Objectives. The Present and Future of Asthma: Birth Cohorts & Public Health Devon A. Greene, MD, MPH June 11, What is Asthma.

Transcription

1 The Present and Future of : Birth Cohorts & Public Health Devon A. Greene, MD, MPH June 11, 2014 Objectives Become familiar with the evidence from available long-term studies on the natural history of asthma. Discuss the role of health disparities in asthma. Discuss current strategies for impacting asthma management. Disclosures What is I have no disclosures. Chronic inflammatory disorder of the airways. Many cells play a role in particular mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. Inflammation causes smooth muscle hypertrophy, bronchial hyperresponsiveness to a variety of stimuli. Inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Episodes associated with variable airflow obstruction which is reversible spontaneously or with treatment. Epidemiology Epidemiology Affects million children. About 5% of general population. Most children develop asthma before age 8 (1/2 before age 3). There s been an increase of 40% in the past decade. Blacks: 5-8% prevalence. Roughly 300 children die of asthma each year. Gender Prior to puberty, asthma is more frequent in boys. In adolescence, the difference equalizes. Adult onset more frequent in women. Hispanic population adolescent males twice as likely as females. 1

2 Burden Cohort Studies accounted for 1.75 million ED visits in One of the most frequent reasons for admission of children to hospitals. Accounts for million missed school days annually for children. About 1/2 of the billions spent annually on asthma is on ED visits and hospitalizations. Natural History of Symptoms in Children Tucson Children s Respiratory Study followed 1,246 unselected subjects from birth until age 6 (66% completed study). 48% of parents reported wheezing at some point, and 3 patterns were recognized. 20% presented with transient wheezing. 15% presented with late-onset wheezing (after age 3). 14% had persistent wheezing. Persistent and late-onset wheezing was associated with atopy. Natural History of Symptoms in Children British Avon Longitudinal Study of Parents and Children (ALSPAC) 45% of 14, 062 unselected children wheezed. 7 time points from birth to 7 years of age assessed. Wheezy phenotypes were analyzed without any specific hypothesis about specific temporal phenotypes. Temporal wheezing patterns and risk factors of Tucson study confirmed, along with an additional intermediate-onset wheeze (onset after 18 months of age) and early prolonged wheeze (wheezing in first year of life, with remission by 69 months of age). Martinez, FD, et al. and wheezing in the first six years of life. New England Journal of Medicine : iations of wheezing phenotypes in the first 6 years of life with atopy, lung function, and airway responsiveness in mid-childhood. T Natural History of Symptoms in Children Predictive Index was developed as a result of the Tucson Children s Respiratory Study. Children younger than 3 years who have had 4 or more significant wheezing episodes in the past year are much more likely to have persistent (lifelong) asthma after 5 years if: One major decisive factor Parent with asthma Physician diagnosis of eczema (atopic dermatitis) Sensitivity to aeroallergens Or two minor decisive factors Food allergies Greater than 4% blood eosinophils Wheezing apart from colds A positive Predictive Index in a 2 or 3 year-old child leads to an 80% chance of a child having the diagnosis of asthma when entering first grade. 2

