Combined Effect of Hot Weather and Outdoor Air Pollution on Respiratory Health: Literature Review

: Association between short-term exposure to ambient air pollution and respiratory health is well documented. At the same time, it is widely known that extreme weather events intrinsically exacerbate air pollution impact. Particularly, hot weather and extreme temperatures during heat waves (HW) signiﬁcantly affect human health, increasing risks of respiratory mortality and morbidity. Concurrently, a synergistic effect of air pollution and high temperatures can be combined with weather–air pollution interaction during wildﬁres. The purpose of the current review is to summarize literature on interplay of hot weather, air pollution, and respiratory health consequences worldwide, with the ultimate goal of identifying the most dangerous pollution agents and vulnerable population groups. A literature search was conducted using electronic databases Web of Science, Pubmed, Science Direct, and Scopus, focusing only on peer-reviewed journal articles published in English from 2000 to 2021. The main ﬁndings demonstrate that the increased level of PM 10 and O 3 results in signiﬁcantly higher rates of respiratory and cardiopulmonary mortality. Increments in PM 2.5 and PM 10 , O 3 , CO, and NO 2 concentrations during high temperature episodes are dramatically associated with higher admissions to hospital in patients with chronic obstructive pulmonary disease, daily hospital emergency transports for asthma, acute and chronic bronchitis, and premature mortality caused by respiratory disease. Excessive respiratory health risk is more pronounced in elderly cohorts and small children. Both heat waves and outdoor air pollution are synergistically linked and are expected to be more serious in the future due to greater climate instability, being a crucial threat to global public health that requires the responsible involvement of researchers at all levels. Sustainable urban planning and smart city design could signiﬁcantly reduce both urban heat islands effect and air pollution. The following characteristics of studies involved in the review were extracted: study; study area; study period; weather parameters such as air temperature and humidity, dew point temperature, wind speed and direction, air pressure, precipitation, hours of sunshine; hot weather description, including deﬁnition of HW or high temperature used in the study; air pollutants such as PM, O 3 , NO 2 , SO 2 , CO; respiratory health indicators; exposure and confounders; statistical methods and study design; results with outcome and associated lag time. The role of effect modiﬁcation was investigated in terms of gender and age. Respiratory health outcomes included daily mortality from respiratory causes, respiratory emergency department visits, hospital admissions, ambulance calls, and lung cancer incidence.


Introduction
The increase in respiratory health indicators, including allergic disease, is welldocumented globally and, most harmfully, is more pronounced in those regions where it was previously low [1]. Studies conducted around the world show that both air pollution, on the one hand, and weather and climate conditions, on the other, have a negative impact on human respiratory health [1,2]. Endeavors to raise awareness and mitigate the health implications of air contamination are long-standing and successful. Extensive scientific assessments make a plausible argument for the theory of negative influence of air pollution on cardiac and pulmonary health, notwithstanding some whitespaces in scientific knowledge and, consequently, some lingering doubts [3]. Among them, less is known about the impact of the dangerously polluted air on health outcomes in various weather and climatic conditions, with the greatest interest being their potential synergy on respiratory tract during hot seasons and episodes with extremely high temperature [1,[4][5][6][7][8][9]. Of special weather, or episodes of heat wave. Wildfires and urban heat island (UHI) effects, pathogenic mechanisms, vulnerable population subgroups, confounder of multiple environmental stressors, climate change impact, and policy implications are discussed.

