
et al., 2015). A multi-city time-series study suggested that both cold and
heat were associated with respiratory mortality, among which asthma
was most vulnerable to extreme cold, with the effect estimate of 6.52%
for 1 ◦ C change among extreme cold (Li et al., 2019). Although extreme
temperatures have been found to be one of the crucial triggers regarding
to asthma attacks, this finding is still inconsistent due to the variations in
weather pattern, geographical environment, regional vulnerability, and
individual adaptability.
Increasing evidence point out that changes of outdoor environments
are associated with urbanization, industrialization, and climate change
are increasing the risk of asthma attacks (Huang et al., 2020). Impor­
tantly, air pollution may be an important risk factor affecting the pro­
gression of asthma (Guarnieri and Balmes, 2014), and there may be
synergistic effects of extreme temperature and air pollutants on asthma
attacks (Bergmann et al., 2020; Cai et al., 2014; Delfino et al., 2014;
Tischer et al., 2017; Ziska et al., 2019). For example, the effects of
extreme cold on asthma were greater at higher concentrations of O3 than
at lower concentrations (Fang et al., 2021). It is possible that air
pollutant-induced damages to airway epithelial cells increases the sen­
sibility of the respiratory system to extreme temperatures (Shin et al.,
2021). Another possible reason is that climate change affects the in­
tensity and frequency of extreme temperature events, which in turn
could modify the distribution and allergenicity of natural allergen, and
meanwhile increase the allergen sensitivity in susceptible individuals
(Acevedo et al., 2019; De Roos et al., 2020; Ziska et al., 2019).
Furthermore, increases in the length of the pollen season would increase
the emergency department visits by 14% for asthma in the 2090s in a
higher greenhouse gas emissions scenario (Neumann et al., 2019).
Therefore, an environmental contribution to asthma attacks, which
related to the complex interplay of extreme temperature, air pollution
and aeroallergen, supports the concept that extreme temperature has an
impact on asthma.
Generally, most people spend 80 to 90 percent of their times indoors
(Leech et al., 2002), where chemical, physical, and biological exposures
can affect the health of these individuals (Paterson et al., 2021). Existing
literature has shown that a 1 ◦ C increase in indoor temperature is
significantly associated with an average increase of 0.010, 0.008,
10.060, 12.060, which in four measures of lung function for children
with asthma (peak expiratory flow rate (PEFR) morning, PEFR evening,
forced expiratory volume in 1 s (FEV1) morning and FEV1 evening)
(Pierse et al., 2013). Additionally, for an increase of 10 ◦ F in classroom
temperature, there was a 53% increase in the rate of asthma-related
school-based healthcare visits (Plott et al., 2021). The indoor microcli­
mate, particularly temperature and relative humidity, could affect the
airborne survival of bacteria, virus, and fungi (dos Santos et al., 2009;
Lofgren et al., 2007; Tang, 2009). A recent animal experiment on quine
asthma indicates that the negative effect of high temperature and rela­
tive humidity on lung function was exacerbated by inhalable pollens and
moulds (Bullone et al., 2016). Further, the use of central air conditioning
and humidifier in the indoor residential environment was positively
associated with asthma prevalence among children (Johnston et al.,
2017; Svendsen et al., 2018).
