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"A" IS FOR ASTHMA: ASTHMA IN ELEMENTARY SCHOOL CHILDREN IN ALACHUA COUNTY, FL BY MOLLY BURGES A Thesis Submitted to the Division o f Natural Sciences New College of Florida in partial fulfillment of the requirements for the degree Bachelor of Arts Under the sponsorship of Dr. Sandra Gilchrist Sarasota, Florida April, 2009
ii Acknowledgements I would like to thank Dr. Gilchrist for sponsoring my thesis and continually improving it, my committee members, Dr. Lowman and Dr. Bauer, and Alachua thank my parents, without whom none of this would have been possible.
iii TABLE OF CONTENTS CHAPTER PAGE TITLE PAGE ................................ ................................ ................................ ..... i ACKNOWLEDGMENTS ................................ ................................ ................... ii TABLE OF CONTENTS ................................ ................................ ................... iii L IST OF FIGURES ................................ ................................ .......................... iv LIST OF TABLES ................................ ................................ ............................. v ABSTRACT ................................ ................................ ................................ ..... vi CHAPTERS CHAPTER 1 Introduction to Asthma ................................ ................... 1 1.1 Epidemiology of Asthma ................................ ............. 1 1.2 Immunology of Asthma ................................ ............. 13 CHAPTER 2 Epidemiological Study ................................ ................. 31 2.1 Intro duction ................................ ............................... 31 2.2 Methods ................................ ................................ .... 34 2.3 Results ................................ ................................ ...... 36 2.4 Discussion ................................ ................................ 41 CHAPTER 3 Asthma Programs ................................ ........................ 49 APPENDICIES Appendix A ................................ ................................ .......................... 54 Appendix B ................................ ................................ ......................... 55 REFERENCES ................................ ................................ ............................... 56
iv LIST OF FIGURES FIGURE PAGE Figure 1 ................................ ................................ ................................ ............ 3 Figure 2 ................................ ................................ ................................ .......... 15 Figure 3 ................................ ................................ ................................ .......... 16 Figure 4 ................................ ................................ ................................ .......... 17 Figure 5 ................................ ................................ ................................ .......... 20 Figure 6 ................................ ................................ ................................ .......... 23 Figure 7 ................................ ................................ ................................ .......... 25 Figure 8 ................................ ................................ ................................ .......... 31 Figure 9 ................................ ................................ ................................ .......... 33 Figure 10 ................................ ................................ ................................ ........ 39 Figure 11 ................................ ................................ ................................ ........ 40
v LIST OF TABLES Table PAGE Table 1 ................................ ................................ ................................ ............. 4 Table 2 ................................ ................................ ................................ ........... 36 Table 3 ................................ ................................ ................................ ........... 37 Table 4 ................................ ................................ ................................ ........... 39 Table 5 ................................ ................................ ................................ ........... 40
vi "A" IS FOR ASTHMA: ASTHMA IN ELEMENTARY SCHOOL CHILDREN IN ALACHUA COUNTY, FL Molly Burges New College of Florida, 2009 ABSTRACT This purpose of this study is to evaluate the rates of asthma in public ed lunch rate, 75), as well as distance and nitrogen oxide (NOx) contribution levels from a 225 megawatt (MW) coal fired power generating plant in Alachua County, FL. The asthma data for this study were obta ined from the parent reported health cards at the twenty four public elementary schools located in Alachua County. The data were statistically analyzed to determine if these factors are correlated to school asthma rates. The rate of students receiving fr ee and reduced price lunches at each school was used as an indicator of the socioeconomic status of the students. The rate of free/reduced lunches and the age of the school are good predictors of asthma rates at local public elementary schools according to the current study. These two factors are highly correlated. Alachua County has higher asthma rates than the state average and as the local municipal utility company is considering plans to add a new power generation plant, the
vii possibility of this chro nic disease becoming even more prevalent is a concern in the community. _______________________________ Sandra Gilchrist Division of Biology
1 Chapter 1: Introduction to Asthma 1.1 Epidemiology of Asthma According to the Department of Health and Human Services, asthma has reached epidemic proportions nationwide and more than doubled in prevalence from 1980 to 1996 (2000) The World Health Organization estimates that 300 million peop le currently suffer from asthma worldwide (2008). Asthma is a chronic respiratory inflammation disease characterized by restricted breathing attack including allergens, exercise, infections, and air pollution (American Lung Association 2004) Asthma disproportionately affects children, and attacks can vary from mild to life threatening In 2006, it was reported that 6.8 millio n children in the United States have asthma with 4 million having had an attack within the previous year (American Lung Association 2007) Asthma in school aged children interferes with athletic participation and is one of the leading causes of school absences Annually, 14 million school days are missed due to asthma (Centers for Disease Control) The annual health costs of this chronic disease were recently estimated to be $791 per child (Wang et al. 2005) a nd cost the nation a total of 19.7 billion dollars in 2007 (National Heart, Lung, and Blood Institute (NHLBI) 2007) Asthma also seems to have a greater impact on those who can least afford it I n 2007, 17% of children living in poverty within the U.S were likely to have ever received a diagnosis of asthma versus 12% of children from families living above the poverty level (NHLBI 2007) The most
2 asthma related deaths also occur in low and lower middle income countries although the prevalence is greater in the westernized world There are many factors that can contribute to the development of asthma Genetics play a key role in most cases though it is clear that this disease has a multifa ctorial foundation G enetics alone cannot fully explain the rising prevalence of asthma in urbanized countries Several theories have been put forth on environmental factors that may partially explain these cross country differences They include cigare tte smoking, the hygiene hypothesis, diet, antenatal exposures, physical activity/obesity, and pollution (Gold and Wright 2005) The importance of most of these factors to the development of asthma is not yet comp letely understood The exception is cigarette smoking which has consistently been a major risk factor Exposure to smoke in utero or in early childhood may both induce asthma (Gi lliland et al. 2001; Jaakkola and Gissler 2004) The hygiene hypothesis proposes that a lack of early childhood exposure to infectious agents and parasites can contribute to the development of allergic diseases It was developed after noticing that afflu ent urban areas had more cases of asthma than rural, farming areas This theory has expanded to include other factors common to urban lifestyles like smaller family size, less exposure to day care, fewer respiratory infections, lower endotoxin levels, red uced exposure to large domestic animal sources of allergens, a change in bacterial colonization of the infant's large bowel through diet or antibiotics, and fewer parasitic infections (Gold and Wright 2005) Longi tudinal studies conducted in the U.S.