Materials and Methods
A systematical literature search was conducted in November 2020-May 2021 using electronic databases Pubmed, Web of Science, Science Direct, and Scopus for papers published before 20 May 2021. Hand searching of the applicable literature was also performed in relevant journals and bibliographies of included studies. Three conceptual categories were used: "ambient/outdoor air pollution", "extremely hot weather", and "respiratory health outcomes", revealing a total of 253 records. We were seeking for key words "heat wave", "hot weather", "high temperature", "warm season", "air pollution'", "particulate matters", "fine particles", "ozone", "respiratory mortality", "respiratory disease", "asthma", or "COPD" and also looked for studies cited in the recognized articles. The search identified 40 studies that were selected for the review. The narrative synthesis included all original studies with time-series or case cross-over design, ambient air-pollution and weather exposure, and mortality and/or hospital admission/ambulance call outcomes. All included studies examined respiratory (8th or 9th revision of the International Classification of Diseases (ICD8) or (ICD9]): 460-519; or 10th revision of the International Classification of Diseases (ICD10): J00-J99) mortality or morbidity in all age groups. Study duplicates were removed, and abstracts were screened independently by two authors (E.G. and A.L.). Final selected studies were chosen based on the inclusion criteria that they attempted to feature recorded respiratory/pulmonary health outcomes (deaths and hospital admissions/emergency room visits), had air pollution, warm/hot weather, heat waves, and health outcomes recorded quantitatively, and controlled for the main confounding variables. We placed no restrictions on study design, however, only studies published in the English language were included.
The conceptual framework for these interactions is summarized in Figure 1. Warm and hot temperatures and heat waves combined with air-pollution (O3, PMx, SO2, NO2, CO) were shown to act consistently as risk factors for respiratory mortality, hospital admissions, and daily emergency transports, where respiratory health outcomes were taken from the main categories: premature mortality; general respiratory complaints, ambulance calls, hospitalizations, and emergency department visits for respiratory reasons; chronic respiratory diseases such as COPD, asthma, etc.; and lung cancer, as shown in Figure 1. Warm and hot temperatures and heat waves combined with air-pollution (O 3 , PM x , SO 2 , NO 2 , CO) were shown to act consistently as risk factors for respiratory mortality, hospital admissions, and daily emergency transports, where respiratory health outcomes were taken from the main categories: premature mortality; general respiratory complaints, ambulance calls, hospitalizations, and emergency department visits for respiratory reasons; chronic respiratory diseases such as COPD, asthma, etc.; and lung cancer, as shown in Figure 1.
Hot weather descriptions were different among the studies. Almost all of them checked for health burden of high temperatures-those levels which exceed the specified percentile of the temperature distribution: 75th, 85th, 95th, 97th, 97.5th, or even 99th percentile for extremely hot weather. In a few papers, high temperature threshold was determined as temperature of minimum mortality [53,116] or temperature with the lowest frequency of ambulance calls [101]. Four studies focused on HW effect in European countries using different definitions of HW and counting for their intensity and duration [5,79,108,110]. Some papers looked at seasonal changes and warm air modifications during warm seasons [41,103,111,113] or in summer [102,104]. In some papers, hot weather influence was corrected by relative humidity expressed in apparent temperature (AT) [117,118] to analyze the perceived rather than the actual thermal load [5,30,41,53,74,79,91,109,110]. Two studies demonstrated the impact of polluted air on respiratory mortality and morbidity for different types of weather, where those with high temperature effects were referred to as dry tropical (DT) and moist tropical (MT) air masses [112,114].
Some studies examined effects of temperature changed by contaminants, and some observed the impact of pollutants modified by hot weather. For instance, a study by Breitner et al. [75] in Germany demonstrated modification in the temperature-mortality association by ozone. Park et al. [96] for South Korea notified the impact changed by temperature on the O 3 exposure, illustrating a pattern consistent with some modification of the effect. The potential interaction between air pollution health outcomes and high temperatures was tested mostly by means of a stratified analysis in time-series; few were tested by case-crossover analyses or through interaction terms. Statistical models used were mainly generalized additive models (GAM), generalized estimating equations (GEE), and generalized linear models (GLM). Almost all models were adjusted for time (seasonal and long-term trends), day of the week, public holidays, and influenza epidemics. Most of them had additional weather confounders such as relative humidity and barometric pressure.
Almost all studies provided consistent evidence of a synergy between the two exposures, with only two showing no evidence of interaction [5,106] and few of them reflecting that low temperature polluted air had a greater impact on respiratory health outcomes than hot air [73,87,101]. In addition, Anderson and Bell [110], for research in urban communities of the USA, showed heat effects on daily mortality from respiratory causes were slightly lower when models included ambient pollution (O 3 and PM 10 ) [110].

