The important contribution to infant morbidity from bronchiolitis is no surprise to practicing pediatricians. The consistent wintertime epidemic of wheezing patients and worried parents makes annual impressions. Less wellknown and understood is the rising rate of hospitalization for this disease.
It is estimated that 1 % of infants with respiratory syncytial virus (RSV) lower respiratory tract disease require hospitalization.1 A number of efforts to estimate the national incidence of bronchiolitis hospitalizations have been undertaken in recent years in both Canada and the United States.2"4 These studies consistently indicate trends of increasing incidence during the past 2 decades in the United States and Canada, with rates more than doubling for infants.2
The most recent data available for the United States indicate bronchiolitis is the leading cause of infant hospitalization. Overall, the annual US hospitalization rate between 1997 and 2000 was 23 per 1,000 infants.3 The rise in rates cannot be explained by shifting diagnostic criteria. National rates for other lower respiratory tract diseases, such as asthma and pneumonia, were roughly stable for infants during this same period.2 Other possible explanations include the increasing numbers of and survival rates for premature infants, use of pulse oximetry, and increased daycare attendance.2"5 Although these factors may partially explain the increase, it is difficult to attribute a doubling of the rate to them. The theory that ambient air pollution may play a role in infant bronchiolitis has been raised recently6 (Karr C, unpublished data, 2004).
Criteria Air Pollutants Linked to Pediatric Respiratory Disease: Sources and Observed Health Effects
AIR POLLUTION AND PEDIATRIC RESPIRATORY DISEASE
A number of regulated outdoor air pollutants consistently have been linked to pediatric respiratory diseases. The US Environmental Protection Agency (EPA) has established national regulatory standards for five "criteria" air pollutants that have known respiratory health effects. These are ozone, carbon monoxide, nitrogen oxides, sulfur dioxide, and respirable particulate matter in two size ranges. PM10 refers to those particles less than 10 um in aerodynamic diameter and PM25 refers to "fine fraction" matter, or those particles less than 2.5 pm in aerodynamic diameter. Fine (PM^sub 2.5^) particulate standards were established in 1997 because of concern that toxicity of respirable particles is largely due to the fine particles.
Health concerns for children were a major reason for revisions of the EPA standards, also in 1997, which included the introduction of the fine particulate standard and a lowered ozone standard. The primary sources and health concerns of these criteria pollutants are summarized in Table 1. Traffic chiefly is responsible for the majority of the outdoor air pollutants of concern.
Asthma has been associated with increases in ozone, particulate matter, nitrogen dioxide, carbon monoxide, and sulfur dioxide. Health effects reported include increased symptom reporting, medication use, emergency department visits, or hospitalizations.711 In addition, negative effects on pulmonary function growth have been associated with exposure to particulate matter, ozone, and nitrogen dioxide.13 Particulate, ozone, sulfur dioxide, carbon monoxide, and nitrogen dioxide have also all been linked to increased hospitalization for respiratory infections or all respiratory disease.8·13·14
Most pediatric studies focus on preschool- and school-aged children. Some studies include infants, but only as part of a larger cohort that aggregates them with older children and aggregates diagnostic categories. Studies focusing on effects of air pollution specifically on infants are fewer. However, infant mortality studies have been undertaken in the Czech Republic,15 Korea,16 Mexico,17 and the United States.18 These have investigated overall and respiratory specific mortality and demonstrate the most consistent and sizeable increased risk is for exposure to particulate matter. Both acute and chronic exposure scenarios have been investigated. The US-based study evaluated the chronic effect (mean of daily average during the first 2 months of life) for PM10 ambient air pollution.18 A modest increase in PM10 (10 pg/m3) was associated with a 20% increase in deaths due to respiratory causes among normal-birth- weight infants.
Currently, no published epidemiologic data directly address the role of outdoor air pollutants in infant bronchiolitis. However, Chilean investigators completed a study describing increased risk for "wheezing bronchitis" among infants exposed to high levels of PM2 5.6 The study followed a cohort of 500 Santiago infants from ages 4 months to 1 year with monthly clinic visits. Wheezing bronchitis is described by these investigators as an acute onset episode of bronchial obstruction characterized by cough and wheeze and wet or dry rhonchi on clinical exam, with or without runny nose or fever, usually lasting less than 2 weeks. This is consistent with the illness termed "bronchiolitis" in the United States. It also would be termed asthma, however, particularly after two prior episodes.
These investigators evaluated 24hour average PM2 5 levels lagged from 1 to 15 days prior to onset of this illness. An increase of 10 pg/m3 in PM2.5 was related to a 5% increase (95%, confidence interval of 0% to 9%) in diagnosis of wheezing bronchitis for a lag of 1 day. The association also was present for different lags but without a clear pattern. The maximum association was observed at a lag of 9 days (9%; 95%, confidence interval of 6% to 12%).
Also investigated for similar lags were 24-hour averages of sulfur dioxide and nitrogen dioxide. Significant effects were observed for only one lag for each pollutant. A 10 ppb increase in nitrogen dioxide was associated with a 7% increase (95% confidence interval of 2% to 14%) after a 7-day lag. A 10 ppb increase in sulfur dioxide was associated with a 21% increase (95% confidence interval of 8% to 39%) after a 7-day lag.