3 have indicated a protective influence from having siblings and a later birth order as well as day care attendance (Ball et al. 2000) It has been theorized that early exposur e to infections is responsible for this trend Conversely, there is mounting evidence that at least some viral infections may actually trigger asthma in predisposed children (Openshaw et al. 2004) It may b e that other factors besides viral infections are influencing this trend however As more of the world becomes urbanized, asthma grows as an international concern although it is a problem for countries of all developmental stages Endotoxin, which occurs as a part of the outer membrane of some bacterial cells, may also play role in asthma induction It is a lipopolysaccharide, a primary component of gram negative bacteria Moderate endotoxin levels during infancy were associated with a reduced risk of a topy but an increased risk of wheeze at seven years of age (Celedn et al. 2007) There is evidence that e could be both dose related and age dependant For those already with asthma, it can in crease morbidity (Michel et al. 1996) Asthma is characterized by an imbalance in the ratio of helper T (Th) cell types There is an overabundance of Th2 cells with fewer Th1 cells Both bacterial and parasitic infe ctions can help to correct this imbalance and in small children may stop this imbalance from occurring (Dittrich et al. 2008; Reed and Milton 2001)
4 Figure 1: A simplified diagram d epicting T cell differentiation from a T cell precursor The differentiation of Th1 and Th2 cells depends on the cytokines interleukin 12 and interleukin 4, respectively In a regulatory loop, interferon (gamma) from Th1 cells inhibits Th2 cells and inte rleukin 4 from Th2 cells inhibits Th1 cells (Schwartz 2002). Air p ollution has long been known to exacerbate asthma symptoms Children are at greater risk from air pollution because of a lower lung capacity, higher respiratory rates, and higher exposure times due to time spent in sports and play (Committee on Environmental Health 2004) Our lungs continue to develop throughout adolescence, and 80% of our alveoli are formed postnatally This developing lung is highly susceptible to damage from environmental pollutants (Dietert et al. 2000) A ten year study conducted by the California Air Resources Board and the University of Southern California deter mined that result in a lower lifetime lung capacity (Peters 2004) Ambient air pollution levels were found to be associated with both n ew cases of asthma and the exacerbation of existing asthma
5 Air pollutant Concentration of exposure Effect Reference Comment SO x Ambient levels Infant deaths (Dales et al. 2004) (Bobak and Leon 1992) NO x Ambient levels Respiratory tract symptoms (Shima and Adachi 2000) Asthma exacerbations (Lipsett et al 1997) Reduced lung fun ction growth (Gauderman et al. 2000) <1 ppm Increased susceptibility to viral and bacterial infections ( U.S. EPA 2008) Lymphoma (especially Hodgkin's) incidence (Raaschou Nielsen et al. 2001b) Proximity to traffic as proxy for exposure during pregnancy >250 ppb Enhanced allergen response (Barck et al. 2005) (Strand et al. 1998) Particulate Matter (PM) Death (Infant and Adult) (Dockery et al. 1993; Ha et al 2003) Sudden infant death syndrome (Ritz, Wilhelm, Zhao 2006) Risk increased about 7% to 12% per 10 g/m 3 increase in particulate matter <10 m Lung inflammation (Ghio, Kim, Devlin 2000) Diesel exhaust particulate Leukemia and c entral nervous system tumors (Feychting, Svensson, Ahlbom 1998) Proximity to traffic as proxy for exposure Lymphoma (especially Hodgkin's) incidence (Raaschou Nie lsen et al. 2001a) Proximity to traffic as proxy for exposure during pregnancy Traffic density >20,000 vehicles/d Childhood leukemia (Pearson, Wachtel, Ebi 2000) Traffic density as proxy for exposure Home <5 00 m of a highway Decreased lung function in children (Gauderman et al. 2007) O 3 Ambient levels Respiratory or asthma hospitalizations (Friedman et al. 2001) School absences for respiratory tract illness (Gilliland et al. 2001) 63% increase per 20 ppb increase in
6 ozone >110 ppb 37% increase in emergency department visits for asthma (Tolbert et al. 2000) Development of asthma (McConnell et al. 2002) 3 fold increase among high ambient ozone, high outdoor activity group >120 ppm Decreased FEV 1 among asthmatic subject s with aeroallergen exposure (Molfino, Slutsky, Zamel 1992) <0.12 ppm over an hour Wheezing incidence (Gent et al. 2003) 35% increase per 50 ppb increase Inc reased allergen reactivity (Trasande and Thurston 2005) Increased need for rescue medications (Gent et al. 2003) (Thur ston et al. 1997) Increased respiratory infections, decreased peak flow (Just et al. 2002) Table 1: Pollutant effects (Trasande and Thurston 2005) Power plant ai r pollutants, including particulate matter (PM), ozone, sulfur dioxide (SO 2 ), nitrogen oxides (NOx), and carbon dioxide (CO 2 ) increase asthmatic symptoms (Committee on Environmental Health 2004) Evidence now shows that children with asthma have increased respiratory symptoms at air pollution levels that are below current United States Environmental Protection Agency (U S EPA) air quality standards (Table 1) This means that current U S EPA standards are not adequate to protect asthma sufferers from air pollution The U S EPA Criteria Document for Particulate Matter was updated to reflect the results of numerous scientific studies that confirm the relationship between serious health threat s and particulate exposure Particulate material
7 (PM) can refer to a mixture of solid particles or liquid droplets that are airborne and have a variety of chemical compositions and properties They are formed by the co mbustion of fuels used in motor vehicles, power plants, and industrial operations, as well as the combustion of wood and other organic material Fine par concern because they can be inhaled deeply into the lungs where they remain lodged or are absorbed into the blood stream (Nemmar et al. 2002) Fi ne particulates, PM 2.5 are emitted from power plants as either soot from the incomplete combustion of fossil fuels or secondarily formed in the atmosphere from sulfur dioxide (SO 2 ) or nitrogen oxide (NOx) emissions retain even larger a mounts of these particulates, which may partially explain their greater susceptibility to pollutants (Pietropaoli et al. 2004) A study of 133 Seattle children with mild to moderate asthma who kept symptom dia ries found that higher levels of PM and carbon monoxide were correlated with increased symptoms, risk of a severe attack, and medication use (Slaughter et al. 2003) Although in this case, carbon monoxide was be lieved to be a marker for other combustion byproducts Vedal and colleagues (2003) documented no lower threshold for premature deaths from the long term inhalation of fine particulate matter The Harvard Six Citie s Study (Dockery et al. 1993) and a study by t he American Cancer Society (Pope et al. 1995) determined that fine particulate matter, especially sulfates, produced largely from coal fired power plants, are especially dangerous Coal burning power plants emit 90% of the SO 2 87% of
8 the NOx, 90% of the PM 10 and 82% of the PM 2.5 air pollution emissions from all electricity generation sources nationally (U.S EPA 2003) NO 2 experiences a high level of covariation with other outdoor pollutants so its effects have been difficult to isolate and may even be synergistic (Trasande and Thurston 2005) In a fourth grade cohort of California children, both NO 2 and PM were found to decrease lung function growth significantly (Gauderman et al. 2000) Exposure to ambient levels of NO 2 in a laboratory setting was fo und to increase allergic response in asthmatics to a normally nonsymptomatic allergen dose (Barck et al. 2005; Strand et al. 1998) Ozone is another dangerous pollutant for asthmatics that primaril y results from the action of sunlight on hydrocarbons and NO x emitted in fuel combustion Although at low levels, NOx are important precursors for ozone, conversely, at the high levels found near power plants the excess NO initiates the net destruction of ozone (U. S EPA 2008) In a controlled laboratory setting, ozone inhalation decreased the ability of the volunteers to exhale rapidly, which, in asthmatics, stemmed from a narrowing of their airways Medication design ed to open their airways could not reverse this constriction, which is a major concern for asthmatics in high ozone areas (U. S EPA 2005) It can also increase strict airways (Trasande and Thurston 2005) Furthermore, an epidemiological study with 271 children in southern New England showed that ozone levels below the current 1 and 8 hour standards (0.12 and 0.085 pp m, respectively) exacerbate asthma (Gent et al 2003)
9 Worse still, ozone may increase the prevalence of asthma (Trasande and Thurston 2005) The California Childr en's Health Study followed a group of 3,535 school age children for five years They were recruited from schools in 12 different communities and had no history of asthma Half of the communities had high levels of ozone while the other half had low level s The concentrations of other pollutants varied Children who played outdoor sports in high ozone areas were found to have 3 times the incidence of asthma than those in the same area who did not play sports or those who played sports in areas with low o zone (McConnell et al 2002) Thus, this correlation between high ozone and asthma should be considered in epidemiological studies There is also compelling evidence of the direct health benefits of reducing oz one During the 1996 Summer Olympics, Atlanta, GA reduced its ozone emissions with citywide traffic control methods This event correlated with significantly decreased hospital admissions for children with asthma (Friedman et al 2001) Chronic asthma sufferers as well as school officials should be aware of local ozone forecasts so they can monitor time and activity levels outdoors Ozone and PM levels are widely publicized in news reports and can be found online for the U.S at http://www.epa.gov/airnow Traffic can be a major source of these pollutants It appears that living near a freeway is especially hazardous At the 8 year follow up for 3,677 children it was found that the children living < 500 m from a freeway had significant deficits in lung function growth as compared to those living > 1500 m away
10 socioeconomic status, ethnicity, sex, and other environmental influences (Gauderman et al 2007) Interestingly, it is specifically freeway traffic that is correlated to an increase in asthma symptoms Proximity to traffic and pollution models for non freeway roads is not associated with a rise in asthma rates (Gauderman et al 2005) Diesel exhaust particles are likely contributors to this trend, as they have the ability to alter the cellular environment of the lungs In mouse models, diesel particles prime the immune system, so when the lungs are exposed to an allergen, they react more strongly and may cause hyperreactivity even without allergen exposure (Hao et al. 2003 ) Ambient pollutants have the potential to act synergistically in ways we do not yet understand Measures to protect sensitive populations need to be in effect. Allergens are another key source of respiratory aggravation for sensitized, atopic, individ uals Common airborne allergens include particles originating from dust mites, cockroaches, pets, pollens, bacteria, and household molds These particles may do more than just induce asthma attacks, however When mice were exposed to Stachybotrys mold c ollected from homes, a disease analogous to asthma was induced (Viana et al. 2002) In children who are at risk for allergies, high dust mite levels in their homes during infancy are correlated with an increase in their risk for developing asthma and late onset wheeze at seven years of age (Celedn et al. 2007) About 24% of American homes have >10 micrograms of dust mite allergen per gram of dust, a level associated with symptomatic asthma Forty six percent of U.S homes have >2 micrograms of dust mite allergen per gram of dust, a level that causes sensitization (Arbes et al.