Heat, Air Pollution and Morbidity
Strong evidence was obtained for the synergistic impact of ambient air pollution with PM, CO, O 3 , SO 2, and NO 2 and hot weather on triggering of health problems [78,119,120]. The magnitude of these effects on respiratory morbidity varies by diseases and individual characteristics; estimates seem to be higher among children and the elderly population. Illustrations of increasing number of daily emergency transports, hospital admissions, and ambulance calls for respiratory problems are summarized in this section. The effect was shown in European cities, especially for elderly aged ≥75 [30], in places with high levels of pollution in China, including Beijing and Nanjing [41,102,103,105], in Tokyo, Japan [104], etc. Increased asthma hospitalization was demonstrated to be extremely related with high levels of ozone in connection with hot weather in Indianapolis in the USA [111], for emergency department visits among children in St. Louis, USA [113] during warm seasons, as well as for cities in the USA such as North Carolina on hot, dry days [112]. Episodes of high PM 2.5 and O 3 and extremely hot temperatures (T > 27.9 • C) were demonstrated for hospital admissions with COPD exacerbations in Taiwan. Especially significant impact was detected in the elderly with odds ratio (OR) = 1.037 and greater lagged effect [89]. An increased rate for lung cancer incidence in association with high temperatures and PM 1 exposure was discussed by Guo with coauthors [37], who showed stronger incident rate for males. High daily ambulance calls for respiratory distress on extremely hot days (with temperature T > 99th percentile of distribution) with high concentrations of PM 2.5 and constituents were demonstrated for Kaohsiung in Taiwan [94]. Respiratory emergency transports during summer for episodes with high exposure of PM 10 and NO 2 were shown to be greater for males than for females in Tokyo, Japan [104]. High temperatures in connection with particulate matter pollution were associated with increases in hospital emergency room visits for respiratory system diseases in Beijing, China, indicating the elderly (age ≥ 65) and women were the more vulnerable groups [105].
Children and adolescents were shown to be a sensitive age cohort. Increased hospitalization of acute bronchiolitis-related disease among children accompanied with high temperature and exposure to NO 2 and PM 10 at different lag times was shown for Hong Kong [91]. Air pollution during hot weather raised asthma ED visits in St. Louis, USA by 9.45% (95% CI = 1.02, 1.17) among patients 11-17 years old [113].
Geography and type of climate were shown to be important. Michelozzi et al. [30], in a study for Europe, emphasized the raise in apparent temperature was more effective for Mediterranean cities with a +4.5% (95% CI: 1.9-7.3) increase in respiratory emergency visits compared with northern continental cities, where a +3.1% (95% CI: 0.8-5.5) increase in respiratory visits was demonstrated.
On the other hand, there was some polemical evidence for no statistically significant effect of air pollution on respiratory emergency department visits in moderately hot and hot days, for example, in Beijing [99]. Likewise, for ambulance calls with respiratory distress in Taiwan, exposure to the extreme level of PM 2.5 was more likely to occur at low temperatures [101].

Heat, Air Pollution and Mortality
The mean daily concentrations of some pollutants can be very high in East Asia; for instance, PM 10 concentration in eight Chinese cities was found to range from 65 µg/m 3 to 124 µg/m 3 , which is significantly higher than in Western countries [95]. Combined impacts of hot weather and ambient pollution on respiratory mortality are presented in many papers around the world, with more recent research being undertaken in East Asian countries, especially in China, than in Europe or other countries.
Hot weather was found to substantially strengthen the impact of air pollution on respiratory mortality, with PM 10 and O 3 being the main pollutants, such as that shown by research in Japan [88]. Examples can be shown for heat effect during the excess PM 10 exposure in Beijing, Tianjin, Guangzhou, Hefei, Wuhan, and other cities in China [92,93,95,97,98,100]. The higher mortality risk was shown for places in China with 0-1 days lag of PM 10 [95]. High temperatures jeopardize the effect of PM 10 pollution in South Korea [90]; in Christchurch, New Zealand [115]; in Sao-Paulo, Brazil, with rate ratio (RR) = 1.60% (95% CI: 0.74-2.46) [116]; in Italian cities, with RR = 2.54% (95% CI: 1.31-3.78) for 35+ age cohort [109]. High temperatures also impact exposure to O 3 pollution in Soul, South Korea [96], Germany [75], England, and Wales [107]. Besides, some studies discussed additional significant effects for SO 2 and NO 2 , e.g., research in Hefei, China [98]. The combined effect of polluted air and weather was shown to be high during weather with tropical air masses, both dry and moist, for Canadian cities in summer [114]. The results highlighted that the synergistic effect varies across regions and countries depending on local climate peculiarities, activity patterns, and physical adjustments [1].
The studies demonstrated strong mortality growth on days with increases in concentration of air pollutants, with the effect being higher in older individuals ≥65 years [92], ≥75 years [53], and ≥85 years [75,96] old, in men [90] and women [97,98], in those who are illiterate [97,98], and in subjects in southern cities compared with northern ones [95]. It can be assumed the differences may arise due to personal behavioral and physiological dissimilarities to high temperature and pollution exposure [97].
Predictably, temperature extremes were found to create the greatest mortality burden, with studies in Wuhan, China, a highly polluted "oven" city [97,98], or cities in South Korea [96] as examples. Additionally, examples are presented for extremely high thermal exposure and pollution that resulted in excess mortality in subjects with chronic pulmonary disease in Italian cities (OR = 2.48 (95% CI: 1.50-4.09)) [74] and COPD for cities of Jiangsu province, China (OR = 4.6% (95% CI: 2.83-5.85%)) [73]. However, in contrast, no significant interaction between polluted air and extremely high temperatures was shown for Shanghai [86] and France [106], and a higher effect for low temperature exposure was demonstrated for locales in Jiangsu province, China [73].