3 Natural History of Symptoms in Children Melbourne Study In 1964, 295 wheezy 7 year-olds and 106 controls were followed. 83 children with severe asthma were added at 10 years of age. 83% of cohort provided information at 42 years of age. 20% of children with asthma at age 7 had persistent symptoms as adults. 50% of severe group added at age 10 had persistent symptoms as adults. Eczema, hay fever, or allergic sensitization in childhood increased the risk of continued disease later in life. Wolfe, R., et al. Association between allergy and asthma from childhood to middle adulthood in an Australian cohort study. Am J Resp Crit Care Med : Natural History of Symptoms in Children Other cohort studies have found that 27% of children with wheeze or asthma at 7 years of age continue to wheeze into adulthood. Dunedin Multidisciplinary Health and Development Study British 1958 Birth Cohort Follow-up of the Tucson Children s Respiratory Study suggested wheezing patterns did not change significantly from 6 to 16 years of age. Bisgaard, H, and K Bonnelykke. Long-term studies of the natural history of asthma in childhood. Clinical Reviews in Allergy and Immunology : at school age is associated with reduced lung function, particularly in patients with severe disease The ALSPAC birth cohort suggested all wheezy phenotypes were associated with impaired lung function by school age. Is loss of lung function associated with asthma a cause or a consequence of the disease? Henderson, J, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function, and airway responsiveness in mid-childhood. Thorax 2008; 66: Tucson Children s Respiratory Study 125 unselected infants An association exists between early airflow limitation and any wheeze in infancy. An association exists between neonatal airflow limitation and development of transient early wheeze. Children with persistent wheeze at 6 years of age had normal infant lung function but significantly reduced spirometry at 6 years of age. Martinez, FD, et al. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. New England Journal of Medicine : Martinez, FD, et al. Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life. Am Rev Respir Dis : Perth Cohort Study 243 unselected infants An association between early airflow limitation and any wheeze in infancy exists. No relationship between early airflow limitation and development of early transient wheeze. Persistent wheeze at 4-6 years and 11 years old was associated with lung function deficit in neonates, and did not seem to progress with time. Young, S., et al. Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma. Journal of Pediatrics : Young, S., et al. The association between early life lung function and wheezing during the first 2 years of life. Eur Respir J : Turner, SW., et al. The relationship between infant airway function, childhood airway responsiveness, and asthma. Am J Respir Crit Care Med : Copenhagen Study on in Childhood (COPSAC) 411 children born of mothers with history of asthma. Exhaled nitric oxide levels were increased in 1 mo symptom-free patients who developed transient wheeze but not persistent wheeze. Nitric oxide levels were unrelated to infant lung function, but suggested a premorbid pathology independent of lung function abnormalities and present in asymptomatic neonates. Chawes, BL, et al. Elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze. Am J Respir Crit Care Med :

4 Melbourne Cohort Children originally classified as having asthma had consistently lower FEV1/FVC ratios vs. controls. No progression of lung function decline was observed during 7 year follow-ups until age 42. Symptoms did persist throughout the follow-up period. Phelan, PD, CF Robertson, and A Olinsky. The Melbourne Study: J Allergy Clin Immunol : Childhood Management Program (CAMP) 1041 asthmatic children 5-12 years of age participating in a trial of anti-inflammatory treatment from 4-6 years with further observation of 4 years. In CAMP, increased airway obstruction was observed from 5 to 18 years of age in children with mild-moderate asthma but only when compared with an external cohort of healthy children. Approximately 1 in 4 children had a 1 percent per year or worse decline in FEV1 percent predicted, although this did not correlate with a change in disease symptoms. Strunk, RC, et al. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol : Viruses Studies The Childhood Origins of birth cohort (COAST) 289 children at high risk for asthma focused on viral infections during wheezy episodes in the first year of life. Rhinovirus appeared to be a strong predictor of asthma by age 6. Hospitalization secondary to RSV lower respiratory tract infection has been associated with asthma, atopy, and early wheezing symptoms. Direction of causality remains unknown: do certain viral infections increase the risk of asthma or does the underlying cause of asthma increase the risk of severe response to viral infections? ckson, DJ, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med : 667- Sigurs, N, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med : Bacteria Studies Bacterial colonization is a major exposure in a newborn. Hygiene Hypothesis? Prospective studies have found no association between infant gut microbiota and risk of recurrent wheeze before 2 years of age. COPSAC showed a strong association between colonization of the airways with common pathogenic bacteria and development of asthma by 5 years of age. Remains unknown whether bacterial colonization acts as the environmental trigger in genetically predisposed persons or whether this colonization is merely a marker of the underlying genetic cause of asthma. Bisgaard, H, and K Bonnelykke. Long-term studies of the natural history of asthma in childhood. Clinical Reviews in Allergy and Immunology : Studies Urban Environment and Childhood (URECA). 560 patient birth cohort at high risk for asthma. 86% assessed at 3 years of age. Factors associated with recurrent wheezing: Annual family income < $15,000 Allergen exposure over the first 3 years of life was associated with recurrent wheezing. First-year exposure to cockroach, mouse, and cat allergens was found to be protective. An additive reduction in wheeze was observed with exposure to more than one allergen. Bisgaard, H, and K Bonnelykke. Long-term studies of the natural history of asthma in childhood. Clinical Reviews in Allergy and Immunology : Lower birth weight and gestational age Relative bacterial richness was significantly lower in those Number of smokers in the home children who developed atopy and/or wheezing. Lynch, SV, et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. Journal of Allergy Clin Immunol Retrieved from 4