The US EPA Air Quality Index
Strengths of this study include close patient follow-up allowing primary collection of information on numerous potential confounders, including exposure to environmental tobacco smoke, socioeconomic status, household crowding, family history of atopy, heating and cooking practices, and breastfeeding practices. Gender, socioeconomic status, family history of asthma, minimum temperature, and number of older siblings were found to be significantly related to wheezing bronchitis. Interestingly, exposure to environmental tobacco smoke, type of heating, and status of breastfeeding were not found to be significantly related to the outcome and were not included in the final model estimating risk.
Applicability of this finding to US infants is problematic. The setting of this study presented relatively higher exposure than typically occurs in most US locations, and the contribution of diesel fuel was also greater. For example, during the time of the study (1995 to 1996), fine particulate levels exceeded EPA standards on approximately 50% of the fall and winter month days, and diesel traffic contributed approximately 80% of the fine particulate air pollution. In contrast, in the South Coast Air Basin of southern California, one area of the United States with the highest levels of air pollution, fewer than 6% of days monitored exceeded the standard in 1999; most areas exceeded the standard only 1% to 2% of days. For most urban areas of the United States, diesel contributes only 10% to 35% of the fine particulate air pollution.19
SUSCEPTIBILITY OF INFANTS TO AIR POLLUTION'S TOXIC EFFECTS
Data to support or refute a role of ambient air pollution in the burden of infant bronchiolitis are inadequate, although the emerging pediatric data previously mentioned raise the possibility. In addition, a number of unique features of the infant respiratory system suggest that infants may be particularly susceptible to air pollution's toxic effects.20-22
To appreciate how this translates to an increased risk for bronchiolitis requires an understanding of the pathophysiology of bronchiolitis. After infection and several days of incubation and replication in the nasopharyngeal epithelium, the viral agent spreads to the lower respiratory tract. In small airways, the virus initiates release of inflammatory mediators, cell lysis, and cell necrosis. Edema and excess mucous production ensues with the regeneration of nonciliated epithelial cells. These changes cause the hyperinflation and atelectasis that produce respiratory distress and derangement in air exchange observed clinically.
The pathogenic mechanisms of pollutants on the respiratory system are an area of ongoing toxicological study but also generally reflect pro-inflammatory immune modulation and cell lysis. Mechanisms of ozone and particulate matter have received the most attention and involve both oxidative stress and induction of cytokine expression by epithelial cells and macrophages leading to inflammation.23·24
Compared with adults, the peripheral airway is both relatively and absolutely smaller in infancy, allowing intralumenal debris to cause proportionately greater obstruction. In addition, infants have relatively more mucous glands, with concomitant increase in secretions.25 Infants also have potential for increased edema because their airway mucosa are less tightly adherent.25 There are fewer pores of Kohn in the infant, producing a negative effect on collateral ventilation and increasing the likelihood of hyperinflation or atelectasis.25 Infants are also at risk due to their potential for greater exposure to air pollutants. The resting minute ventilation normalized for body weight is more than double in a newborn infant, at 400 cc/kg per minute, compared with an adult, at 150 cc/kg per minute.20
One of the most well-recognized and significant risk factors for infant bronchiolitis is indoor air pollution, in the form of environmental tobacco smoke. While outdoor air pollution is suspected to play a role, a review of the literature shows adequate evidence is lacking. Epidemiologic studies designed to address infant bronchiolitis and exposure to routinely encountered variation in ambient air pollutants are in progress6 (Karr C, unpublished data, 2004).
In the meantime, a precautionary approach to exposure control is appropriate. In addition to counseling regarding the protective role of breastfeeding, frequent hand washing, and avoidance of environmental tobacco smoke, families should be educated regarding the air quality index (AQI).26 Most large metropolitan areas are required to monitor air quality regularly, and the result of this monitoring is expressed as the AQI. The AQI converts the concentration of carbon monoxide, ozone, nitrogen dioxide, sulfur dioxide and particulate matter into one number, scaled from 0 to 500. The AQI of 100 corresponds to the short-term air quality standard. Thus, a value greater than 100 indicates the concentration of one or more pollutants exceeds its national standards. Information about air quality is often available through local news media. Table 2 (see page 457) summarizes this index and advisory statements for older children and adults. Parents may adapt this to limit infant exposure to outdoor environments on days when the AQI exceeds 200.
SUMMARY Bronchiolitis is the leading cause of infant morbidity, and hospitalization rates are rising. The effect of this disease is not limited to the acute illness episode. Approximately 40% to 50% of children diagnosed with bronchiolitis suffer from subsequent wheezing and airway reactivity or asthma.27·28 Attempts to address the burden of this disease via vaccine development have been largely unsuccessful, and treatment is purely supportive rather than curative.
As such, primary prevention is paramount. If outdoor air pollution exacerbates this disease, as has been found for other pediatric respiratory diseases, actions to ensure that regulatory standards protect this vulnerable population will be paramount.