Heat Wave Episodes
As frequency, intensity, and duration of heat waves are expected to increase with climate change, HW episodes are of special interest for public health [37,121]. While most of the studies cited above addressed joint effects of pollutants with high temperature, only four focused on heat wave episodes [5,70,108,110].
Heat waves in urban places of the USA were explored in detail by Anderson and Bell [110]. The joint effect of air pollution caused by elevated levels of PM 10 and O 3 during the HW showed the higher estimates of exposure for respiratory disease compared with the total mortality [110].
European studies by Analitis et al. [5,79] focused on specific heat wave episodes, analyzing total and course-specific mortality, including respiratory disease, where they provided evidence of a significant interaction between high temperature and pollutants, mainly ozone, especially for the elderly [79].
A synergistic effect of heat and air pollution on mortality was shown for extremely long and intensive heat waves in European Russia accompanied with a disastrous wildfire in summer 2010, with Moscow as an example [108]. Main pollutants estimated were PM 10 and O 3 . The major HW lasted for 44 days, with 24 h average temperatures ranging from 24 • C to 31 • C and PM 10 levels exceeding 300 µg/m 3 on several days [108]. An increase of 339 deaths in Moscow from respiratory diseases was found compared to the same period in summer 2009, with RR = 2.05 (95% CI: 1.80-2.39) 9 [108].
Although there was evidence of a synergetic effect of air pollution and high temperatures during HW episodes, a slight decrease in thermal effects was found when models included O 3 and PM 10 [5,110], which should be analyzed in the future.
All results from 40 papers mentioned above are summarized in Table 1, where the papers are arranged alphabetically by the first author in the included studies.   (1) and (2) 10 µg/m 3 increase in PM 10

Discussion
Episodes of hot weather and poor air quality pose significant consequences for public health. Numerous researchers revealed that both ambient temperature and air pollution are associated with human health. Although many studies on the association of temperature and mortality/morbidity adjusted for concentration of air pollutants, few of them considered the potential synergistic effects of temperature and air contaminants. In this review, we looked for relevant studies and summarized the findings to get a general understanding of this problem. We focused on the main air pollutants: sulphur dioxide, oxides of nitrogen, including nitrogen dioxide; carbon monoxide; particulate matter (PM) with PM 10 and PM 2.5 being the main pollutants; and ozone. Most studies suggested that there were interactive effects between temperature and air pollution on human health, and the results varied among different geographic regions. The health consequences varied from premature death to decreases in lung function, new onset of diseases, exacerbation of chronic respiratory diseases, and lung cancer.
Much is known about the relation between high ambient temperature, air pollution, all-course and cardiovascular mortality [122], independent associations of hot weather, polluted air environment, and respiratory health [1,67,123], but the combined effect on disease-specific events, such as respiratory, is less clear. The current review shows the role of pollutants on respiratory health impacts may vary with hot weather conditions. The modifying effect of the high temperature on the air pollution-respiratory health indicators relationship was scarcely reported in recent years, although it is well known that high temperatures have an important action on the transport and the dispersion of pollutants in the air and vice versa [78], causing the plausible effect on respiration. Increased mortality and morbidity are associated with heat wave episodes; an interesting aspect is the role of air pollution in this relationship [1,67].
In the reviewed studies on effects of air pollution and temperature on human health, temperature was generally corrected to efficiently analyze the health impacts of ambient particles; otherwise, air pollutants were also adjusted when investigating the influence of temperature on mortality. Each identified a significantly enhanced mortality and morbidity effect for increasing values of both air contaminants and high temperature. However, a relatively small number of papers were found to confirm our hypothesis, which considerably limits the scientific significance of the current paper and is a great potential for further research. The large differences in the results obtained do not allow us to collect them in a meta-analysis and provide reliable, mathematically confirmed evidence with statistical weights about the jeopardized effect of exposure to both high temperature and air pollution on respiratory outcomes. Another problem identified is that the interaction between the temperature and the pollution continues to be vague, as some studies showed non-statistically significant coefficients for the interaction between air pollution, high temperature, and respiratory outcomes [57,86,99,106].
Many additional factors could shed more light on the confounding effect of interactions in the relationship of hot weather-air pollution-respiratory health and ways to mitigate these implications, which are discussed below.