11 2003) High levels tended to be found in older homes, homes with musty or mildew odor, lower income households, and bedrooms with higher humidity For children at risk for atopic asthma, efforts should be made to lower the levels of dust mites in their homes, especially in their beds. Asthma triggere d by cockroaches is an important public health concern because it typically affects the people least likely to follow asthma management programs Asthma morbidity is demonstrably increased in sensitized children that reside in houses with high cockroach a ntigen levels (Rosenstreich et al. 1997) High levels are associated with the degree of housing disrepair regardless of income or ethnicity (Rauh et al. 2002) It is believed that the high exposure to this antigen may contribute to the high rates of asthma in inner city children, as it increases the permeability of airway epithelial cells (Antony et al. 2002) Moreover levels of cockroach allergen have been difficult to reduce Extermination plus extensive cleaning has been shown to be effective in inner city homes, however (Arbes et al. 2004) The relationship of socioeconom ic status (SES) on asthma prevalence is perhaps one of the most interesting and complex factors associated with this disease Various studies have shown conflicting results regarding the relationship between asthma and socioeconomic status As a multitud e of environmental and genetic factors may contribute to asthma development, it is not surprising that it has been difficult to isolate all variables Lawlor and associates (2004) studied the effects of childhood SES and found a correlation between decreased adult lung function for adults raised in the lower SES group
12 compared with the higher SES group after correction for age, height, smoking status, and other confounding factors Harik Khan and colleagues (2001) used education level and a poverty index to determine SES, and then assessed the effect of SES on lung function They determined that the effect of poverty or education were more likely contributors to decr eased lung function than race It low SES area raises their risk for asthma (Basagana et al. 2004) Factors associated with low er SES that may affect lung function include: childhood respiratory infections, housing conditions, tobacco smoking exposure, air pollution, poor nutrition, prenatal exposures, and intrauterine growth restrictions. Determining what factors, including pollu tion and socioeconomic status affect asthma distribution in a community is an important first step in managing the disease However, before proceeding to the findings of the current study it is important to briefly review the physiological mechanisms of a sthma.
13 1.2 Immunology of Asthma These mechanisms are important to understand if the quality of life for asthma sufferers is to be improved Airway walls are infiltrated with mo nonuclear cells, the majority of which are CD4+ T cells and eosinophils Mast cells, macrophages, plasma cells, and neutrophils are variably increased in the airways of asthmatics compared with individuals with normal lung function (Laitinen et al. 1997) Most of the CD4+ T helper (Th) cells are of type 2 variety (Th2 bias) (Cohn et al. 2004) between ind ividuals (Georas et al. 2005) Much is still unknown about why this Th2 bias occurs and how environmental factors contribute In normally responsive individuals, these cells perform the vital function of stimulating the production of immunoglobulin E (IgE) antibodies and activating eosinophils and mast cells to destroy helminthic parasites (Abbas et al. 2007) They also respond to allergens, however, and it is this function that can lead to problems for allergic, or atopic, individuals Various animal models indicate that chronic activation of Th2 cells is relevant to atopy and the inception of asthma (El Biaze et al. 2003) Th2 cells secrete a variety of cytokines, including IL 4, IL 5, IL 9 and IL 13, which are believed to contribute to many of the symptoms typically associate with asthma, including airway hyperresponsiveness (AHR), mucus secretion, and airway inflammation (Venkayya et al 2002; Zhou et al 2005) Asthma is a highly heterogeneous disease, however The most recent models
14 suggest that asthma pathogenesis is determined by a mixed Th1/Th2 response that varies between individuals (Heaton et al. 2005) About 70% of asthma cases are due to IgE mediated hypersensitivity reactions (Abbas et al. 2007) and these cases are what shall most co ncern us here The other 30% of asthmatics have reactions that can be caused by drugs, exercise, and exposure to cold A typical hypersensitivity reaction begins with exposure to an allergen (Figure 1) This first exposure causes antigen presenting cell s, or cells that possess major histocompatibility complex (MHC) surface molecules, to capture the antigen and then present a part of it on the The combination of a MHC II molecule and an antigen activates nave helper T cells, or in other words, helper T cells which have never been exposed to an antigen before This stimulates the T cells to release cytokines some of which cause B cells to switch to producing IgE antibodies sensitive to the antigen
15 Figure 2: Summary of acquired immunity (1) An antigen presenting cell (APC) ingests an antigen It then presents part of the antigen along with MHC peptides, in this case, MHC II peptides (2) The nave helper T cell forms a synapse with the APC and is stimulated to pro duce the cytokine IL 2 (3) IL 2 causes the T cell to reproduce and form a clone (4) Additional cytokines are released These can cause B cell or cytotoxic T cell activation (McPhee et al. 2003) IgE is most eff and basophils, so the majority of IgE will end up attached to these cells These cells are now sensitized to this allergen, and exposure to it will induce the cells to release various me diators (Fahy 2006) Vasoactive amines and lipid mediators will cause immediate hypersensitivity reactions while cytokines will cause late phase reactions (Akdis 2006; Choi et al. 2005) Th2 Cytokines In addition to being able to communicate via direct contact, T cells release cytokines for cell to cell communication Th2 cells produce a wide variety of
16 these molecules, including interleukin (IL) 4, IL 5, IL 9 and IL 13, which are believed to contribute to many of the physiological responses associated with asthma (Georas et al. 2005) There is especially strong evidence that human asthma is linked to IL 4 and IL 13 The region on chromosome 5q that contains genes for several Th2 cytokines has been shown to be related to the disease (Marsh et al. 1994) Figure 3: Th2 cytokine gene cluster on chromosome 5 Arrows repres ent gene promoter regions Single nucleotide mutations in this area have been shown to be associated with asthma and atopic disease RAD: radiation sensitive 50; KIF: kinesin family member (Georas et al. 2005). IL 4 is vital to induce a Th2 phenotype It stimulates the transcription factor signal transducer and activator of transcription (Stat) 6, as well as other downstream effectors ( Tahvanainen et al. 2009) IL 4 also activates eosinophils that in turn produce more IL 4, creating a self perpetuating cycle (Rothenberg 1998) Administration of recombinant IL 4 causes airway hyperresponsiveness (AHR) in asthmatic patients as well as an increase in mucus production (Georas et al. 2005) However, it is not necessary for the expression of asthma If an antibody mediated blockade of IL 4 is given before or after an antigen challenge, inflammation and AHR still occur It is only if IL 4 is blocked during the antigen challenge that allergic asthma is prevented (Coyle et al. 1995) T he ability of the T cell clones to produce IL 4 in vitro is highly correlated with their ability to induce
17 spontaneous IgE synthesis in human B cells (Del Prete et al. 1988) IgE may bind to many different cells, but the highest affinity receptors are found on mast and basophil cells Once the antibody is coupled with the antigen t he cells are stimulated to release a variety of toxic products that cause many of the symptoms of atopic disease (Corry and Kheradmand 1999) Figure 4: After being activated by the MHC/antigen complex, Th2 cells re lease IL 4 and IL 13, which stimulate IgE production by B cells They also release IL 5, which is required for eosinophil growth and reproduction subsequent encounter with an antigen wi ll cross link the receptors and cause eosinophils and mast cells to release toxic products (Corry and Kheradmand 1999) Another interesting function of IL 4 is that it increases the expression of vascular cell adhesi on molecule 1 (VCAM 1) on endothelial and airway epithelial cells This may be important in eosinophil and lymphocyte trafficking, perhaps (Schleimer et al. 1992) Eosinophils are antigen presenting cells and as such have the ability to activate nave T cells After being exposed to an antigen, eosinophils can increase IL 4, IL 5, and IL 13 production in cultured Th2 cells Howeve r eosinophils do not only activate Th2 cells to release disease