5 Tobacco Exposure Studies Strongest known environmental modifier in the natural history of asthma. Mother s smoking status was associated with a 7% deficit in lung function among newborns in the COPSAC cohort. Prenatal and postnatal smoke exposure has been linked to asthma and wheezing, particularly to disease in the first years of life and less strongly to later in life. Bisgaard, H, et al. Prenatal deterinants of neonatal lung function in high-risk newborns. J Allergy Clin Immunol : Allergic Sensitization Studies The German Multicenter Allergy Study (MAS) cohort showed that early and persistent sensitization was associated with asthma. Specifically, this association was noted was noted in children with a family history of atopy, indicating some genetic factor is involved. High levels of early allergen exposure combined with sensitization to perennial allergens before 3 years of age were associated with loss of lung function and development of airway hyper-responsiveness at school age. Illi, S, et al. The pattern of atopic sensitization is associated with the development of asthma in childhood.\ J Allergy Clin Immunol : Air Pollution Studies Studies using experimental models suggest particulate matter, including diesel exhaust) has immunologic and epigenetic effects influencing wheezing phenotypes and allergic sensitization. Southern California Children s Health Study (CHS) evaluated asthma incidence in 2,057 schoolchildren in 12 communities, measuring traffic-related air pollutants as high or low. High lung function testing at the start of the study was associated with low risk for asthma, but this effect was attenuated in children living in areas with high pollution. Braback, L, and Forsberg, B. Does traffic exhaust contribute to the development of asthma and allergic sensitization in children: findings from recent cohort studies. Environmental Health : Studies Air Pollution Traffic congestion may have a greater impact on asthma than traffic flow. In this study, evidence of higher socioeconomic status was associated with increased ED visits for asthma. Pereira, G, De Vos, AJBM, and Cook, A. Residential traffic exposure and children s emergency presentation for asthma: a spatial study. International Journal of Health Geographics : Studies Antibiotics Longitudinal cohort study in British Columbia consists of all live births from Jan 1997 through Dec 2013 (n = 251,817). Antibiotic exposure in the first year of life was associated with a small risk of developing asthma in early childhood. Increased number of antibiotic exposures was associated with increased asthma risk, with the highest risk in those children with > 4 courses of antibiotics. All antibiotics were associated with increased risk of developing asthma, with the exception of sulfonamides. Marra, F, et al. Antibiotic Use in Children is associated with increased risk of asthma. Pediatrics : Marra, F, et al. Antibiotic Use in Children is associated with increased risk of asthma. Pediatrics :

6 Acetaminophen Studies Acetaminophen is thought to interfere with the antioxidant glutathione, which can result in endothelial damage in the lungs, particularly during viral infections. Acetaminophen has been associated with wheezing and asthma. Multiple studies have not statistically accounted for viral infections. According to Wickens et al. increasing doses of acetaminophen appeared to increase risk for wheeze, recurrent asthma, and atopy. Kim, H and CC Johnson. The association between acetaminophen and asthma: is there anything to learn from the upper airways Curr Opin Allergy Immunol : Genetics Studies It is likely that genetics contributes to the different clinical phenotypes of asthma Genes associated with asthma. Filaggrin (FLG)- a skin barrier protein. Strongly associated with development of atopic dermatitis. Chromosome 17q21 locus (ORMDL3). Associated with nonatopic asthma phenotype characterized by bronchial hyperresponsiveness in newborns and early onset acute asthma exacerbations. DENND1B - involved in adaptive immune response. Risk factor in both white and African-American populations. Bisgaard, H, and K Bonnelykke. Long-term studies of the natural history of asthma in childhood. Clinical Reviews in Allergy and Immunology : Advantages and Limitations of Cohort Studies Advantages Suitable for studying rare exposures. Allow for studying more than one outcome. No temporal ambiguity between exposure and outcome. Less prone to bias than case-control and crosssectional studies. Advantages and Limitations of Cohort Limitations Studies Expensive Time-consuming Not appropriate for studying rare outcomes Observational studies can only suggest associations. Confounding of associations in observational long-term studies remains a risk, despite extensive attempts to adjust for covariates, because underlying variables are either unknown or unavailable. Advantages and Limitations of Cohort Studies Limitations Loss to follow-up, in which adherence might relate to symptoms or risk, is critical in long-term studies Some follow-up studies include only a fraction of the original cohort with a potential bias from overrepresentation of symptomatic subjects and loss of external validity 6