Wildfires
A very significant consideration is the occurrence of wildfires caused by hot weather, which are associated with dangerous levels of pollutants and therefore affect respiratory health [9,63,108,124,125]. A vivid manifestation is the several large wildfires of unprecedented scale and duration that occurred recently, including wildfires in European Russia in 2010 [108,126], Australia in 2019 to 2020, the Amazon rainforest in Brazil in 2019 and 2020, the western United States in 2018 and 2020, and British Columbia, Canada in 2017 and 2018, with the huge impact on the population in terms of adverse effects on respiratory health [127].
The mechanisms that explain the respiratory effects of wildfires are mainly related to the air pollution associated with these events. Wildfire smoke is a complex mixture of thousands of compounds, primarily PM 2.5 , carbon dioxide, hydrocarbons, and nitrogen oxides, which contribute to increase air pollution locally and regionally. In multiple studies, air pollution from wildfire smoke was associated with more asthma exacerbations, ED visits, and hospitalizations for bronchitis, dyspnea, and COPD symptoms. Wood smoke particles can activate systemic and pulmonary inflammation, even in healthy human subjects [1,125,[128][129][130][131][132][133][134][135][136].
Extreme events such as wildfires and prolonged heat waves and drought are causing increases in pollutants such as particulate matter and ground level ozone, often to dangerous levels. Due to high ambient temperature during wildfire, there is also a potential for interaction as evidenced by the combination of HW and wildfire conditions [1,108,126,137]. This mutual influence can be explained at the point of emissions by changes in smoke components caused by temperature, sunlight, water vapor, and interaction with other pollutants [138].
Next, a few more important points should be discussed. An in vivo experiment showed that the responses to wood smoke consist of higher inflammatory and cytotoxic reactions than those caused by urban particulate matter [139], suggesting that wildfire contamination is more dangerous than urban pollution. Another problem is that, although forest fires can only occur in certain regions, their smoke plumes can spread over long distances [130]. More research is needed to assess long-term health effects from wildfires [129]. The understanding of such factors is vital to ensuring that health care services are prepared for these events.

Urban Heat Island Effect
The problem of outdoor pollution is not new, but rapid urbanization is making the problem of air pollution more visible and its load on human health more noticeable [12,140,141]. Extreme heat events at urban centers in combination with air pollution pose a serious risk to human health. Studies showed the coupled interaction of urban heat island and air pollution increases hospital respiratory admissions and hospitalizations in the warm center of urban areas [141][142][143]. The prognostic doubling of urban population within the next two decades and the disproportionate growth of megacities make it critical to explore the synergism between urban heat and pollution [143].
Urban populations are likely to be particularly at risk, but the role of urban characteristics in changing the direct health effects of temperature is still debated due to a variety of modulating causes. For example, the impact of heat on mortality is higher in cities characterized by high population density, higher levels air pollution, fewer green spaces, and lower availability of health services [144].

Possible Biological Mechanisms
Several different explanations are proposed for the synergistic effects between ambient pollution and high temperature on human health [1,7,93,145]. Since the respiratory surface is a primary route by which air pollutants enter the body, prolonged heat exposure may activate three key mechanisms of thermoregulatory responses, which include: secretion of sweat glands, vasodilatation, and increase in ventilation rate and lung volumes, which in turn can directly or indirectly affect toxic substances entering the body and raise the total intake of airborne pollutants [1,7,[145][146][147]. Next, high ambient temperature increases skin permeability, providing an easier way for air pollutants to be absorbed by the skin surface [145,148].
Pathophysiological mechanisms are discussed in detail in [55]. First, a combination of heat load and gaseous polluted environment leads to an inflammation of the bronchial mucosa and lowers the bronchoconstriction threshold; the accompanying fluid loss additionally contributes to subsequent changes in perfusion and ventilation, causing acute and chronic injury to lung tissue by gaseous particles in polluted air, such as greenhouse gases, nitrogen dioxide, sulfur dioxide, and ozone [149]. Secondly, fine PM of different size "destroys the integrity of endothelial cells via the signal transduction pathways that depend on reactive oxygen derivates and p38-activated protein kinase and is involved in the pathogenesis of cardiopulmonary disorders", which is explained in detail in [47,50]. Moreover, the synergistic interaction of heat and concentrations of noxious/toxic substances in the air leads to exacerbations, especially of asthma and COPD [150,151]. Experiments on animals show the importance of hot air as a pathological substrate of bronchoconstriction and penetration of tissue-toxic elements [152,153]. Additionally, some evidence was found to demonstrate the increase in airway resistance during hot and humid days more rapidly than in cold air, triggering asthma symptoms, most likely by stimulating airway C-fiber nerves [130,154,155].
The delayed associations between exposure and outcome-or the "lagged" effect of air pollution, thermal exposure, or both-of different lengths (mostly 0-2 days) on respiratory mortality and morbidity were demonstrated in many studies [68,78,89,97,111,115]. It can be supposed that respiratory diseases are slower in their development and are therefore more lagged [29].
However, excess mortality may be followed by fewer deaths than expected during the next period of time, which is called a harvesting effect or mortality displacement [30,53,55,75,[156][157][158][159][160]. A harvesting effect is found to partly or even fully balance the observed excess health outcomes due to heat. One more consideration can be shown for a sharp decrease in deaths to hospital admissions, with some suggestion of displacement or harvesting for respiratory admissions [159].