Asthma can be caused by complex interaction of environmental
factors and individual vulnerabilities, including thermoregulatory
A. Han et al.
capacity, respiratory sensitivity and socioeconomic status (Asher et al.,
2021; Ma et al., 2020; O’Lenick et al., 2017). In fact, rates of hospital­
ization for asthma exacerbations and trends in these rates over time are
different in the elderly, adults and children with the patterns varying by
gender, season and environmental conditions. Many studies have shown
that the elderly and children with respiratory diseases are vulnerable to
extreme temperatures (Hu et al., 2020a; Lam et al., 2016, 2019; Liu
et al., 2021a; Wang and Lin, 2015; Xu et al., 2013a, 2013b). It is possible
that children who are less mature in physiological metabolism, ther­
moregulation, and acclimatization would have higher lung ventilation
rates, and are more likely to have airway inflammation and obstruction
when exposuring to extreme temperatures (Anderko et al., 2020; Hanna
and Tait, 2015). However, the elders who have low immunity, severe
respiratory diseases, or other comorbidity were tend to have asthma
under non-optimum ambient temperatures (Anderson et al., 2013;
Kenny et al., 2010). In addition, a nationwide case-crossover study has
found that less developed cities displayed stronger associations between
heat exposure and all-cause hospitalizations in Brazil, particularly every
5 ◦ C increase in daily mean temperature during the hot season would
increase the asthma-related hospitalization risk by 3.7% for lower
middle income (LMI) cities versus − 6.4% for high income (HI) cities (Xu
et al., 2020).
3.2. Meta-analysis of extreme temperatures and asthma attacks
For extreme heat exposures, the overall pooled RR was 1.0723 (95%
CI: 1.1.0289–1.1174; I2 = 81.2%; n = 20 studies) for asthma attacks
(Fig. 2). Additionally, we found that asthma attacks were associated
with heat (RR = 1.0638) and heatwaves (RR = 1.1956) (Fig. 3 & Sup­
plementary Fig. 2). Subgroup analyses indicated that male, elderly, and
emergency visits yielded the highest positive association with asthma
attacks. We found significant pooled effect estimates for studies from
Australia and Europe, whereas the effect estimates for studies from Asia
and North America did not reach significance. Stratification of studies by
exposure lag days showed that the short-term exposure to extreme heat
of SL2, CL1-2, and CL3-6 days yielded a significant increase on the risk of
asthma, with RRs ranging from 1.02 to 1.19 (Fig. 3). We applied funnel
plots along with Egger’s test (P = 0.03) and Begg’s test (P = 0.02) to
detect publication bias in extreme heat estimates, which showed that
there is significant publication bias in most of the secondary analyses
(Supplementary Fig. 3). With 7 added studies, the trim and fill analysis
showed the association between extreme heat and asthma with random
Fig. 2. Forest plot of extreme heat and asthma attacks.
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Environmental Research 216 (2023) 114489
effects was 1.0250(95%CI: 0.9789–1.0733). The one-study remove
sensitivity analyses indicated the robustness of the results (Supple­
mentary Fig. 4).
The extreme cold exposures were associated with an increased risk of
asthma by 19.77% (RR = 1.1781, 95% CI: 1.1154–1.2861; I2 = 88.4%; n
= 16 studies) (Fig. 4). Specifically, the pooled estimate of RRs in cold
(RR = 1.3261) was larger than that in cold spells (RR = 1.0028) (Fig. 5 &
Supplementary Fig. 5). Subgroup analyses indicated that extreme cold
exposures were significantly associated with male, female, children,
elderly, emergency visits, and inpatient admissions (Fig. 5). Addition­
ally, the effects of extreme cold exposures in CL3-6, CL7-14, and CL15-
30 days were statistically significant, with RRs ranging from 1.17 to
1.36. A significant publication bias was detected using Egger’s test (P﹤
0.01) and Begg’s test (P﹤0.01) (Supplementary Fig. 6). The publication
bias is highlighted by the asymmetrical spread of points with more
points to the right of the funnel. With 8 added studies, the trim and fill
analysis showed the association between extreme cold and asthma with
random effects was 1.0526(95%CI: 0.9764–1.1347). However, the one-
study remove sensitivity analyses indicated the robustness of the results
(Supplementary Fig. 7).
The definition of temperature variations is diverse and complex, and
it is usually studied using many different metrics, such as intra-day
temperature variability (i.e., DTR) and inter-day temperature vari­
ability (i.e., temperature changes between neighbouring days, TCN;
temperature variation between neighbouring days, TVN). Therefore, we
reported the average combined effect of the intra- and inter-day tem­
perature variations and asthma. Intra-day temperature variations ex­
posures have a higher risk of asthma when comparing high versus low
levels of exposures (Supplementary Fig. 8). Moreover, most studies
found that associations between DTR and asthma were higher in lag
more than 2 days than current day (Supplementary Fig. 9). There is only
one study (Wasilevich et al., 2012) showed that a greater 24-h tem­
perature change decreased the risk of asthma-related emergency visits,
whereas the overall results suggested there is no association found for
short-term temperature change.