Increased anatomic and physiologic susceptibility to the pro-inflammatory effects of air pollutants, coupled with the pro-inflammatory response in bronchiolitis, underlies the concern that infants exposed to higher levels of ambient air pollutants may be at increased risk for developing more severe bronchiolitis requiring hospitalization.
1. Panitch HB. Bronchiolitis in infants. Curr Opin Pediatr. 2001;13(3):256-260.
2. Shay DK, Holman RC, Newman RD, et ai. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282( 15): 1440- 1446.
3. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143(5 Suppl):S127-S132.
4. Langley JM, LeBlanc JC, Smith B, Wang EE. Increasing incidence of hospitalization for bronchiolitis among Canadian children, 1980-2000. J Infect Dis. 2003; 188(1 1):17641767.
5. Mallory MD, Shay DK, Garrett J, Bordley WC. Bronchiolitis management preferences and the influence of pulse oximetry and respiratory rate on the decision to admit. Pediatrics. 2003? I Ì(ì):&i5-e5ì.
6. Pino P, Walter T, Oyarzun M, Villegas R, Romieu I. Fine particulate levels and the incidence of wheezing illness in the first year of life. Epidemiology. 2004. In press.
7. Buchdahl R, Willems CD, Vander M, Babiker A. Associations between ambient ozone, hydrocarbons, and childhood wheezy episodes: a prospective observational study in south east London. Occup Environ Med. 2000;57(2):86-93.
8. Braga AL, Saldiva PH, Pereira LA, et al. Health effects of air pollution exposure on children and adolescents in Sao Paulo, Brazil. Pediatr Pulmonal. 200 1;3 1(2): 106-1 13.
9. Chauhan AJ, Inskip HM, Linaker CH, et al. Personal exposure to nitrogen dioxide (N02) and the severity of virus-induced asthma in children. Lancet. 2003:361(9373): 1939-1944.
10. Lee JT, Kim H, Song H, et al. Air pollution and asthma among children in Seoul, Korea. Epidemiology. 2002; 13(4):48 1-484.
1 1. Hajat S, Haines A, Goubet SA, Atkinson RW, Anderson HR. Association of air pollution with daily GP consultations for asthma and other lower respiratory conditions in London. Thorax. 1999;54(7):597-605.
12. Kunzli N, McConnelI R, Bates D, et al. Breathless in Los Angeles: the exhausting search for clean air. Am J Public Health. 2003:93(9): 1494- 1499.
13. Burnett RT, Smith-Doiron M, Stieb D, et al. Association between ozone and hospitalization for acute respiratory diseases in children less than 2 years of age. Am J Epidemiol. 2001;153(5):444-452.
14. Lin CA, Martins MA, Farhat SC, et al. Air pollution and respiratory illness of children in Sao Paulo, Brazil. Paediatr Perinea Epidemiol. 1999;13(4):475^88.
15. Bobak M, Leon DA. The effect of air pollution on infant mortality appears specific for respiratory causes in the postneonatal period. Epidemiology. 1999;10(6):666-670.
16. Ha EH, Lee JT, Kim H, et al. Infant susceptibility of mortality to air pollution in Seoul, South Korea. Pediatrics. 2003;111(2):284290.
17. Loomis D, Castillejos M, Gold DR, McDonnell W, Borja-Aburto VH. Air pollution and infant mortality in Mexico City. Epidemiology. 1999; 10(2): 1 18-123.
18. Woodruff TJ, Grillo J, Schoendorf KC. The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environ Health Perspect. 1997;105(6):608-612.
19. Health Assessment Document for Diesel Engine Exhaust. Washington, DC: US Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment. 2002. EPA publication 600/8-90/057F.
20. Teague WG, Bayer CW. Outdoor air pollution. Asthma and other concerns. Pediatr Clin North Am. 2001;48(5):1 167-1 183.
21. Bates DV. The effects of air pollution on children. Environ Health Perspect. 1995;103(Suppl6):49-53.
22. American Academy of Pediatrics Committee on Environmental Health. Special considerations based on age and developmental stage. In: Etzel RA, ed. Pediatric Environmental Health. Elk Grove Village, IL: American Academy of Pediatrics; 2003.
23. Pope CA 3rd. Epidemiology of fine particulate air pollution and human health: biologic mechanisms and who's at risk? Environ Health Perspect. 2000;108(Suppl 4):7 13-723.
24. Stone V. Environmental air pollution. Am J Respir Crit Care Med. 2000; 162(2 Pt 2):S44S47.
25. Bar-on ME, Zanga JR. Bronchiolitis. Prim Care. 1996;23(4):805-819.
26. Air Quality Index. Available at: http://www. epa.gov/aimow/aqibroch/. Accessed May 19, 2004.
27. Staat MA. Respiratory syncytial virus infections in children. Semin Respir Infect. 2002; 17(1): 15-20.
28. Piedimonte G, Simoes EA. Respiratory syncytial virus and subsequent asthma: one step closer to unravelling the Gordian knot? Eur Respir/. 2002;20(3):5I5-517.
Criteria Air Pollutants Linked to Pediatric Respiratory Disease: Sources and Observed Health Effects
The US EPA Air Quality Index