Virus and Bacteria Infections and Epidemics
Evidence supports a clear effect of air pollution on respiratory infections interacting to adversely affect the respiratory system, contributing to the recent coronavirus disease 2019 (COVID-19) pandemic. Most research indicated that chronic exposure to air pollutants leads to more severe and lethal forms of COVID-19, delaying and complicating the recovery period after the disease [161,162]. Areas with frequently high levels of air pollutionexceeding safe levels of ozone or particulate matter-had higher numbers of COVID-19 related infected individuals and deaths [163].
The biochemical and the physiological mechanisms behind this effect include a number of functional changes involving endothelial dysfunction, endothelial activation, and injury [44]. These local changes in the lung promote pulmonary responses, affecting airway function and resistance to viruses and bacteria, increasing the risk of infection, for example, upper respiratory tract infections, bronchitis, and pneumonia [44]. Moreover, high concentrations of nitrogen dioxide and particulate air pollutant induce serious damages to the immune system of people, weakening it to cope with infectious diseases of viral agents [164]. Knowing the associations between polluted environment and human respiratory infections in different temperature regimes may decrease turbulence and spread of a new COVID-19 pandemic and any other in the future.

Indoor Pollution
Indoor pollution obtained from a variety of sources such as ventilation and building materials, use of biomass fuels for heating and cooking, active indoor smoking, pesticides, incense, and biological pollutants such as dust, dandruff, furniture, and mold might be combined with high indoor temperatures [9,21,28,165,166]. In addition to ambient contaminants, exposure to poor indoor air quality is linked to many acute and chronic respiratory health outcomes such as general respiratory complaints, exacerbation of asthma symptoms and COPD, diminished lung function, lung cancer, and mortality, with women and young children being disproportionately affected due to time spent indoors [21,24,28,36,45,167,168].

Vulnerable or Susceptible Population Groups
Pre-existing respiratory diseases are important vulnerabilities to both thermal effect and air contamination. Since exposure factors are specific to each climate hazard and can vary by populations and over time, more research is needed, particularly for younger age cohorts and children as well as for other parts of the population, such as socioeconomic groups with low income [46]. Vulnerable population subgroups were identified in regard to the effects of air pollution and/or heat, including: elderly; care homes' residents; young children; patients with cardio-respiratory disease asthma, renal diseases, and diabetes; people with obesity as well as those who takes certain drug therapy; and those who live in densely populated urban neighborhoods [1,5,40,46,75,95,107,[169][170][171]. For example, some evidence was shown in England and Wales that ozone effects were worse on hot days, particularly for those aged <75 [107]. In addition, there were clear differences by sex: specifically, females showed higher mortality risk, and males showed higher hospitalization risk [172].
The elderly age cohort shows an increased sensitivity to exposure of both atmospheric pollution and thermal impact, which is probably explained by an excessive manifestation of concomitant diseases (diabetes, various acute heart disease such as congestive heart failure or myocardial infarction, etc.), by reduced respiratory and antioxidant capabilities, and by rise of inflammatory phenomena, even in healthy people [2,144,173]. The interacting effect between air contaminants and extremely high temperature is biologically plausible for the elderly, whose ability to thermo-regulate body temperatures is reduced, and sweating thresholds are generally elevated in comparison with younger people [95]. Inflammatory and immunological reactions in children are significantly contrasted compared to other age groups, which may possibly determine a higher degree of influence on children [120,174].

