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We review current knowledge on the trends and drivers of global wildfire activity, advances in the measurement of wildfire smoke exposure, and evidence on the health effects of this exposure. We discuss methodological issues in estimating the causal effects of wildfire smoke exposures on health. We conduct a systematic review and meta-analysis of the effects of wildfire smoke exposure on all-cause mortality and respiratory and cardiovascular morbidity. We conclude by highlighting high priority areas for future research, including leveraging recently-developed spatially and temporally resolved wildfire specific ambient air pollution data to improve estimates of the health effects of wildfire smoke exposure.

Background. Given the increasing prevalence of wildfires worldwide, understanding the effects of wildfire air pollutants on human health—particularly in specific immunologic pathways—is crucial. Exposure to air pollutants is associated with cardiorespiratory disease; however, immune and epithelial barrier alterations require further investigation. Objective. We sought to determine the impact of wildfire smoke exposure on the immune system and epithelial barriers by using proteomics and immune cell phenotyping. Methods. A San Francisco Bay area cohort (n = 15; age 30 ± 10 years) provided blood samples before (October 2019 to March 2020; air quality index = 37) and during (August 2020; air quality index = 80) a major wildfire. Exposure samples were collected 11 days (range, 10-12 days) after continuous exposure to wildfire smoke. We determined alterations in 506 proteins, including zonulin family peptide (ZFP); immune cell phenotypes by cytometry by time of flight (CyTOF); and their interrelationship using a correlation matrix. Results. Targeted proteomic analyses (n = 15) revealed a decrease of spondin-2 and an increase of granzymes A, B, and H, killer cell immunoglobulin-like receptor 3DL1, IL-16, nibrin, poly(ADP-ribose) polymerase 1, C1q TNF-related protein, fibroblast growth factor 19, and von Willebrand factor after 11 days’ average continuous exposure to smoke from a large wildfire (P < .05). We also observed a large correlation cluster between immune regulation pathways (IL-16, granzymes A, B, and H, and killer cell immunoglobulin-like receptor 3DL1), DNA repair [poly(ADP-ribose) 1, nibrin], and natural killer cells. We did not observe changes in ZFP levels suggesting a change in epithelial barriers. However, ZFP was associated with immune cell phenotypes (naive CD4+, TH2 cells). Conclusion. We observed functional changes in critical immune cells and their proteins during wildfire smoke exposure. Future studies in larger cohorts or in firefighters exposed to wildfire smoke should further assess immune changes and intervention targets. ispartof: The Journal of Allergy and Clinical Immunology: Global vol:2 issue:2 status: published

The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma are not well understood. We investigated whether the ambient levels of fine PM with aerodynamic diameter ≤ 2.5 microns (PM ) are associated with alterations in circulating monocytes in children with or without asthma. Increased exposure to ambient PM was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or LPS. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

BackgroundAmbient air pollutant (AAP) exposure is associated with adverse pregnancy outcomes, such as preeclampsia, preterm labor, and low birth weight. Previous studies have shown methylation of immune genes associate with exposure to air pollutants in pregnant women, but the cell-mediated response in the context of typical pregnancy cell alterations has not been investigated. Pregnancy causes attenuation in cell-mediated immunity with alterations in the Th1/Th2/Th17/Treg environment, contributing to maternal susceptibility. We recruited women (n = 186) who were 20 weeks pregnant from Fresno, CA, an area with chronically elevated AAP levels. Associations of average pollution concentration estimates for 1 week, 1 month, 3 months, and 6 months prior to blood draw were associated with Th cell subset (Th1, Th2, Th17, and Treg) percentages and methylation of CpG sites (IL4,IL10, IFNγ,andFoxP3). Linear regression models were adjusted for weight, age, season, race, and asthma, using aQvalue as the false-discovery-rate-adjustedp-value across all genes.ResultsShort-term and mid-term AAP exposures to fine particulate matter (PM2.5), nitrogen dioxide (NO2) carbon monoxide (CO), and polycyclic aromatic hydrocarbons (PAH456) were associated with percentages of immune cells. A decrease in Th1 cell percentage was negatively associated with PM2.5(1 mo/3 mo:Q 2(1 mo/3 mo/6 mo:Q 456(1 week/1 mo/3 mo:Q 2.5(1 week/1 mo/3 mo/6 mo:Q 2(1 week/1 mo/3 mo/6 mo:Q 2(3 mo/6 mo:Q Q 2.5(3 mo/6 mo:Q 456(1 mo/3 mo/6 mo:Q IL10gene was positively associated with CO (1 week/1 mo/3 mo:Q 2(1 mo/3 mo/6 mo:Q 456(1 week/1 mo/3 mo:Q 2.5(3 mo:Q = 0.06) whileIL4gene methylation was positively associated with concentrations of CO (1 week/1 mo/3 mo/6 mo:Q IFNγgene methylation was positively associated with CO (1 week/1 mo/3 mo:Q 456(1 week/1 mo/3 mo:Q ConclusionExposure to several AAPs was negatively associated with T-helper subsets involved in pro-inflammatory and anti-inflammatory responses during pregnancy. Methylation ofIL4, IL10, andIFNγ geneswith pollution exposure confirms previous research. These results offer insights into the detrimental effects of air pollution during pregnancy, the demand for more epigenetic studies, and mitigation strategies to decrease pollution exposure during pregnancy.