18 modulating cytokines, they also can prime the immune system for allergic responses (MacKenzie et al. 2001) While early trials showed promising r esults in asthmatics when given IL 4 blockers, to date, large scale studies have not demonstrated clinical improvements in these subjects and it remains an area of research (Kasaian and Miller 2008) IL 13 ap pears to be the primary cytokine involved in allergen induced airway hyperresponsiveness ( AHR) Mice with the targeted deletion of IL 13 did not develop AHR, despite vigorous allergen challenge However, with the administration of recombinant IL 13, AHR was restored in these mice (Walter et al. 2001) It also resulted in a time dependent increase in total serum IgE In contrast to IL 4, blockade of IL 13 saw a complete reversal of AHR symptoms even after the ph enotype was fully developed in these mice (Wills Karp et al. 1998) IL 13 stimulates airway fibrosis and promotes epithelial damage, mucus production, and eosinophilia Inflammation is then amplified by local responses from epithelium, smooth muscle, and fibroblasts through the production of chemokines, cytokines, and proteases This inflammation causes adenosine to be formed, which, in turn, causes more IL 13 to be produced (Cohn et al. 2004) This creates a cycle of lung damage that is difficult to halt Conversely, in non atopic individuals IL 13 can actually serve in a protective role It converts injured lung epithelium from an absorptive state to a secretory stat e, thus increasing mucus production In theory, this protects the cells from injury from the outside world by providing a larger volume in which to bind or dissolve mediators, inhaled substances, and cellular debris However, IL 13 simultaneously reduces ciliary
19 (Laoukili et al 2001) This causes the mucus to pool in the lungs and decreases airflow, a serious problem in asthmatics where airflow is already restricted due to chronic inflammation In humans it appears that IL 13 may not have an exclusive role in inducing mucus production In vitro, it appears that IL 9 and IL 4 can also increase mucus staining (Cohn et al. 2004) These cellular events le ad to the clinical symptoms of asthma including difficulty breathing IL 4 and IL 13 share a common receptor, IL 4 receptor alpha, and many therapies have begun targeting this site There have been promising results in murine studies in which long term g ene therapy targeted against IL 4 and IL 13 inhibited development of airway eosinophilia and mucus production while simultaneously reducing Th2 cytokines and AHR (Zavorotinskaya et al. 2003) There has even be en success in human clinical trials targeting the IL 4/IL 13 pathway In phase 2a trials with asthmatics, Pitrakinra (Aerov reduced asthma related adverse events, the use of rescue medication following allergen challenge, and preserved lung function (Wenzel et al. 2007) This is a promising area of research that may one day allow a sthmatics not to just treat their symptoms, as many of their current medications do, but also to halt damage from being done at the cellular level. Other cytokines are implicated in the asthma phenotype as well IL 5 supports the growth and differentiati on of B cells Its overexpression causes significant increases in eosinophils and antibody levels (Takatsu and Nakajima 2008) IL 9 is a mast cell growth factor and increases their levels of high affinity IgE re ceptors It contributes to airway eosinophilia as well (Zhou et al. 2005) IL
20 25 promotes AHR (Ballantyne et al. 2007) IL 10, although it inhibits lipopolysaccharide ind uced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis (Lee et al. 2002) IL 17 has somewhat contradictory roles in asthmatics It is required during antigen sensitization to develop allergic asthma, but once asthma is established it is a negative regulator of allergic response (Schnyder Candrian et al. 2006) These are just a few of the most important or well studied of the cytokine s produced by Th2 cells However, Th2 cells do not exclusively produce these cytokines CD8+ cells, eosinophils, mast cells, basophils, natural killer (NK) cells, and subsets of Class II MHC expressing accessory cells all can produce influencing cytokine s (Cohn et al. 2004) although that is beyond the scope of this paper. (Ab bas et al. 2007)
21 Roles of Th1 cells in Asthma Th1 cells produce interferon (IFN) and IL 2, IL 12, and IL 18 These cytokines help to eliminate bacteria and viruses and are generally associated with cell mediated immunity Given that Th2 cells seem to have such pro inflammatory effects in the lung it is natural to wonder if Th1 cells and their signature cytokines which can reduce the prevalence of the Th2 type, could also reduce inflammation While the heterogeneity of asthma pathogenesis makes a definitive answer difficult, it has been shown that un affected individuals have significantly greater numbers of Th1 cells than asthmatics (Wong et al. 2001) Additional studies also observed a decrease in the Th1 transcription factor, T bet, in asthmatics Its loss may be associated with asthma Further evidence of the importance of T bet, and the importance of the Th1 cell in general, was established when mice lacking the T bet gene spontaneously developed asthmatic symptoms ( Finotto et al. 2002) Smart and colleagues (2002) followed a cohort of asthmatic children into adulthood over a 42 year period Adults who had resolved their asthma showed a normalization of IFN imbalance contributes to asthma Another study showed that mutations in IFNG and related genes conferred genetic susceptibility to atopic asthma on Japanese children (Nakao et al. 2001) A small clinical trial that had severe corticosteroid resistant asthmatics take IFN reported a dramatic improvement in their condition and showed greater Th1 cell levels (Simon et al. 2003a) In the short
22 term at least, IFN could be beneficial in the treatment of asthma This looks to be an area ripe for future studies IL 12 is the cytokine that drives Th1 cell differentiation IL 12 activates the transcription factor Stat4, which enhances IFN regulatory sequences near the IFN IL 12 would appear to be a good target for therapy, and murine studies have indicated that it has the possibility to reduce airway inflammation Thus far however, all human trails have ended quickly due to adverse affects (Leonard and Sur 2003) TNF exhibits pro inflammatory properties that may contribute to some asthma phenotypes Approximately 5 10% of asthmatics have severe asthma that does not respond well to the standard treatment of inhaled corticosteroids and it is in the subpopulation that anti TNF therapy may be effective (Brightling et al. 2008) In these asthmatics, increased levels of TNF are found in bronchoalveolar lavage (BAL) fluid Preliminary studies have established an increase in quality of life, lung function, and airway hyperresponsiveness and a reduction in exacerbation frequenc y in patients treated with anti TNF (Cazzola and Polosa 2006) Clearly viewing asthma only as a disease caused by a Th2 inflammatory response is inadequate, especially at the severe end of the spectrum.
23 Figure 6: Role of TNF (Brightling et al. 2008) Mechanisms Accounting for High Th2 levels Th2 chronic activation should not occur in normal individuals Internal mechanisms should eliminate CD4+ T cells after activation, and failing that, the responsive cells should be eliminated The continued presence of Th2 cells must then be due to one or a combination of ( a ) increased generation from naive CD4+ T cell precursors, ( b ) increased recruitment and/or proliferation of effector/memory helper T cells, or ( c ) reduced elimination of effector/memory helper T cells (Cohn et al. 2004) Interestingly, recent studies have shown that continued recruitme nt of memory cells may be much more important than the expansion of resident lymphocytes (Harris et al. 2002; Reinhardt et al. 2003)