Confounder Effect of Multiple Environmental Stressors
Exposure to poor air quality and thermal load both already affect human health independently, but their combined occurrence poses an intensified threat to human life, especially as synergistic effects lead to a risk beyond the sum of their individual effects [4]. The idea of multiple environmental stressors supports the assumption that it is a scientific apparatus for organizing and evaluating relevant scientific data to identify and evaluate the cumulative effects of various environmental factors that negatively affect human health [175,176]. For instance, the Air Pollution Index assesses the combined effects of main air pollutants to determine whether their impacts on respiratory morbidity and mortality are affected by temperature, age, gender, pre-existing disease, as well as other confounders and effect modifiers, such as socioeconomic conditions, urbanicity, and central air conditioning [99]. Multiple air pollutants may be most responsible for increased impact on cardiopulmonary health, which would need to be taken into account in the future research [41]. Heterogeneity of the results of the joint effect of high temperature and air contamination on respiratory health may reflect the characteristics of the study sites, such as weather patterns, air pollution levels and components of pollution mixture, use of air-conditioning or heating systems, sensitivity of local residents to air pollution (e.g., gender, age, and smoking rate), and possibly other socioeconomic characteristics [79]. An important addition was proposed by Abed Al Ahad with coauthors [177] that the analysis of interaction between air pollution and weather stressors beyond specific limits and their effect on respiratory health should be supplemented by study of the major sociodemographics modifiers, such as ethnicity, occupational/educational/marital status, and others [177].
Other challenges may be specific parameters of the study area. For example, the impact on the population of outdoor temperature and air pollution may vary depending on social-economic status, use of air conditioners, local habits associated with opening windows, traditions in the house design, etc. Results from studies on the interaction of temperature and air pollution suggest that this topic cannot be ignored when detecting the effects of temperature or air pollution on respiratory causes, since the real scale of the relations may be understated. Overall, results differ depending on the pollutant under consideration and the study area, assuming that the original regularities are led by local conditions.
Many studies showed that, to explore the respiratory system status under environmental exposure, not only temperature is used but also air humidity [178,179] as well as special indices such as apparent temperature, which determines the combined effect of weather parameters together with air pollutants [6,114,117,118]. It should be noted that, although absolute humidity correlates with air temperature, it can itself significantly change the impact of air pollutants on health outcomes [180].
Some results for mortality and hospital respiratory admissions showed the synergistic effects of long-term exposures to air pollution and temperature were associated with larger effects compared to short-term exposures; one possible explanation is the suggested evidence provided in studies on the effects of heat waves and air pollution on mortality that respiratory diseases are slower in their development and are therefore more lagged than, for example, cardiovascular diseases, which can initiate an acute body response [29,59,181].
Although there was evidence of a synergetic effect of air pollution and high temperatures during HW episodes, a slight decrease in thermal effects was found when models included O 3 and PM 10 [5,110], which should be analyzed in future research.

Climate Change
Almost all climate events will worsen under climate change, as will the related disease burden. Climate and climate change are modifying air pollution effects on respiratory health in several ways: climate variations are predicted to increase frequency and intensity of heatwaves and wildfires, cause longer fire and pollen seasons, influence start, duration, and intensity of the pollen season, increase aero-allergenic plant pollen production, and raise long-term transport of air pollutants and allergens [1,9,84,121,182,183].
To better assess the potential impact of current climate change scenarios on human health, it is mandatory to comprehend not only the separate effects of temperature and other weather characteristics (adjusted for confounders, including air contamination) but also to understand any combined effect between meteorology and air pollution. It is proper to assume that the synergistic interactions between high ambient temperature and air pollution will become more important under extreme conditions that could occur in the future due to larger climate volatility [5,37,184]. Global climate models predict not only warmer temperatures on average but more frequent extreme weather events [6,185], which increase the threat of weather-related health outcomes [186].
Mitigation and age-specific adaptation strategies might greatly reduce the temperaturerelated mortality burden in the future climate change realm. If people cannot adapt to future climate change, heatwave-related excess mortality is expected to increase the most in tropical and subtropical countries/regions, while European countries and the United States will have smaller increases [37]. At the same time, considering future impacts on respiratory diseases, progressive population aging, growing spread of chronic diseases, and socioeconomic transformations that are currently taking place in a number of countries, especially in Europe and Northern America, will probably raise the portion of the population at risk [186,187]. This is crucial for individuals with impaired adaptation to weather variability, such as the elderly.
Another consideration is the increase in both urbanized and wildfire areas due to climate change. The risk of wildfire frequency is increasing in most areas of the world as climate change worsens [119], with projections of the fires to raise excess mortality and morbidity as well as mental health effects from burns and wildfire smoke [124,127,129]. Therefore, there is an urgent need to further understand the health effects and the public awareness of wildfires [108,183]. Due to climate change and other factors, such as the relatively rapid grow of urban population up to 5.2 billion in 2050 [188], the nature of pollution is changing in several urbanized areas worldwide, which has a significant impact on respiratory health, both separately and synergistically with weather state [1,188].
Another key research need for future studies is to compare the health burdens of future air quality under a changing climate with alterations in other risk factors. Warmer temperatures from climate change and increased amounts of carbon dioxide can cause increased growth of aero-allergenic plant pollen production, which leads to extension of pollen seasons with warmer springs and delays in first fall frost, therefore leading to increased production of pollen [9,182,189]. Climate change may impact the incidence of bacterial, viral, fungal, and tick-borne respiratory infections in terms of incidence, total duration, and severity of these infectious diseases, increasing their overall incidence and geographical spread [9,17]. The only way to solve this problem is to inform the public using the multisectoral approach of the scientific community. National and international organizations must deal with the emergence of this threat and offer sustainable, viable decisions.