There is increasing understanding, globally, that climate change and increased pollution will have a profound and mostly harmful effect on human health. This review brings together international experts to describe both the direct (such as heat waves) and indirect (such as vector-borne disease incidence) health impacts of climate change. These impacts vary depending on vulnerability (i.e., existing diseases) and the international, economic, political, and environmental context. This unique review also expands on these issues to address a third category of potential longer-term impacts on global health: famine, population dislocation, and environmental justice and education. This scholarly resource explores these issues fully, linking them to global health in urban and rural settings in developed and developing countries. The review finishes with a practical discussion of action that health professionals around the world in our field can yet take.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal, and pulmonary diseases and is linked to COVID-19 pathology. The correlates of temporal changes in soluble ACE2 (sACE2) remain understudied. OBJECTIVES: We explored the associations of sACE2 with metabolic health and proteome dynamics during a weight loss diet intervention. METHODS: We analyzed 457 healthy individuals (mean ± SD age: 39.8 ± 6.6 y) with BMI 28-40 kg/m2 in the DIETFITS (Diet Intervention Examining the Factors Interacting with Treatment Success) study. Biochemical markers of metabolic health and 236 proteins were measured by Olink CVDII, CVDIII, and Inflammation I arrays at baseline and at 6 mo during the dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (ΔsACE2) using stepwise linear regression. We combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with ΔsACE2. RESULTS: sACE2 decreased on average at 6 mo during the diet intervention. Stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL cholesterol, and fat mass. Participants with decreasing HOMA-IR (OR: 1.97; 95% CI: 1.28, 3.03) and triglycerides (OR: 2.71; 95% CI: 1.72, 4.26) had significantly higher odds for a decrease in sACE2 during the diet intervention than those without (P ≤ 0.0073). Feature selection models linked ΔsACE2 to changes in α-1-microglobulin/bikunin precursor, E-selectin, hydroxyacid oxidase 1, kidney injury molecule 1, tyrosine-protein kinase Mer, placental growth factor, thrombomodulin, and TNF receptor superfamily member 10B. ΔsACE2 remained associated with these protein changes in multivariable-adjusted linear regression. CONCLUSIONS: Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass, and markers of angiotensin peptide metabolism, hepatic and vascular injury, renal function, chronic inflammation, and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic complications.This trial was registered at clinicaltrials.gov as NCT01826591. ispartof: AMERICAN JOURNAL OF CLINICAL NUTRITION vol:114 issue:5 pages:1655-1665 ispartof: location:United States status: published

Ambient air pollution exposure is associated with cardiovascular dysregulation and immune system alterations, yet no study has investigated both simultaneously in children. Understanding the multifaceted impacts may provide early clues for clinical intervention prior to actual disease presentation. We therefore determined the associations between exposure to multiple air pollutants and both immunological outcomes (methylation and protein expression of immune cell types associated with immune regulation) and cardiovascular outcomes (blood pressure) in a cohort of school-aged children (6–8 years; n = 221) living in a city with known elevated pollution levels. Exposure to fine particular matter (PM2.5), carbon monoxide (CO), and ozone (O3) was linked to altered methylation of most CpG sites for genes Foxp3, IL-4, IL-10 and IFN-g, all involved in immune regulation (e.g. higher PM2.5 exposure 1 month prior to the study visit was independently associated with methylation of the IL-4 CpG24 site (est = 0.16; P = 0.0095). Also, immune T helper cell types (Th1, Th2 and Th17) were associated with short-term exposure to PM2.5, O3 and CO (e.g. Th1 cells associated with PM2.5 at 30 days: est = − 0.34, P 456, NOx and/or NO2 (P ≤ 0.038 for all). Finally, diastolic BP (DBP) was inversely associated with long-term exposures to both CO and PAH456, and both systolic and pulse pressure were associated with short-term NO2 and chronic NOx exposure. Our findings demonstrate links between air pollution exposure and methylation of immunoregulatory genes, immune cell profiles and blood pressure, suggesting that even at a young age, the immune and cardiovascular systems are negatively impacted by exposure to air pollution.