7 Health Disparities and Health Disparity: a chain of events signified by a difference in: environment access to, utilization of, and quality of care Health Disparities and Effective asthma management depends on factors such as: Access to care Education Understanding of therapies health status a particular health outcome that deserves scrutiny If a health outcome is seen in a greater or lesser extent between populations, there is disparity Adherence to prescribed regimens Affordability of treatments/care Treatment efficacy Many of these factors are linked to socioeconomic status Homer, C.J., et al. Does quality of care affect rates of hospitalization for childhood asthma? Pediatrics : Health Disparities and Poverty is often associated with Reduced access to health care Lower quality of health care Reduced continuity of care Poor housing Increased exposure to pollution and tobacco smoke Lower education Premature birth Higher rates of respiratory infection These factors have been linked to higher admission rates in the pediatric asthma population Halfon, N. and Newacheck, P.W. Childhood asthma and poverty: differential impacts and utilization of health services. Pediatrics : Capitals St. Louis, MO 2 Milwaukee, WI 3 Birmingham, AL 4 Chattanooga, TN 5 Charlotte, VA 6 Memphis, TN 7 Knoxville, TN Capitals 2010 Capitals Richmond, VA 2 St. Louis, MO 3 Chattanooga, TN 4 Knoxville, TN 5 Milwaukee, WI 6 Memphis, TN 7 Tulsa, OK 1 Richmond, VA 2 Knoxville, TN 3 Memphis, TN 4 Chattanooga, TN 5 St. Louis, MO 6 Augusta, GA 7 Virginia Beach, VA 7

8 Capitals 2012 Capitals Memphis, TN 2 New Haven, CT 3 Knoxville, TN 4 Pittsburgh, PA 5 Chattanooga, TN 6 Hartford, CT 7 St. Louis, MO 1 Richmond, VA 2 Chattanooga, TN 3 Memphis, TN 4 Philadelphia, PA 5 Oklahoma City, OK 6 Detroit, MI 7 Dayton, OH Capitals Richmond, VA 2 Memphis, TN 3 McAllen, TX 4 Oklahoma City, OK 5 Philadelphia, PA 6 Chattanooga, TN 7 Fresno, CA Health Disparities,, and Tennessee State of Tennessee Task Force (STAT) Over 750,000 Tennesseans are estimated to have asthma. Among children in Tennessee schools reporting a chronic disease, 42.1% identify that disease as asthma. In 2006, the death rate due to asthma was 13.1 per 1,000,000 in Tennessee. Rates were similar for males (12.6) and females (13.7), though mortality was significantly higher for African-Americans (33.1) than for Caucasians (9.4). State of Tennessee Taskforce (2009). STAT plan to reduce asthma in Tennessee, Retrieved from Health Disparities and provides an example of the relationships that exist between environmental risk factors, socioeconomic vulnerability, and poor health. and asthma attack prevalence, 2002 Joseph, C.L. et al. Applying epidemiologic concepts of primary, secondary, and tertiary prevention to the elimination of racial disparities in asthma. Journal of Allergy and Clinical Immunology (2): 233. A variety of outdoor and indoor triggers may impact severity and control of asthma Many triggers are linked to low socioeconomic status Children from low-income homes are more likely to have asthma; they are also more likely to be exposed to environmental triggers in their homes, schools, and communities. McDaniel, M., Paxson, C., and Waldfogel, J. Racial disparities in childhood asthma in the United States: evidence from the National Health Interview Survey, Pediatrics (5): e868-e877. 8