Prevention Policy
At last, decades-long periods of both high air temperature and air pollution, including wildfires, are becoming an important issue of global concern, exacerbating health outcomes and corresponding health-care expenditures. A significant impact of air pollution, including episodes of wildfires, on health-care costs related to respiratory diseases was identified [42,108,159,183,190,191]. Addressing these challenges requires the interdisciplinary cooperation of epidemiologists, climate scientists, respiratory and allergy physicians, policy makers, and public health professionals to jointly guide the world through the climate crisis, making the environment sustainable for future generations. Furthermore, the governments should strengthen environmental management, pay attention to the heterogeneity of the healthcare expenditure burden affected by both high temperatures and environmental pollution, ameliorate the medical insurance system, and improve the health of residents [65,66,137,159,192,193]. Moreover, policy makers should enhance the emission control of air pollution in high temperature days, especially to target pollutants produced by motor vehicles [78,91], and strengthen health education propaganda [89].
Taking into account the interrelationships between current and future climates and pollution challenges, adequate mitigation policy and public health actions are needed to face the two hazardous exposures. Considering the predicted increase in heat waves and stagnation events, it is time to enclose air pollution within public health heat prevention plans.
The prospect of global warming requires a more accurate assessment of how a hotter environment can affect the human response to toxic chemicals [192,193]. In climate change scenarios, the increase in extreme weather events and some air contaminants, particularly ozone, is likely to further exacerbate chronic respiratory disorders. Public health measures should aim to prevent this additional burden of illness in summer periods and especially during HW [30,65,193,194]. Identifying population groups that are more susceptible to weather variability is of paramount importance for the development of public health policies that protect them [5,195,196]. Recognizing the sources and the concentrations of air pollutants helps to establish the new regulations for control measures. This subsequently leads to the diminishing mortality of infants and children under the age of five [25], the elderly [196,197], and the low-income population [194,195]. Short-term public health activities to decrease heat-related morbidity should target sensitive population groups to assure access to air conditioning, evaporative coolers, fans, adequate fluid intake, etc. [194,195,197]. On the other hand, on hot days, emissions of pollutants may be further increased by behavioral changes when inhabitants of cities may choose to use their possibly air-conditioned car more often [79].
Long-term prevention efforts should aim to improve the general health condition of people at risk, implementing special prevention plans for cities [125,137,198,199] and conceptualizing special green and blue infrastructure in the built environment [199][200][201], with the paramount need to establish joint heat and air pollution warning systems [59,66,186,193,202]. Sustainable urban planning and smart city design developing integrated sustainability performance for innovative energy systems in smart cities could significantly reduce both UHIs and air pollution [203,204], enhance human thermal comfort, and decrease heat-and pollution-related mortality, thus saving lives [200].
It is also important to better comprehend the influence of climate characteristics on the direction and the spatio-temporal spread of wild fires [205]. The use of remote sensors would help identify the components of pollution during fires and assess the temperature rise associated with fires [125,131,136].

Conclusions
Air-pollution and hot weather exposure beyond certain thresholds have serious effects on respiratory health, with the elderly and young children being the most vulnerable groups. However, there is a lack of information on broader perspectives, including the role of some exposure modifiers and the interaction between air pollution and weather characteristics. The purpose of this paper is to provide a holistic overview and descriptive synopsis of the literature on the association of air pollution and weather with mortality and hospitalization and to identify gaps in scientific knowledge that need further research. The final review included 40 articles, from which 24 involved mortality, 15 incorporated respiratory emergency transportations and hospital admissions, and 1 reviewed lung cancer incidence. Air-pollution was shown to act consistently as a risk factor for respiratory mortality and morbidity. Hot temperature was a risk factor for a wide range of respiratory disease. The role of effect modification in the included studies was investigated in terms of gender and age. These findings are important for public health, as the high spread of chronic diseases such as COPD is expected to increase, especially in developed countries as a result of an aging population. Effect alteration of important socio-demographics and the interaction between air pollution and weather is often missed in the literature. Climate and climate change are shifting, combining influences of hot weather and air pollution on respiratory health in several ways. Climate variations are predicted to increase frequency and intensity of heat waves and wildfires, raise long-range transport of air pollutants and allergens, and influence start, duration, and intensity of the pollen season. Moreover, with regard to climate changes, it is generally accepted that global warming increases the health effects of outdoor air pollution, resulting in more heat waves, during which levels of air pollutants raise and high temperatures and air contamination act in synergy, causing more serious health impacts than those estimated from heat or pollution alone.