3.3. Biological plausibility
In general, asthma can be divided into allergic and non-allergic
phenotypes (Agache and Akdis, 2016; Kuruvilla et al., 2019), mainly
are associated with an increase in helper T cell 2 mediated eosinophil
granulocyte and an inflammatory response to neutrophil, respectively.
A. Han et al.
Fig. 3. Subgroup analyses of extreme heat and asthma attacks. SL: single lag; CL: cumulative lag; CI: confidence interval; RR: relative risks.
Fig. 4. Forest plot of extreme cold and asthma attacks.
As asthma is a complex biological network of distinct and interrelated
inflammatory pathways, we discuss potential mechanisms behind
extreme temperatures and asthma exacerbations, and highlight the
regulatory role of immunological pathways and transient receptor po­
tential (TRP) ion channels in asthma triggered by extreme temperatures.
Herein, we provide a mechanistic framework for understanding extreme
temperatures in asthma pathogenesis, with a focus on environment,
individual vulnerabilities, as well as airway inflammation (Fig. 6).
Extreme temperature exposures could affect the inflammatory
response, which could lead to airways constrictions (Mustafa, 2019).
Previous evidence suggested that both healthy subjects and asthmatic
patients with inhalation of cold and dry air may induce airway heat loss,
and increase the release of airway inflammatory mediators, which
induced airway bronchoconstriction (Anderson and Daviskas, 2000;
Clary-Meinesz et al., 1992; Koskela and Tukiainen, 1995; Larsson et al.,
1998; Lee et al., 1983). Although people are more adaptable to heat than
6
Environmental Research 216 (2023) 114489
cold (Andrade et al., 2011), long-term heat exposure can affect the
thermoregulatory system, increasing in tidal volume and frequency of
breathing, and increase the systemic inflammatory response (Leon and
Helwig, 2010; White, 2006). Moreover, specific airway resistance
increased by 112% immediately after hyperventilation of humid air
(49 ◦ C) and by 38% after room temperature (20–22 ◦ C) for 4 min in
patients with asthma, suggesting that the bronchopulmonary C-fibers
are activated by an increase in airway tissue temperature in patients
with asthma (Hayes et al., 2012). It is therefore likely that the rela­
tionship between temperature and pro-inflammatory is U-shaped, and
extreme temperature (extreme heat, cold and temperature variations)
could affect airway inflammation response, alter mucus production,
damage the airway epithelium, and trigger airway hyper-reactivity
(Deng et al., 2020; Du et al., 2019; Larsson et al., 1998; Wu et al., 2020).
Furthermore, temperature could stimulate the imbalance of Th1/
Th2, suggesting an alternative immunological pathway to airway
A. Han et al. Environmental Research 216 (2023) 114489

Fig. 5. Subgroup analyses of extreme cold and asthma attacks. SL: single lag; CL: cumulative lag; CI: confidence interval; RR: relative risks.

Fig. 6. Mechanistic framework for the effects of extreme temperature on asthma attacks. CGRP: calcitonin gene-related peptide; COPD: chronic obstructive pul­
monary disease; DC: dendritic cell; EOS: eosinophil; IAQ: indoor air quality; NE: neutrophil endopeptidase; NEU: neutrophil; NKA: neurokinin A; MC: mast cell;
MMPs: Matrix metalloproteinases; PGs: prostaglandins; ROS: Reactive oxygen species; SES: socioeconomic status; TRP: transient receptor potential.

