TABLE I.

Summary of studies on extreme heat exposures and airway outcomes

Study	Study design	Study size	Main outcome/finding	Strengths	Limitations
Rice (2019)22	Cohort study	5896 participants	• Each 5°C higher previous-week temperature was associated with 20 mL lower FEV1. • This association was present in winter or spring only.	• Validated spatiotemporal temperature model using satellite surface temperature data was used to more precisely predict temperature. • Individual, neighborhood, and seasonal confounders were considered in measurements.	• Includes only White, middle-age, and older people, so not representative. • Only 2 repeated measures.
Han (2022)24	Meta-analysis	111 studies	• Extreme heat increases tidal volume, respiratory rate, and SIR. • Extreme heat is an independent trigger of asthma exacerbations. • TRP receptors are activated by breathing hot air.	• Systematically summarized studies with epidemiologic evidence and clinical implications.	• Lack of standardization across studies for meteorologic definitions, measurements, and exposure assessment.
Deng (2020)26	Animal model	60 mice	• High temperature caused bronchial epithelium thickness, subepithelial fibrosis and inflammatory cell infiltration around airways; triggered IL-4, IL-1β, IL-6, TNF-α releasing and shifted TH1/Th2 balance to TH2. • High temperatures aggravated airway wall remodeling. • TRPs are important in high temperature-induced allergic asthma. • TRPV1 expression was higher at 40°C.	• Can be a predictor for human studies due to success of mouse model.	• Obscurity of way high temperature activates TRPs and changes at different humidity.
Nikolaizik (2020)27	Experimental human study	100 healthy adults	• Nasal ciliary beat frequency gradually increased at 25°C, 32°C, and 37°C. • Optimum temperature to measure ciliary beat frequency was 32°C.	• Important to indicate physiologic temperature for nasal ciliary activity in humans.	• Effects of cofactors such as pH were not measured. • For ethical reasons, healthy children were not included in study.
Clary-Meinesz (1992)29	Ex vivo and in vitro	30 adults	• Cilia motility of nasal and bronchial mucosa reached normal level at 20–45°C and decreased above 45°C.	• Effect of a wide range of temperature on human cilia of both upper and lower respiratory tract was evaluated.	• Small sample size.
Harford (2021)31	In vitro	Based on primary human bronchial epithelial cells derived from anonymous patient donors	• TRPV1 channels were overexpressed in airways of patients with asthma and activated by chemical mediators during chronic airway inflammation.	• First study to show increased basal and RSV-induced TRPV1 expression in lower airway epithelium of children with asthma.	• Performed in vitro, so cannot fully understand process in vivo.
Lu (2023)32	In vivo/animal model	90 Balb/c mice	TRPV1 upregulated after either separate or combined exposure to high temperature (35°C) and NO2. • Both separate and combined exposure to high temperature and NO2 aggravated AHR. • Total white blood cells, total IgE, IL-4, IL-4, IFN-γ increased after both separate and combined exposure to high temperature and NO2.	• Supports epidemiologic evidence by revealing mechanism of heat-NO2-induced toxicity.	• Uncertainty of human health risk analysis through animal experimental studies. • Although effect of extreme heat alone was shown in study, its main purpose was to examine effect of high temperature-NO2 interaction on allergic asthma.
Bonvini (2020)34	In vivo and in vitro/guinea pigs, human airway samples from donor tissue and cell culture	NA	• TRPV4 agonist caused contraction in vivo in guinea pig, and in human and guinea pig tracheal tissue. • TRPV4 activation increased intracellular Ca2+ and released ATP from ASM cells, triggering mast cell degranulation resulting in bronchoconstriction.	• Revealed novel mast cell-ASM interaction and TRPV4 as driver of IgE-independent mast cell-dependent bronchospasm.	NA
Hayes (2012)35	Experimental human study	6 patients with asthma and 6 healthy volunteers	• Exposure to humidified air at high temperature (49°C) significantly increased specific airway resistance and triggered cough in patients with asthma. • Ipratropium pretreatment had a blocking effect on humidified hot air-induced bronchoconstriction in patients with asthma. • Humidified hot air-induced bronchoconstriction was mediated by cholinergic reflex pathway.	• This rare human study shows that inhalation of warm, moist air causes cough and bronchoconstriction in patients with asthma and that airway constriction is mediated by cholinergic reflex.	NA
Yombo (2019)37	Mouse model	NA	• Lack of HSP-70 caused significant decrease in airway inflammation, goblet cell hyperplasia, IL-4, IL-5, and IL-13 in mouse model of SEA-induced airway inflammation.	• Identified pathogenic role of HSP-70 in allergic airway inflammation. • Indicated potential utility of targeting HSP-70 to reduce allergen-induced TH2 cytokines, goblet cell hyperplasia, and airway inflammation.	NA
Hulina-Tomašković (2019)38	Human bronchial epithelial cell culture	NA	• Recombinant human HSP-70 induced IL-6 and IL-8 secretion depending on concentration and time. • Rh HSP-70 suppressed caspase-3/7 activities.	• Suggested proinflammatory effects of extracellular HSP-70 in chronic inflammation of human bronchial epithelium.	• Nature of study.
Nava (2020)39	Meta-analysis	12 studies including 118 human participants	• Heat acclimation increases HSP-70 protein and mRNA expression. • HSP-70 plays an important part in ability of cells become thermotolerant.	• Notable in terms of showing effect of heat acclimation on HSP-70 induction in humans and indicating lack of work in field as well.	• Small number of studies. • High levels of statistical heterogeneity. • Failure to take into account systemic adaptation to heat exposure.
Ye (2019)41	Mouse model	NA	• Secreted HSP-90a participated in epithelial barrier dysfunction of asthmatic mice. • Secreted HSP-90a promoted release of TH2 cytokines in asthmatic mice. • Neutralization of HSP-90α inhibited phosphorylation of AKT and ameliorated epithelial barrier dysfunction.	• Well designed. • Can be a predictive model for human asthma and targeted therapy.	• Need to be supported by human studies.
Carey (2022)42	In vitro /cell culture	NA	• HSP-90 inhibition reduced T2R-stimulated NO production and ciliary beating.	• Important in demonstrating that HSP-90 plays important role in airway innate immunity.	• It is unclear how HSP-90 contributed to immune function performed by airway epithelial cells.
Bouchama (2017)43	Experimental human study	15 volunteers	• HSPA1A gene (encodes heat shock proteins HSP-70–1), upregulated immediately after heat stress. • Unfolded protein response was most significant pathway in early response to heat stress. • HSP90AB1 and HSPB11 genes (encode HSP-90 alpha family) were downregulated. • HSPB6 and HSPB8 were upregulated. • NF-κB pathways inhibited immediately after heat stress and 1 hour after heat stress.	• First study to demonstrate human gene expression response to extreme heat.	• It is unclear whether gene changes observed in this study are generalizable to cell types other than peripheral blood mononuclear cells.

AHR, Airway hyperresponsiveness; ASM, airway smooth muscle; ATP, adenosine triphosphate; NA, not applicable; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; RSV, respiratory syncytial virus; SEA, soluble egg antigen; SIR, systemic inflammatory response.