24 Although continued recruitment may be the most important f actor in maintaining high levels of Th2, there are certainly other significant mechanisms Th1 cells have higher rates of apoptosis than Th2 cells in peripheral blood and from airway biopsies (Refaeli et al. 2002) I FN a pivotal role in activation induced cell death It acts through its receptor and Stat 1, stimulating apoptosis by activating caspase 8 just downstream of the death receptor Conversely, IL 4, produced by Th2 cells, p rolongs the survival of activated T cells by inducing expression of Bcl 2, a pathway that is independent of caspase 8 (Cohn et al. 2004) IFN 4 have a cross regulatory effect upon one another, so an increas e in one leads to the decrease in the other Once an imbalance between the T cell types occurs, this effect helps to maintain it However, the presence of IFN that this is not the sole mechanism of Th cell le vel maintenance (Magnan et al. 2000) Another reason for the high Th2 survival rate may be an abnormal Fas death receptor A deficient Fas receptor in mice has been shown to be sufficient for the long term developme nt of airway disease (Tong et al. 2006) When Fas deficient T cells were transplanted into mice they developed persistent inflammation that was not resolved even at 6 weeks after the last challenge This persistent phase correlated with lower levels of IFN production by Fas deficient T cells In Th2 cells, c FLIP is up regulated, which protects them from Fas mediated cell death In addition to that, Th2 cells produce less Fas ligand than Th1 cells (Zhang et al. 2003) In asthmatic humans, altered apoptotic potential
25 through the Fas death receptor is found as well Th2 cells seem to have a selective resistance to Fas mediated apoptosis (Jayaraman et al. 1999) Figure 7: Environmental factors that affect the Th1/Th2 balance (Busse and Lemanske 2001) Other Vital Cells Monocytes, in addition to Th cells, are implicated in worsening as thma symptoms Eosinophil inflammation has often been considered to be a hallmark of asthma although i t is now known to only to occur in 50% of asthma patients (Kamath et al. 2005) It is not clear exactly how they affect disease progression or persistence It is known, however, that they produce IL 13, present antigens to Th2 cells, and stimulate subepithelial fibrosis CD4+ T cells provide essential signals for eosinophil mobilization, activation, and recruitmen t to the lung (Cohn et al. 2004)
26 Neutrophils are promising as an alternative pathway for some cases of asthma These cells increase as the duration and severity of the disease increases, replacing eosinophils in the respiratory tract They tend to respond vigorously to physical triggers including viruses, lipopolysaccharides, and ozone (Kamath et al. 2005) be an interesting area of future research Additionally, CD8+ cytotoxic T cells participate in the delayed hypersensitivity response They produce IL 4 which helps drive the Th2 cycle (Stanciu et al. 1997) Murine mode ls have further indicated that the interaction between CD8+ cells and CD4+ cells can be vital, in part through IL 4 release during the sensitization phase, for AHR to occur (Koya et al. 2007) The gene for cytotox ic T lymphocyte antigen 4 (CTLA 4) an important surface molecule that regulates T cell activation and differentiation, on chromosome 2q33 has been implicated in the emergence of atopic disease (Munthe Ka as et al. 2004) At least four single nucleotide polymorphisms have been implicated in atopy although since no association with AHR was seen they were not judged as playing a direct role in asthma per se Interestingly these mutations had a negative ass ociation with autoimmune disorders, which can exhibit a Th1 bias. Finally, dendritic cells are the major antigen presenting cells in vivo (Hammad and Lambrecht 2008) Though the process is not completely understood, these cells can secrete cytokines to promote either Th1 or Th2 type cells (Lambrecht 2001)
27 Airway smooth muscle remodeling Airway smooth muscle (ASM) remodeling is symptomatic of all asthma cases The airway wa lls can thicken 10% to 300% of normal, significantly decreasing airflow (Homer and Elias 2000) This remodeling consists of increase in airway smooth muscle (ASM) mass, an increase in the size and number of mucous gla nds, and subepithelial fibrosis This thickened, hyperresponsive airway is responsible for the clinical manifestations of asthma, including difficulty breathing, wheezing, and chest tightness The thicker muscle allows for stronger bronchial spasms and m ore dangerous asthmatic attacks (Lambert et al. 1993) T lymphocytes activated by an antigen have been shown to induce DNA synthesis and proliferation in ASM cells and are prevented from undergoing apoptosis upon di rect contact (Ramos Barbon et al. 2005) This positive inflammation The method of attachment to ASM cells is via integrins and CD44 (Lazaar et al. 1994) In addition to mounting in vitro evidence that the remodeling is caused by CD4+ T cells, there is now in vivo evidence (Lazaar et al. 1994) Adoptive tran sfer of Green Florescent Protein (GFP) labeled T cells from OVA sensitized rats into non sensitized rats found that the cells migrated to the lung and induced ASM remodeling Previous studies have shown that the transferred T cells from the lung are the T h2 variety (Watanabe et al. 1997)
28 Responses to Pollution In addition to allergens, other environmental factors can lead to the exacerbation of asthma Pollution from a variety of sources can cause serious proble ms Diesel exhaust particles (DEP) in conjunction with an antigen were found to increase IgG, mucus producing goblet cells, BAL fluid neutrophils, eosinophils, and IL 5 more than either DEP or the antigen alone in a mouse model (Takano et al. 1997) Another study evaluated the effect of residual oil fly ash (ROFA), a fine particulate with a high content of bioavailable transition metals, including V, Ni, and Fe, on an asthma like mouse model ROFA plus a previously s ensitized allergen resulted in greater than additive increases in lavage fluid IL 4 and IL 5, eosinophil numbers, and airway responsiveness to methacholine challenge (Gavett et al. 1999) These studies have grave im plications for susceptible persons living near power plants, factories, or in urban areas. NO 2 a commonly emitted pollutant, has been shown to impair host defense systems and to increase susceptibility to both viral and bacterial infections in epidemiolo gic, human clinical, and animal toxicological studies Numerous studies have also shown that these effects can even be shown at concentrations of <1 ppm (U.S EPA 2008) Chauhan and colleagues (2003) observed that higher levels of NO 2 in the week before the start of a respiratory viral infection in asthmatic children, and at levels within current air quality standards, are associated with an increase in the severity of the ast hma exacerbation caused by the virus Exposure to N O 2 may also alter the balance
29 of lymphocyte subsets in the body After repeated exposure, a decrease in cytotoxic suppressor cells and natural killer cells in BAL fluid was seen A significant, dose rel ated increase in lymphocytes and mast cells recovered by BAL has also been found (Sandstr m et al. 1991; Sandstrm et al. 1992) However, the clinical implications of these changes in cell dis tribution have yet to be determined. Ozone, NO 2 and particulate matter (PM) have all been shown to increase immediate and late phase reactions after antigen challenge They also all act as oxidants or induce oxidant responses in the lung (Peden 2005) As antioxidants in the airway confer some protection from this pollution exposure and glutathione is an important antioxidant, mutations in the Glutathione S transferases (GST) antioxidant genes have been studied in asthmatics GSTM1 null children have decreased lung function (Gilliland et al. 2002) In a study with 218 asthmatic Mexican children with the GSTM1 null allele, the Nicotinamide adenine dinucleotide (pho sphate) reduced:quinone oxidoreductase (NQO1) Ser allele conferred a protective effect in a high ozone environment (David et al. 2003) These and other antioxidant genes could be important determinants of asthma tic severity where pollution levels are high. Conclusion Asthma is a chronic respiratory inflammation disease that exhibits a Th2 cell bias Th2 cells are believed to be primarily responsible for creating a self perpetuating cycle of injury to lung cells in the majority of asthmatics This
30 response is typical of a hypersensitive immune system, as active inflammation should not be induced in the respiratory system under normal exposure to foreign protein antigens The cascading immune response of Th2 cel ls to allergens is key to explaining many of the pathological symptoms seen in asthmatics Airway hyperresponsiveness, excess mucus secretion, airway inflammation, and thicke ning of airway walls can all be the direct result of Th2 cells Asthma continues to affect more of our population every year Understanding the basic biological mechanisms associated with this disease will help us develop more targeted treatments and will hopefully one day lead to a prevention. In the meantime, it is important to con tinue to examine the many factors that contribute to expression of asthmatic symptoms The following study is one approach to add to the database for assisting asthmatics in making choices about where they might live.