9 Health Disparities and Triggers Animal dander Dust mites Cockroaches Pollen Mold Tobacco smoke Air pollutants (ozone, etc) Strong odors or scented products Triggers Cold air or weather changes Physical exertion (exercise) Strong emotions or stress Certain medications Sulfites GERD Respiratory infections State of Tennessee Taskforce (2009). STAT plan to reduce asthma in Tennessee, Retrieved from Addressing Health Disparities in Primary Prevention: prevents an illness or injury from ever occurring, by preventing exposure to risk factors. Secondary Prevention: minimize the severity of the illness or the damage due to an injury-causing event once that event has occurred. Tertiary Prevention: medical treatment and rehabilitation services that seek to mitigate disability. Joseph, CLM, et al. Applying epidemiologic concepts of primary, secondary, and tertiary prevention to the elimination of racial disparities in asthma. J Allergy Clin Immunol : Addressing Health Disparities in Primary Prevention: prevent exposures to potential instigators of phenotypic asthma Secondary Prevention: Early detection of asthma Classifying Severity in Patients Not Taking Long-term Controller Medication (Children 5-11 Years) Components of Severity Impairment Symptoms Nighttime awakenings SABA use for symptom control (not prevention of EIB) Interference with normal activity Intermittent (step 1) 2 days/week 2x/month 2 days/week Mild (step 2) >2 days/week but not daily 3-4x/month >2 days/week but not daily Daily >1x/week but not nightly Daily Persistent Moderate (step 3) Severe (step 3 or 4) Throughout the day Often 7x/week Several times per day None Minor limitation Some limitation Extremely limited Impact attitudes and beliefs about treatment Reduce obesity Reduce stress and violence Improve access to health care and health care delivery Tertiary Prevention: management Joseph, CLM, et al. Applying epidemiologic concepts of primary, secondary, and tertiary prevention to the elimination of racial disparities in asthma. J Allergy Clin Immunol : Risk Lung function Exacerbations requiring oral systemic corticosteroids Normal FEV1 when well FEV1 >80% predicted FEV1/FVC >85% 0-1/year EIB=exercise-induced bronchospasm; FVC=forced vital capacity. FEV1 80% predicted FEV1/FVC >80% 2/year FEV1=60%-80% predicted FEV1/FVC =75%-80% Consider severity and interval since last exacerbation. FEV1 <60% predicted FEV1/FVC <75% Frequency and severity may fluctuate over time for patients in any severity category. Relative annual risk of exacerbations may be related to FEV1. National Education and Prevention Program (NAEPP) Expert Panel Report 3 (EPR-3) Guidelines for the Diagnosis and Management of Full Report, Assessing Control in Children 5 to 11 Years of Age Components of Control Well Controlled Not Well Controlled Very Poorly Controlled Symptoms 2 days/week >2 days/week or multiple times on 2 days/week Throughout the day Nighttime awakenings 1x/month 2x/month 2x/week Impairment SABA use for symptom control (not prevention of EIB) 2 days/week >2 days/week Several times per day Interference with normal activity Lung function FEV 1 or peak flow FEV1/FVC Exacerbations requiring oral systemic corticosteroids None Some limitation Extremely limited 60%-80% predicted/ <60% predicted/ >80% predicted/ personal best personal best personal best 75%-80% <75% >80% 0-1/year 2/year Consider severity and interval since last exacerbation Spirometry Risk Reduction in lung growth Treatment-related adverse effects Evaluation requires long-term follow-up. Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in overall assessment of risk. National Education and Prevention Program (NAEPP) Expert Panel Report 3 (EPR- 3) Guidelines for the Diagnosis and Management of Full Report,

10 Management: Step Up/Step Down Step 1: SABA (Albuterol) as needed Step 2: Low-dose ICS Alternatives may include cromolyn, Leukotriene Antagonist (LTRA), or theophylline Step 3: Medium-dose ICS or Low-dose ICS + LABA, LTRA, or theophylline Step 4: Medium-dose ICS + LABA or Medium-dose ICS + LTRA, theophylline Step 5: High-dose ICS + LABA, possibly in association with oral systemic corticosteroids Action Plan With all steps, provide education on self-management and controlling environmental factors; management of co-morbidities, the word which properly signifies difficulty of breathing, has been as much misused, and has been made the cognomen of as many different diseases as any word in medicine. Questions? - Laennec,