inflammation (Wu et al., 2020). For example, Liao et al. (2017) found
that thermoneutral temperature (30 ◦ C) influenced asthmatic mouse
immunity via a shift in the Th1/Th2 cell subsets profile from the pre­
dominant Th2 to Th1 pattern in the lung when compared to a standard
temperature (20 ◦ C). Another important consideration is the possibility
that the cold and dry exposures are suitable for the spread and survival
of viruses such as influenza and respiratory syncytial virus (RSV)
(Bloom-Feshbach et al., 2013; Lofgren et al., 2007; Tang, 2009), which
reduce the humidity of the airway mucosa and damage the epithelial
cilia, then increase the susceptibility of the body to viruses and allergens
(Chan et al., 2009; Clary-Meinesz et al., 1992; Jaakkola et al., 2014), and
finally lead to asthma attacks. Recent experimental evidence suggests
that IL-17A is a common and critical driver of impaired lung function
and immunopathology is induced by the influenza virus, rhinovirus, and
RSV (Liu et al., 2021b). However, heat stress usually leads to a high level
of heat shock protein (HSP), and clinical studies have shown that an

7
A. Han et al.
increase in circulating HSP70 is associated with asthma (Qu et al.,
2015). The extracellular HSP70 can manifest different activities in
airway inflammatory processes and asthma attacks, acting either as a
pro-inflammatory trigger or an anti-inflammatory agent (Shevchenko
et al., 2020).
Over the past decades, the new knowledge on the ability of several
airway TRP channels to sense and react to temperature have opened new
windows for understanding the pathogenesis of respiratory diseases
(Millqvist, 2015). TRP channels are involved in temperature induced
airway symptoms associated with neurogenic inflammation but via
different pathways (Millqvist, 2015; Silverman et al., 2020), focusing on
four members, TRPM8 (activated at 8–22 ◦ C), TRPA1 (<8 ◦ C), TRPV1
(≥42 ◦ C), and TRPV4 (22–40 ◦ C) as these represent the channels where
most information has been gathered with the relevance to the airways
(Bonvini et al., 2015; Millqvist, 2015; Silverman et al., 2020). Both
TRPM8 and TRPA1 temperature sensors could lead to an increased
expression of several cytokines and chemokine genes (Du et al., 2019;
Naumov et al., 2015; Sabnis et al., 2008; Wu et al., 2020). Repeated
exposure to temperature variations aggravated airway hyper­
responsiveness in mice, and TRPA1 mediated the
temperature-dependent airway inflammatory effect (Du et al., 2019).
Additionally, the bronchoconstriction induced by increasing airway
temperatures among asthma is mediated through cholinergic reflex
resulting from activation of these airway sensory nerves (Hayes et al.,
2012; Lin et al., 2015), and the TRPV1 channels overexpressed in the
airways of patients with refractory asthma (Dumitrache et al., 2021;
McGarvey et al., 2014). In pulmonary inflammatory diseases, TRPV4
may improve ciliary beat frequency enhancing mucociliary clearance,
and increase pro-inflammatory cytokine secretion/lung tissue injury
(Scheraga et al., 2017), particularly linked with fungal sensitization and
asthma in children (Wiesner et al., 2020).
4. Discussion
4.1. Principal findings
This comprehensive review found that extreme temperature expo­
sures play an essential role in the pathogenesis of asthma attacks, and
the meta-analysis further confirms the associations between extreme
temperatures and asthma attacks. The pooled RR for asthma attacks in
extreme cold and extreme heat were 1.20 (95%CI: 1.12–1.29) and 1.07
(95%CI: 1.03–1.12), respectively. This review further highlights the
regulatory role of immunological pathways and TRP channels in asthma
triggered by extreme temperatures. The mechanistic framework for the
synergistic effect among extreme temperatures, indoor/outdoor envi­
ronments, and individual vulnerability on asthma attacks provides new
insights for future research in this field.