31 Chapter 2: Epidemiological Study 2.1 Introduction From 1995 2002, children in Alachua County schools have consistently higher reported rates of asthma than average (Wilson 2003) In this study, I examine the p 75 and a local coal fired power plant on the number of asthma cases in public elementary school children from 2004 2007 Any trends discovered will only reflect a correlation Other factors besides those examined may explain trends and further research would need to be conducted to determine any causality The reported health information from over 12,000 students was used for each of the four years evaluated Figure 8: Asthma Rates reported by the School Districts for 2001 2002 School Year (Wilson 2003)
3 2 All of the schools, excluding the three schools built less than 17 years ago, have had an overhaul of maj or components of their heating, ventilation, and air conditioning (HVAC) systems within the last ten years (Gable 2008) Additionally, the filters on all elementary school HVAC systems are scheduled to be changed ever y 60 days These efforts help to maintain improved indoor air quality which is beneficial to asthmatics. Alachua County has a total population of 252,388 about half of which reside in the city of Gainesville (City of Gainesville 2008) Gainesville is located in north central Florida, a subtropical zone, so pollen can be a major factor for allergic individuals Electricity for this county is primarily provided by a 225 megawatt (MW) coal fired power plant lo cated in the NW corner of Gainesville (Gainesville Regional Utilities (GRU) 2004a) The over twenty year old plant (Deerhaven 2) is the largest, stationary, single point pollution source in the county The 2001/2002 average for pollutants emitted were 6,992.6 tons of SO 2 3,316.5 tons of NOx, and 162.9 tons of particulate matter (PM) per year (GRU 2004b) The effects of pollution from the powe r plant is a particular concern to the community as the local utility company desires to increase electricity generation by building an additional generator Due to this fact, the current study has paid special attention to potential effects of the coal p Some of the other major pollution sources are the John R Kelly Generating Station, University of Florida, plant (Green Media Toolshed 2005) Cars are a key source of mobile pollution
33 The largest highway through Alachua County is I 75 and is a source of diesel exhaust fumes Unfortunately detailed air pollution monitoring is n ot available in Alachua County Only one monitoring station is currently in use (Florida Department of Environmental Protection 2008) Two additional monitoring stations used prev iously have closed One of the closed monitoring stations was operational until January of 2006, the other until February 2008, but neither was located near the coal plant The station still in operation is over 15 miles away from the plant and is locate d in Paynes Prairie Preserve State Park Figure 9: Pollution monito ring stations and pollution sources in Alachua County: Ozone Discontinued particle p ollution monitoring Discontinu ed o zone monitoring Deerhaven 2 (Florida Department of Environmental Protection 2008) While Alachua County has met the air quality standards determined by the Environmental P rotection Agency (EPA), it has barely done so with regards to ozone T hour ozone standards, the averages for last three years ( 2006 2008 ) are used three year attainment average was 74 ppb An average over 75 ppb would not meet EPA standards (FL Department of Environmental Protection 2008) In 2005, Alachua County was reported to have 331days of good air quality and 34 I 75 Gainesville 301
34 days of moderate air quality (Division of Air Resource Management of the EPA 2005) Understanding how asthma is distributed in Alachua County will be valuable in determining wh ere to focus resources related to asthma management and education These data will also serve as a baseline against which changes in asthma prevalence or distribution correlated with county pollution levels or public policy decisions can be measured. 2.2 Methods For the 2004 2007 school years, the data on the number of students at each school that self reported asthma on a parent completed student health card were Office The total nu mber of students enrolled and the number of students receiving free or reduced price lunches at each public elementary school was also obtained from the Alachua County School Board The rate of federally subsidized lunches was used as an indicator of the socioeconomic levels of students attending each school Finally, the age of the schools was requested from the Alachua County Public School Facilities office. The distance of each school from I 75 was calculated using Google Earth ruler tools This dista nce was used as a relative measure for pollution exposure from the interstate while attending school P utative effects of air pollution emissions from the local 225 Megawatt (MW) coal fired power plant were examined using two parameters The direct
35 line ar distance from the pollution source to the elementary school gave a measure of potential pollution load Distance to each public elementary school was measured on an Alachua County GIS map as a straight line from the coal fired power plant (Deerhaven 2) The second parameter was the average annual NOx contribution levels from power plant generation at each school campus location NOx levels were determined using a 2003 contour sample map (Gaines ville Regional Utilities 2004b) This contour map, developed by Black and Veatch using the Industrial Source Complex Long Term model (ISCST3), simulates the dispersion of power plant NOx emissions in the atmosphere and predicts the average annual ground level concentration This model does not include the chemical transformation processes of creating secondary pollution products that take place in the atmosphere after a plume pollutant leaves the smoke stack The model is approved by the U.S. EPA and is widely used for assessing impacts from various types of air pollution sources on surrounding ambient air quality (U.S Environmental Protection Agency 2009) Statistical analysis, includi ng Spearman rank correlation, was performed to determine if socioeconomic status, age of the school, distance from I 75, proximity to the power plant, or NOx contribution levels were associated with the asthma rates observed at the elementary schools Thi s test was used because the data distributions were nonparametric
36 2.3 Results The mean asthma rate for Alachua County elementary school students from 2004 2007 was 8.7% (table 1) 19.8% The percent of student s receiving free or reduced price lunches varied at schools from a low of 13.6% to a high of 92.7% with the mean being 58.7% The average age of the schools was 41.6 years, with a range from 9 to 86 years old. Table 2: Alachua County Data 1 Alachua County has twenty four public elementary schools serving Kindergarten through fifth grade students (K 5) Public funded charter schools and school centers as well as private schools were not included in the survey. ELEM SCHOOL 1 % STUDENTS W/ ASTHMA (4 YR AV G) % STUDENTS FREE/ REDUCED LUNCH (4 YR AVG) DISTANCE FROM COAL PLANT (MILES) 2 AVG ANNUAL N0x CONTRIBUTION FROM POWER PLANT 3 Miles to I 75 TALBOT 6.8% 14.1% 3.1 0.36 3.92 NORTON 4.7% 39.8% 4.4 0.28 4.93 STEPHEN FOSTER 12.7% 64.1% 5.7 0.28 4.88 GLEN S PRINGS 9.5% 44.0% 5.1 0.20 3.92 LITTTLEWOOD 9.5% 42.6% 6.5 0.20 2.35 FINLEY 4.6% 55.4% 7.1 0.20 3.75 HIDDEN OAK 6.5% 15.8% 6.5 0.20 0.48 DUVAL 12.7% 86.9% 8.4 0.20 6.63 RAWLINGS 9.2% 86.2% 6.8 0.20 7.15 TERWILLIGER 8.3% 74.0% 6.7 0.12 0.35 ALACHUA 8 .1% 52.5% 6.9 0.12 1.10 IRBY 4.6% 50.8% 6.6 0.12 0.95 METCALF 7.3% 88.0% 7.5 0.12 6.80 WILLIAMS 8.0% 67.0% 8.8 0.12 5.23 IDYLWILD 11.4% 66.9% 10.2 0.12 1.74 LAKE FOREST 16.8% 89.9% 10.2 0.12 7.50 PRARIE VIEW 7.0% 90.0% 10.4 0.12 4.62 CHILES 6.9% 33 .2% 9.2 0.12 2.96 WILES 7.4% 35.0% 10 0.12 2.18 WALDO 14.7% 77.3% 13.4 0.12 22.00 NEWBERRY 11.0% 50.5% 15.7 0.12 10.10 ARCHER COMM 9.3% 65.4% 18 0.12 17.40 HIGH SPRINGS 3.8% 33.3% 13.4 3.12 SHELL 8.1% 85.6% 21 13.20
37 2 Distance from the coal fire d power plant was measured to nearest tenth of a mile as straight line to the center of school property as noted on Alachua County school maps 3 N0x average annual contributions from power plant operations from contour map (Appendix A). # OF STUDENTS WITH ASTHMA (TOTAL STUDENT POPULATION) ELEM SCHOOL 2004 2005 2005 2006 2006 2007 2007 2008 TALBOT 62 (772) N/A (755) 42 (740) 46 (701) NORTON 60 (679) 19 (709) 22 (705) 28 (668) STEPHEN FOSTER 59 (400) 63 (485) 57 (445) 48 (476) GLEN SPRINGS 25 ( 341) 32 (395) 52 (465) 53 (461) LITTTLEWOOD 58 (674) 58 (681) 62 (659) 71 (626) FINLEY 20 (437) 14 (427) 19 (448) 27 (433) HIDDEN OAK 45 (690) 44 (693) 49 (763) 54 (827) DUVAL 33 (421) 32 (491) 98 (495) 80 (477) RAWLINGS 28 (482) 38 (457) 53 (437) 47 (443) TERWILLIGER 55 (672) 66 (662) 53 (627) 43 (642) ALACHUA 30 (440) 33 (429) 36 (429) 44 (465) IRBY 35 (568) 25 (594) 27 (549) 17 (535) METCALF 40 (511) 34 (506) 36 (433) 27 (424) WILLIAMS 28 (411) 26 (453) 46 (502) 53 (507) IDYLWILD 57 (500) 69 (591) 76 (666) 66 (584) LAKE FOREST 60 (372) 60 (395) 69 (408) 73 (385) PRARIE VIEW 37 (410) 30 (359) 18 (296) 14 (322) CHILES 50 (738) 49 (777) 58 (791) 57 (799) WILES 37 (621) 53 (647) 53 (696) 54 (680) WALDO 26 (203) 31 (194) 33 (217) 34 (228) NEW BERRY 50 (475) 53 (537) 75 (592) 68 (623) ARCHER COMM 14 (297) 31 (310) 44 (350) 34 (339) HIGH SPRINGS 11 (673) 41 (677) 50 (1018) 24 (978) SHELL 20 (320) 27 (258) 20 (251) 16 (210) TOTALS 940 (12,107) 928 (12,482) 1148 (12,982) 1078 (12,833) Table 3: 1) Association between the Coal fired Power Plant and Asthma Rates: The statistical association between proximity of the elementary school to the coal fired power plant and school asthma rates was weak ( r s = 0.19 ; p = 0.72 ) The linear distance of the school site from the coal fired plant is not statistically sufficient to distinguish the multiple causes and contributing factors influencing the asthma rates at Alachua Coun ty elementary schools for the school years
38 2004 2007 These results remained constant even after accounting for whether the schools were generally upwind or downwind from the coal plant. The NOx contribution levels from the coal plant were also not stati stically significant u si ng the data from all four years ( r s = 0.16; p = 0.12 ) The lack of statistical correlation in this study does not conclusively show that the plant pollutants do not influence the rates of asthma in Alachua County, however Since se condary particulate formation peaks downwind of the plant, the maximum distance of the schools may not have been large enough to distinguish an effect on the rate of asthma prevalence There are also other major sources of pollution that the contour map d id not account for, such as pollution from car exhaust The data also do no t include exposure at home. 2) Association between the Interstate and Asthma Rates: Proximity of the elementary school to the major interstate in Alachua County, I 75, and scho ol asthma rates showed a trend towards increasing asthma rates with increasing distance from I 75 ( r s = 0.36; p= 0.0003 ) As highway pollutants have been shown to increase asthma rates it is likely that another trend could be o verriding the effect that the highway has or that the highway pollutant effects cannot be seen at the school level Distance from the highway is positively correlated with both free/reduced lunch rates ( r s = 0.52; p < 0.0001) and school age ( r s = 0.36; p = 0.0004)