Abstract Background Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents. Methods We randomly recruited 100 adolescents (mean age, 16 years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant’s home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders. Results Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P ≤ 0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P ≤ 0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation. Conclusions For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

Background Metabolic syndrome increases the risk of cardiovascular disease in adults. Antecedents likely begin in childhood and whether childhood exposure to air pollution plays a contributory role is not well understood. Objectives To assess whether children's exposure to air pollution is associated with markers of risk for metabolic syndrome and oxidative stress, a hypothesized mediator of air pollution-related health effects. Methods We studied 299 children (ages 6–8) living in the Fresno, CA area. At a study center visit, questionnaire and biomarker data were collected. Outcomes included hemoglobin A1c (HbA1c), urinary 8-isoprostane, systolic blood pressure (SBP), and BMI. Individual-level exposure estimates for a set of four pollutants that are constituents of traffic-related air pollution (TRAP) – the sum of 4-, 5-, and 6-ring polycyclic aromatic hydrocarbon compounds (PAH456), NO2, elemental carbon, and fine particulate matter (PM2.5) – were modeled at the primary residential location for 1-day lag, and 1-week, 1-month, 3-month, 6-month, and 1-year averages prior to each participant's visit date. Generalized additive models were used to estimate associations between each air pollutant exposure and outcome. Results The study population was 53% male, 80% Latinx, 11% Black and largely low-income (6% were White and 3% were Asian/Pacific Islander). HbA1c percentage was associated with longer-term increases in TRAP; for example a 4.42 ng/m3 increase in 6-month average PAH456 was associated with a 0.07% increase (95% CI: 0.01, 0.14) and a 3.62 μg/m3 increase in 6-month average PM2.5 was associated with a 0.06% increase (95% CI: 0.01, 0.10). The influence of air pollutants on blood pressure was strongest at 3 months; for example, a 6.2 ppb increase in 3-month average NO2 was associated with a 9.4 mmHg increase in SBP (95% CI: 2.8, 15.9). TRAP concentrations were not significantly associated with anthropometric or adipokine measures. Short-term TRAP exposure averages were significantly associated with creatinine-adjusted urinary 8-isoprostane. Discussion Our results suggest that both short- and longer-term estimated individual-level outdoor residential exposures to several traffic-related air pollutants, including ambient PAHs, are associated with biomarkers of risk for metabolic syndrome and oxidative stress in children.

With the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS‐CoV‐2‐induced Coronavirus disease‐19 (COVID‐19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS‐CoV‐2 infection and COVID‐19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multi‐organ disease. The similarities of the human immune response to SARS‐CoV‐2 and the SARS‐CoV and MERS‐CoV are underlined. We also summarize known and potential SARS‐CoV‐2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender and age in development of COVID‐19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID‐19 studies., The authors would like to thank the European Academy of Allergy and Clinical Immunology (EAACI) for the financial support to the sections, interest groups and working groups enabling the development of this paper. The research of SM is supported by a SNSF grant 310039_189334; JSR is funded by Ministerio de Economía y Competitividad (IJCI-2016-27619); KKI is supported by the FWO Post doc mandate 12W2219N; BW and PF were supported by funding from the Istituto Italiano di Tecnologia, Fondazione Telethon (project GGP19103), and Ricerca Finalizzata Giovani Ricercatori 2016 - Ministero Salute Italia (project GR-2016-02362413); GCC is supported by a postdoctoral contract cofounded by the competitive Program “Attracting Talent,” Community of Madrid, Spain; the research of SWCB was funded by DFG (398577603), “ADAPT” EIT Health is a body of the EU receiving support from H2020 and BMBF “ESCAPE” 01KI20169A; the research of UE is supported by the H2020 grant 768641 and by the BMF grant 19056.

Atopic diseases have increased in prevalence over the last few decades and the rapid increases suggest that the predominant driving forces behind these increases are environmental factors rather than genetic alterations. A number of environmental factors have been implicated in the increased prevalence of allergic diseases. Predominant among them are increased exposure to pollutants and decreased exposure to microbes and parasitic infections. The hygiene hypothesis suggests that increased hygiene and lack of exposure to microbes and parasitic infections at an early age prevents the necessary stimulus to train the developing immune system to develop tolerogenic responses. Lifestyle factors, such as increased time spent indoors, use of antibiotics, and consumption of processed foods and decreased exposure to farm animals and pets, limit exposure to environmental allergens, infectious parasitic worms, and microbes. The lack of exposure to these factors is thought to prevent proper education and training of the immune system. Other factors that are also associated with increased risk of allergic diseases are Caesarian birth, birth order, tobacco smoke exposure and psychosomatic factors. Here, we review current knowledge on the environmental factors that have been shown to affect the development of allergic diseases and the recent developments in the field.