In this study, we found that both extreme cold and heat significantly
increase daily asthma attacks, but cold conditions affect the daily hos­
pital visits for asthma more than heat conditions. These findings are
substantiated by previous vitro experiments (Koskela and Tukiainen,
1995; Larsson et al., 1998; Togias et al., 1985) and more recent epide­
miological evidence (Chen et al., 2018; Son et al., 2014). We also found
the effects of extreme heat on hospital visits showed a short-term lag
effect, appeared to be relatively acute and lasted for a week, whereas the
extreme cold effect showed a long-term lag effect, lasting from 3 to 30
days (Feng et al., 2021; Zhang et al., 2014). Consistent with other
findings (Xu et al., 2013b; Zhao et al., 2019), subgroup meta-analyses
also found that exposure to extreme temperature could increase the
risk of asthma in vulnerable population, particularly in the elderly and
children (Fang et al., 2021; Lam et al., 2016; Lei et al., 2021). For
example, a recent study showed greater sensitivity to high temperatures
for hospital re-admission than for first admission for asthma among
children aged 0–5 years (Lam et al., 2019). The influence of ambient
temperature on respiratory mortality has attracted growing concerns in
the background of climate change. It is important to note that asthma
8
Environmental Research 216 (2023) 114489
triggered by extreme ambient temperature could have a major impact on
public health since exposure to extreme temperatures is common and
increasing due to the impacts of climate change.
We found that both indoor and outdoor environmental factors can
affect the new onset and exacerbation of asthma directly and indirectly.
Asthma is commonly triggered or exacerbated by environmental con­
ditions such as aeroallergens, air quality and meteorological factors
(Gleason et al., 2014; Kwon et al., 2016; Obando-Pacheco et al., 2018;
Park et al., 2022; Yan et al., 2022). Recently findings indicated that
outdoor PM could modify the association between temperature and
childhood asthma hospitalization, for instance, females and children
were more sensitive to the modification effect of PM2.5 or PM10 on the
cold-asthma association (Jin et al., 2022). Moreover, prenatal and
postnatal exposure to ambient air pollution and high temperatures are
independently and jointly associated with asthma risk in early child­
hood, and a significant positive interaction of temperature and PM10 or
SO2 on asthma risk were among boys and younger children (Lu et al.,
2022). In particular, short-term increases in ambient temperature and
relative humidity have substantial adverse effects on lung function in
the elderly, whereas these effects are stronger when combined with
higher exposures to black carbon (Lepeule et al., 2018). However,
whether the negative effect of high indoor environmental temperature
and relative humidity on lung function is exacerbated by inhalable
pollens and moulds or by other undefined factors, remains to be ascer­
tained (Bullone et al., 2016). Further research should elucidate the na­
ture of the association for extreme temperature, as well as the effect
modification by different individuals and environmental characteristics.
It is possible to explain the observed associations between extreme
temperature and asthma. The temperature and pro-inflammatory asso­
ciations are U-shaped, and both extreme heat and cold not only enhance
the susceptibility to viruses and allergens, but also reduce lung function
and immunity (Kaminsky et al., 2000; Koskela et al., 1994; Koskela,
2007; Lin et al., 2018). Recently, Deng et al. (2020) found a U-shape for
immune proteins and pro-inflammatory factors with a peak value at
24 ◦ C with the increase of temperature in ovalbumin-based mouse
asthma model. For asthma, the most persuasive current hypothesis is
that the TRP channels are the sensors that provide vital information on
environmental temperature, and thereby quickly react to both noxious
heat and cold involved in temperature-induced airway symptoms
(Millqvist, 2015). However, the roles of these cation channels in regu­
lating the overall respiratory function are still not clearly understood
(Jia and Lee, 2007; Liu et al., 2018). At present, the TRP channels are
important pharmacological targets as novel therapeutic option for res­
piratory disease (Jia and Lee, 2007; Rajan et al., 2021). Since the
mechanisms of asthma triggered by temperature are complex and
interrelated, there is an avenue for future studies linking Th2-type cy­
tokines and TRP channels in the pathogenesis of asthma.
4.2. Strengths and limitations
Our findings suggest that more studies are needed on associations
between extreme temperatures and asthma attacks, especially for
extreme heat and extreme cold. Strengths of this study is that we sum­
marized evidence both quantitatively and qualitatively, assessed risk of
bias and provided subgroup analyses of meta-analysis to identify
vulnerable populations. However, this review has several limitations.