39 3) Associa tion between Free/Reduced Price Lunches and Asthma Rates: Socioeconomic status of the student population, as measured by the number of students receiving free or reduced price lunches, was a very good predictor of the reported student asthma rates ( p = 0.00 04 ) according to the Spearman rank correlation analysis The Spearman correlation coefficient was 0.36 However, year to year the significance varied, as could be expected with a sample size of 24 schools While significant, this means that a small amou nt of variance is explained by this factor. All years 2004 2005 2006 2007 Mean Asthma 8.72% 8.05% 8.40% 9.45% 8.99% Mean Free/ Reduced Lunch 58.7% 59.9% 58.9% 57.2% 58.8% p 0.0004 0.216 0.0125 0.0322 0.163 Table 4: Asthma and Free/Reduced Lunch Data Figure 1 0 : Percentage of students with asthma vs. the percentage of students receiving free/reduced price lunches
40 4) Association between School Age and Asthma Rates: years of data ( p < 0.0001) But again, the significance varied when viewed on a yearly basis due to the small sample size The Spearman correlation coefficient was 0.46 The age of the school was strongly positively correlated with the percent of students on free/ r educed price lunches, as well ( r s = 0.46; p < 0.0001 ) This correlation was significant over each year individually, in addition to the overall data set Like free/reduced lunch rates, while significant statistically, little of the variance is explained b y these parameters. All years 2004 2005 2006 2007 r s 0.46 0.26 0.34 0.59 0.52 p < 0.0001 0.23 0.11 0.0024 0.0089 Table 5: Asthma and School Age Spearman Correlation Coefficients and Significance Values Figure 11 : Average p ercenta ge of students with asthma vs. school age
41 Factors such as overhauling of the schools and changes in policies concerning cleaning vents and changing filters likely add to the variance in these data. However, all schools built over 17 years ago have had a ma jor overhaul to their heating, ventilating, and air conditioning (HVAC) systems within the last ten years. 2.4 Discussion S everal factors and the prevalence of asthma in elementary school children in Alachua County, Florida over a four year period were ex amined Socioeconomic status, school age, proximity to I 75, distance from a coal fired power plant, and modeled NOx contribution levels from a 220 MW coal fired power plant were all considered in this study (Cooper, 2009) The rates of free and reduced lunch prices in Alachua County were found to be strongly correlated with asthma rates at local public elementary schools over the four year period examined ( r s = 0.0009) The number of students receiving free or reduced lunch prices was used to indicate the socioeconomic status of students These results are consistent with previous research findings (Simon et al. 2003b) Interestingly, the Alachua County elementary schools with the highest percentage of student s receiving free or reduced price lunches are generally located in areas farther away from the coal plant and I 75 while schools located closest to the Deerhaven 2 coal fired power plant and the interstate have more affluent student populations using the s elected measure According to this measure, the trend was highly significa nt for both pollution sources. In many
42 cities the reverse trend is seen as a form of environmental injustice It is possible that if the lower income areas were near the plant and interstate an even more dramatic trend could be seen (Peled et al. 2005) Averaged annual 2003 NOx contribution levels and the distance from the coal power plant operations in Alachua County were not statistically correl ated with asthma rates at local public elementary schools in this longitudinal study (p= 0.12) Prior studies suggest that the coal plant located in the northwest area of Alachua County could contribute to the high rate of asthma at the entire county leve l as it releases large amounts of air pollution (Levy et al. 2002; Perera 2008) Spengler and colleagues (2000) reported that ambient concentr ations of the primary pollutants SOx and PM 10 were greatest within 5 miles of two coal fired power plants examined, whereas secondary particles peaked approximately 20 miles downwind These secondary particles include PM 2.5 formed by atmospheric transform ations of SO 2 and NO 2 However, since these plants were larger than those found in Alachua County it is difficult to compare their pollution distribution to those from Deerhaven 2 Further, the Spengler study was conducted in a cold, dry climate and seco ndary particle formation (i.e PM 2.5 ) is known to increase with the higher temperature and greater humidity conditions like those found in Alachua County (Levy et al. 2002) Nevertheless, because 23 of the 24 elementary schools examined in this study were located within 18 miles of the power plant, it must be questioned if their distance from the power plant would have allowed for sufficient discrimination of impacts at the individual schools Only one school was located outside the 20 mile range for the peak
43 secondary particle formation It is unknown where the children live or how much lifetime exposure they have received, further complicating the situation A cohort study with a county of similar demograph ics, climate, and no coal fired power plant within 20 miles of elementary schools could yield additional clarification of the effects of the coal fired power plant air pollutants vs socioeconomic status Of course, other factors may be responsible for t he lack of statistical correlation for the two power plant parameters examined First, other large stationary pollution sources located in different parts of the county may confound the specific contributions of coal plant operations to the asthma rates For example, a combined cycle gas power plant and gas turbine peaking units located in the low socioeconomic area of southeast Gainesville has not been modeled for air pollutant contributions Additional air pollution stationary sources such as a chemica l plant, marine fabrication facilities, the University of Florida facilities, and a cement production plant also have not been modeled and may obscure the contribution to asthma of coal fired power plant pollutants Secondly, mobile sources of criteria ai r pollutants, beyond those estimated from traffic on I 75, were not examined because air quality monitoring in Alachua County is minimal The Alachua County Environmental Protection Department currently operates only one air quality monitoring station fo r ozone This station is located in an area with relatively low NOx contributions (12%) from power plant operations as delineated by the NOx contour map (Appendix A) Increasing the number of air quality monitoring locations and the number of criteria ai r pollutants
44 monitored at each station could result in more complete analysis of the epidemiological impacts from all air pollution sources Air quality monitoring in high air pollution concentration level areas would help provide the basis for a more qua ntitative analysis, better modeling, and allow for examination of additional air pollutant species Additionally, the schools closest to Deerhaven 2 are more forested than many of the low income areas with the correspondingly high free and reduced lunch r ates located in downtown Gainesville The differing environments may alter pollution exposure, but without better monitoring it cannot be determined. stance from I 75 did not show a negative effect on asthma trends in this study, d iesel fumes have been shown to have an effect on asthma when home exposure was evaluated, so other factors may be at work Exposure to diesel school bus fumes, other traffic related air pollution, the indoor air quality of a specific school, and participa tion in outdoor athletic activities in high pollution areas can increase asthma prevalence, but were beyond the scope of this study to elucidate Future research to determine the amount of time asthmatic students spend riding diesel school buses, walking to school along busy streets, and participating in outdoor sport activities could provide a clearer picture of confounding factors in the asthma rates observed Affluent families are also more likely to be living in newer or better maintained homes that are more airtight and have better air conditioning systems The same applies to newer schools Building codes have become stricter resulting in tighter building construction methodology, properly sized and
45 higher efficiency air conditioning systems and improvements in air distribution (ductwork) systems These codes result in better indoor air quality and reduced indoor humidity as does regularly changing the air filters Additionally, new buildings are better protected from humidity If a building i s damp, mold may begin to grow and exacerbate asthmatic symptoms Interestingly, it appears that uncontrolled ventilation through cracks may increase spore concentration while controlled ventilation, i.e opening windows, can decrease it (Ucci et al. 2004) Sufficient ventilation can help stop mold growth However, ventilation levels must be sufficiently higher to halt dust mites, which also thrive in humid buildings Better ventilation and upkeep should provide more protection from pollution in newer buildings Further research should be done to determine if these factors are influencing the trend of higher asthma rates in older schools The data for N0x contributions from power plant operations were modeled for the year prior to the first year of data collection on student asthma rates Because the coal continuously at maximum output, operational data would be expected to be similar over the years Variations in the chemical composition of the supplies of coal could, however, can have an effect on the amount of NOx produced (Gainesville Regional Utilities 2004a) Gainesville Regional Utilities has made a c ommitment to buy fuel with both low amounts of nitrogen and sulfur in an effort to reduce emissions, but it is possible that different coal deposits may have different levels of these pollutants
46 Wind velocity and direction data for Alachua County shows that there was no prevailing wind direction locally in 2003 (Appendix B), but climate and meteorological differences from 2004 to 2007 could affect the relative distributions and concentrations of NOx The change, if any, in the NOx concentration level at school locations attributable to variation in yearly weather conditions is unknown Attempts to retrieve student health card information at the individual school level for the 2003/2004 school year and earlier were unsuccessful Individual school data had been combined and only totalized information at the school district level was available Retention of unamalgamated student information on an annual basis at the individual school level could provide epidemiologists with valuable information for futur e studies. The observed results may also be due to a number of other factors including health card reporting errors, the multiple causes of asthma, and the effects of wind distribution on pollutants All estimates of the school asthma rates were collected from a single source, the student health card This data source is subject to a number of potential errors including: Students identified with asthma by the parent may or may not have been diagnosed by a physician The diagnosis of asthma is subject to errors and the diagnosis of asthma may vary in different ethnic populations. Because asthma is an intermittent problem, parents may believe their child has outgrown asthma and may under report the condition.