The disease burden associated with air pollution continues to grow. The World Health Organization (WHO) estimates ≈7 million people worldwide die yearly from exposure to polluted air, half of which—3.3 million—are attributable to cardiovascular disease (CVD), greater than from major modifiable CVD risks including smoking, hypertension, hyperlipidemia, and diabetes mellitus. This serious and growing health threat is attributed to increasing urbanization of the world's populations with consequent exposure to polluted air. Especially vulnerable are the elderly, patients with pre‐existing CVD, and children. The cumulative lifetime burden in children is particularly of concern because their rapidly developing cardiopulmonary systems are more susceptible to damage and they spend more time outdoors and therefore inhale more pollutants. World Health Organization estimates that 93% of the world's children aged

Although genetic factors play a role in the etiology of atopic disease, the rapid increases in the prevalence of these diseases over the last few decades suggest that environmental, rather than genetic factors are the driving force behind the increasing prevalence. In modern societies, there is increased time spent indoors, use of antibiotics, and consumption of processed foods and decreased contact with farm animals and pets, which limit exposure to environmental allergens, infectious parasitic worms, and microbes. The lack of exposure to these factors is thought to prevent proper education and training of the immune system. Increased industrialization and urbanization have brought about increases in organic and inorganic pollutants. In addition, Caesarian birth, birth order, increased use of soaps and detergents, tobacco smoke exposure and psychosomatic factors are other factors that have been associated with increased rate of allergic diseases. Here, we review current knowledge on the environmental factors that have been shown to affect the development of allergic diseases and the recent developments in the field.

Objective To investigate the association between wildfire smoke exposure and DNA methylation of Foxp3-related genes using targeted bisulfite specific methylation sequencing assays recently developed by EpigenDx. Methods Subjects (n=16) from the San Francisco Bay area were recruited and gave blood samples during wildfire smoke exposure from the Paradise, CA wildfire 165 miles away. Subjects had their blood re-drawn 3 months later when there was no smoke exposure. An immunology/Foxp3 methylation panel was developed for 20 genes covering 150 CpG sites, targeting genes known to exhibit distinctive methylation profiles in regulatory T cells. Multiplex PCR amplified the regions of interest, using minimal sample DNA and generates inserts ready for NGS adaptor ligation. By initially amplifying specific regions of bisulfite treated DNA, library preparation is enriched with a population of molecules that have potential as indicators or affecters of gene regulation. Using our EpigenDx Ion Torrent library preparation kit, we can ligate these amplified regions to barcoded adaptors in one step. Results Paired t-tests revealed less methylation of the PDL2 gene during wildfire exposure at sites immediately upstream of the transcriptional start sites (CpG #-85: p=.002; χ̄ wildfire= 26.3 +14.0; χ̄ no wildfire= 30.8+15.9 and CpG #-86:p=.004; χ̄ wildfire = 22.2+13.4; χ̄ no wildfire= 25.7+15.6), but not in the 5′UTR region (CpG #-84; p=.53). No significant differences were found for the other genes. Conclusion Wildfire smoke is associated with decreased PDL2 gene methylation. PDL2, a programmed death ligand, downregulates T cell responses and has previously been associated with airway inflammation and cancer, but not pollution exposure.

Background DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10. Electronic supplementary material The online version of this article (10.1186/s13148-017-0433-4) contains supplementary material, which is available to authorized users.

This chapter investigates the connection between extreme weather and respiratory health in and around Fresno California, home to over 1 million people. In this chapter, we use Fresno as an important example of a location in the U.S. where its residents are at high risk for short and long term health consequences of extreme conditions of weather. However, there are many other examples of short term extreme weather conditions (forest fires in Yarnell, Arizona) and long term extreme weather conditions (Mediterranean Region) (WHO 2015). Fresno serves as an excellent example since there are combinations of weather, topography, and geography that can be helpful to our understanding of how air pollution affects health. Poor air quality shortens life expectancy, lowers quality of life and, we assert, affects the health and wellbeing of generations to come. Today we see the consequences of air pollution in incidence and severity of Chronic Obstructive Pulmonary Disease (COPD), asthma, cardio-vascular illness and even valley fever, the consequence of inhaling a fungal spore found in the local soils and carried with the wind and mineral dusts of neighboring deserts. Because extremes of temperature, aridity and wind are components of climate and determinants of air quality and respiratory health, strategic planning for public health should monitor and anticipate as best as possible climate variability and change. There is a need to continue to educate ourselves on how climate, extreme weather, and health are linked.