First, differences in the ways that temperature and lag measures were
used meant that we had to develop decision rules for classifying tem­
perature metrics and other variables. The main reason is that the defi­
nition of extreme temperatures in different areas is inconsistent. Second,
most of exposure assessments in epidemiological studies were based on
meteorological station or remote sensing data, which may have some
inherent limitations, including correlation rather than causation, expo­
sure misclassification and lack of information on several important
factors related to the risk of asthma. Third, publication bias and selective
reporting of positive associations (eg, at different lag days) might have
A. Han et al.
been common, as with all observational research.
4.3. Directions for future research
The features of asthma provide meaningful insights for understand­
ing the disease heterogeneity. Due to the knowledge of the pathophys­
iology of asthma are climate sensitive based on their exposure pathways,
it is worth considering asthma for sentinel surveillance as a marker for
the full-spectrum diseases under climate change scenarios.
We need to focus on the following aspects: (1) To clarify this issue,
further and specifically designed studies are needed in order to accu­
rately evaluate the effects of extreme temperature and asthma by indi­
vidual exposure assessments rather than exposure assessments based on
meteorological station or remote sensing data from epidemiological
studies, and the creation of multidisciplinary research teams and the
support for personalized environmental monitoring should be the first
step; (2) a further challenge is to efficiently and effectively identify those
who are at risk and also the target prevention strategies. Hospital
morbidity records (diagnosed cases, death) are the tip of the ice-berg
phenomena and do not reflect the actual burden of those who are
experiencing temperature related asthma exacerbation. It is necessary
for evidence-based early warning systems to target vulnerable pop­
ulations, particularly for those at risk with undiagnosed or pre-
symptomatic cases; (3) future researches about the effect of tempera­
ture on respiratory health should consider how temperature affects the
activity patterns and also the outdoor/indoor exposures to pollutants
and allergens for distinguishing health effects of temperature and other
outdoor exposures; (4) further explorations of the climate sensitive
biomarkers of airway epithelial injury in early phase development for
asthma is important. The long-term health effects of extreme tempera­
tures and the life-cycle perspective on the occurrence and development
of asthma is lacking. Whether extreme temperature impacts the initia­
tion and progress of asthma in early life should be further explored; and
(5) based on novel methods (eg, deep learning model, neural network
techniques), public health authorities should consider the temperature
effects on respiratory diseases, in order to develop an early asthma-
weather warning syndromic surveillance systems, evaluate a full-chain
health impact and protect human health.
5. Conclusions
By providing a comprehensively descriptive epidemiological evi­
dence and underlying mechanism of asthma triggered by extreme tem­
perature, this review is intended to support future researches on the
mechanisms underlying the exposures of extreme temperature. In
particular, extreme temperature plays an essential role in the patho­
genesis of asthma attacks, and highlights the regulatory role of immu­
nological pathways and TRP channels in asthma triggered by extreme
temperatures, particularly for extreme heat and extreme cold. We pro­
vide a potential mechanistic framework for the synergistic effect of
extreme temperatures, indoor/outdoor environments, and individual
vulnerabilities on asthma attacks in order to provide a comprehensive
insight for adaptation to the impacts of extreme weather events and
climate change. By tracking and predicting the climate change, efforts
can be made to alert the public, adjust clinical practice, reduce
temperature-related asthma attacks, and protect vulnerable individuals
who are at risk for adverse respiratory health outcomes.
Author contributions
C.H. conceived and designed the study. A.H. and S.D. contributed to
the study search, study selection, data extraction, and risk of bias
assessment. A.H. performed the statistical analysis and drafted the
manuscript and appendix. A.H., S.D., J.Y., Y.Z., B.J., and C.H. contrib­
uted to the interpretation of the results and editing of the paper. All
authors read the final version of the manuscript and approved the
9
Environmental Research 216 (2023) 114489
submission.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
The more detailed data used to support the findings of this study are
available in the Supplementary Table 3
Acknowledgement
This work was supported by the National Key R&D Program of China
(grant number 2018YFA0606200).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.envres.2022.114489.
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