47 The data may not reflect migration in/out of sc hools School nurses may use different standards in counting/reporting number of children identified by the health cards as asthmatic. While acknowledging the limitations of this study, the information and results supply valuable baseline data and sugge st several avenues for further investigation Modeling of ambient air pollutant concentration levels, not only pollutants from the power plant, and determining their relationship to asthma rates would provide a more robust epidemiological study Compilin g and retaining the individual school data on asthma rates from year to year would facilitate any future analysis and provide the opportunity to perform a longer term study The issue of medical records privacy and student confidentiality made cross refer encing asthma rates with student home location problematic If student home addresses, or even zip code information were available from the student health card records, additional trends such as the effects of air pollution levels at student homes could b e evaluated The results of epidemiological studies often influence public policy decisions There are a number of local public policy decisions where the results of this study may be useful Asthma awareness programs in public schools may wish to foc us more resources on locations with high rates of free and reduced lunches Before new air pollutant sources are permitted, additional studies should be conducted to determine the adverse health effects of current air pollution emissions Additional air quality monitoring should be implemented to more adequately identify the sources and quantify the types and levels of air
48 pollutants More precise information could add confidence to modeling programs The high asthma rates for public elementary school children in Alachua County are a public health issue of great concern to the community T he local utility company intends to add new scrubbers to the existing coal plant to meet stricter federal air pollution regulations (Gainesville Regional Utilities 2004a) However, these reductions may be offset by plans to build a new 100 MW biomass plant The results obtained in this study could serve as an important tool to assess the impact of air pollution le vel reductions or additions, the value of asthma awareness programs, and the effectiveness of public policy decisions on public health The data collected can serve as a base line for future studies, and allow them to observe changes in county trends Cu rrently the only school program available for children is Open Airways for Schools (OAS) There are currently no activity programs designed specifically for asthmatic needs, although they could improve the health of the community
49 Ch apter 3: Asthma Programs There are several obstacles for schools to develop asthma management and education programs Funding and time appear to be the most daunting challenges (Roy 2009) To help lower these barr iers, this section has a compilation of free online resources There are resources for the children afflicted with asthma and their parents, as well as tips on what the school and teachers can do to help minimize the risk of asthma attacks in students It is important for children who have asthma to understand what asthma is and what triggers their asthma attacks so they can help to manage their disease The only program in Alachua County elementary schools for asthmatic children is Open Airways for Sc hools (OAS) Fortunately, a tax increase with specific provisions to fund school nurses was recently passed (Roy 2009) That means that the future of this program looks bright OAS programs have been demonstrably shown to reduce student absences and use of health care services (American Lung Association 2008a) The OAS program consists of six 40 minute sessions taught by a certified instructor Although asthma tic students are removed from their normal classes for these lessons, the time they miss adds up to less than one day of absence due to asthma This is a great program for students It lets them learn how to cope with and prevent attacks in a fun manner It also provides material for them to take home to their parents Interventions in urban areas in which OAS was taught and school nurses followed up on students' school absences and coordinated students' asthma care
50 with families, school personnel, and medical providers showed that students who participated in the intervention had fewer school absences, experienced significantly fewer emergency department visits, and fewer hospital days than those who received the usual level of care (Levy et al. 2006) While this level of nurse involvement would be time intensive it could prove helpful in schools where asthma is severely impacting the student body In addition to the OAS program there are good online sources of inf ormation for children educational computer game called Quest for the Code Foundation) It is designed to teach 7 15 year olds about asthma Celebrities guide players through an asthma adventure In addition to educational games for several other chronic diseases, Starlight provides a community where chronically ill teens can talk to each other This will be a good resour ce for these elementary students in the future Another online resource is the U.S EPA They have several publications available for downloading at no cost at www.epa.gov/ asthma/publications.html crosswords, mazes, and other activities Since asthma is more prevalent in disadvantaged socioeconomic groups, it is important to make sure information is available for parents of all readi ng levels and languages The EPA provides an quality of life called Help Your Child Gain Control Over Asthma It has advice on simple ways to reduce common asthma triggers and explains asthma action
51 plans There are also several other more detailed documents on asthma on this site and most of them are available in multiple languages. There are several different formats for action plans available The important information it needs to have is medications, emergency numbers, and what to do in the case of an attack They responsible for the child including thei r teachers and coaches Templates for Managing Asthma in the School Environment Handing out action cards would be easy for d well being It would gifted teachers, would know that the child had asthma and knew the proper procedure in the case of an attack Managing Asthma in the School Environmen t also contains 10 simple Indoor Air Quality Tools for Schools (IAQ TfS) Action Kit IAQ TfS Action Kit can be found at www.epa.gov/iaq/schools/tools4s2 .html This kit provides low or no cost ways of improving indoor air quality for schools and school districts using in house staff There are checklists for teachers and school staff to determine the current indoor air quality and to show areas that need improvement Poor indoor air quality can result in increased absenteeism, poor health, and lower productivity for students, teachers, and staff Improvements in air quality can help save schools money in the long term by reducing these negative side eff ects.
52 Initiating Change: Creating an Asthma Friendly School helpful as well It is designed to help asthma advocates persuade their community on the importance of asthma friendly schools There is a guide to help schools determine how asthma friendly they are and power points that can be presented at meetings They explain the basics of asthma and what schools can do to help They offer advice on planning and maintaini ng an asthma management program The National Heart, Lung, and Blood Institute (NHLBI) has similar information plus samples of elementary class curriculums dealing with asthma and an assessment sheet for nurses to determine how well an asthma action plan is working for a student at http://www.nhlbi.nih.gov/ health/prof/lung/ Friendly Schools Initiative is a planning tool that provi des a framework for the community and school to achieve their goals Some of the resources it provides that may be of special interest to teachers are the emergency response poster, which would be a good reference if a child has an attack in the classroom, and the one page summary about the management of an acute asthma episode in the school This summary has a description of what to look for, what to listen for, what to do during an attack, and whe n to seek emergency medical attention A major improvement that schools can make with little effort is to minimize school bus idling Diesel fumes have negative health consequences and can exacerbate asthma (Hao et a l. 2003) Additionally it will save the school system money on gas and prolong engine life due to reduced wear and tear According
53 to the EPA, students spend an average of an hour and a half on the bus, so retrofitting older buses with better emission c ontrol technologies and replacing the oldest buses with less polluting buses is also important ( U.S. Environmental Protection Agency 2008b) At www.epa.gov/cleanschoolbus/ there is advice on how to accomplish these goals, including funding suggestions Successful programs have also been developed to reduce car idling at school pick up and drop off areas A compilation of free sources for idle reduction programs targeting parents and driver s of personal automobiles is available online at http://www.idlefreebc.ca/resources/downloads/ IdleFreeResources/Links_to_Anti Idling_School_Programs.pdf Interestingly, it appears that just putting signs up to ask drivers to stop idling was ineffective, while the signs plus information cards and reminder stickers for their windshield were very effective (Mckenzie Mohr Associates and Lura Consulting 2008) Increasing air quality will help students who a re sensitive to these pollutants and Although there are obstacles for implementing any school program, these resources will help schools overcome knowledge barriers and give them a solid framework to begin formulating their plans Alachua County has high rates of asthma so education and prevention must become a priority.
55 Appendix B The length of each bar plotted for a given direction indicates the percenta ge of the time the wind came from that direction The percentage of time for a given velocity is shown by the thickness of the direction bar Each bar is separated by 22.5 degrees measured from true north (Gainesville Regional Utilities 2004b)
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