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Nchh.orgAdvances in childhood asthma: Hygiene
hypothesis, natural history, and
Andrew H. Liu, MD,a and Stanley J. Szefler, MDb Denver, Colo
There is significant interest in early identification and inter-
vention in childhood asthma. Current asthma guidelines iden-
tify inhaled corticosteroids (ICS) as the preferred initial long-
term control therapy even in young children. ICS clearly
improve asthma control in children with mild to moderate per-
sistent asthma, but it is not clear that they can alter the natu-
ral history and progression of asthma. New insights regarding
the origins of asthma and allergy and their natural history will
continue to stimulate questions regarding the appropriate time
for intervention and will stimulate the design of new treatment
strategies and the discovery of new medications. (J Allergy
ICAM-1: Intercellular cell adhesion molecule 1 Clin Immunol 2003;111:S785-92.)
Key words: Asthma, children, hygiene, risk factors, management,
NHLBI: National Heart, Lung and Blood Institute In January 2002, Spahn and Szefler1 summarized key studies that formulated the current paradigm of asthma ORIGINS OF ASTHMA AND THE “HYGIENE
management for children. Several recent reports indicate HYPOTHESIS”
that the rate of asthma mortality and morbidity hasreached a plateau2,3; however, significant racial and ethic Many questions have been raised regarding the rea- disparities for asthma health care utilization and mortali- sons for the rise in prevalence of asthma and allergy ty remain.3 The next challenge is to see a decline in asth- despite improvements in health care and pharmacothera- ma mortality and morbidity in all subgroups of asthma py. In one recent example from Nottingham, UK of the patients (Table I). It might be possible to influence these rise in atopy, the prevalence of allergen sensitization in outcomes through a proactive approach for asthma based 18- to 80-year-old adults in 1991 was more than double on early diagnosis and intervention. This review will in the youngest (ie, 18–27 year olds) when compared summarize recent reports that relate to the origins and with the older 63- to 70-year-old adults (46% vs 21%, natural history of asthma and allergy, and therapeutic respectively).10 Nine years later, atopy prevalence for the strategies directed at early intervention and improved different age groups remained essentially unchanged as they became older, suggesting that higher atopy preva- Inhaled corticosteroids (ICS) are now considered the lence in young adults was not the result of a decline in cornerstone for managing persistent asthma even in atopy rate with aging, but from a prevalence rise that young children.4-6 New medications and delivery sys- began with those born between 1938 and 1946.
tems have been introduced, including a nebulized ICS for One proposition for this prevalence increase has been children as young as age 1.7 New initiatives to improve popularly called the “hygiene hypothesis.” If naturally medication labeling for young children have now made it occurring infections and microbial exposures can essen- possible to intervene at a very early age.8,9 tially immunize against asthma, then reductions in theseexposures over the past century may be a major factor inthe global rise in these conditions. In the past year, pro-lific hygiene hypothesis-related research has continued to From athe National Jewish Medical and Research Center, and bthe Universi- provide insights to these questions. In a large US study, ty of Colorado Health Sciences Center, Denver, Colo.
previous hepatitis A, Toxoplasma gondii, and herpes sim- Supported in part by Public Health Services Research Grants 1NO1-HR- plex virus 1 infections were associated with less asthma, 16048, HL36577, HL 51834, HL-04272 (Liu), General Clinical Research hay fever, and allergen sensitization, mirroring a similar Center Grant 5 MO1 RR00051 from the Division of Research Resources,and the NICHHD Pediatric Pharmacology Research Unit Network Grant study of Italian military cadets.11 Recent evidence in a mouse model of asthma of a new asthma susceptibility Reprint requests: Stanley J. Szefler, MD, National Jewish Medical and gene for T-cell membrane proteins that is homologous to Research Center, 1400 Jackson St, Rm B121, Denver, CO 80206.
the human hepatitis A receptor implicates hepatitis A and 2003 Mosby, Inc. All rights reserved.
its receptor as a possible gene-environment interaction in 0091-6749/2003 $30.00 + 0doi:10.1067/mai.2003.148 S786 Liu and Szefler
TABLE I. Consequences of poor asthma control
Leading hygiene hypothesis insights have also been gained through the study of naturally occurring endotoxin exposure. Endotoxin might be one example of how potent microbial component exposures may influence immune development without the potential harm of infections. An extensive history of endotoxin studies in humans, in basic Course of systemic glucocorticoid therapy research, and in rodent asthma models has identified fun- damental factors underlying outcomes from endotoxin Breakthrough symptoms—spontaneous or activity induced exposure. Timing of exposure relative to disease develop- Variability in pulmonary function because of airway sensitivity ment (eg, early life exposure), dose of exposure, nature of the stimulus, co-exposures, and genetics underlying the response are all expected to contribute.21 Longitudinal prospective birth cohort studies on endotoxin exposure in infancy and allergic and asthma outcomes are in their early stages but already suggest that endotoxin exposure in infancy is associated with less atopic dermatitis, as possi- ble evidence of an effect on the allergic march of early childhood.22 However, in this and another birth cohort Airway remodeling and irrecoverable loss of pulmonary function study of infants in Boston, greater endotoxin exposure was Adverse effects related to overuse of rescue therapy, for example, associated with more wheezing in infancy.23 bronchodilators and systemic glucocorticoids Endotoxin clinical studies may be particularly helpful as a prototypical gene-environment interaction with healthversus disease outcomes, as the specific receptors for endo- Furthering the concept that gastrointestinal microbes toxin and the associated cell signal cascades have been elu- may influence the development of asthma and allergy, cidated. For example, the importance of genetic polymor- some investigators have identified differences in the gas- phisms in one of endotoxin’s receptor/enhancer proteins, trointestinal flora of infants who develop allergic disease.
CD14, their functional consequences for CD14 expression, Allergic infants were gastrointestinal tract–colonized and their association with less allergen sensitization and with more clostridia and Staphylococcus aureus, where- IgE have been reviewed.24 Soluble CD14 is in high levels as nonallergic infants had more enterococci, bifidobacte- in breast milk, and breast-fed infants with atopic dermatitis ria, and bacteroides.13,14 Even differences in the vaginal were associated with lower sCD14 in the breast milk of microflora of pregnant women have been associated their mothers, piquing interest in the possible role of mater- recently with wheezing outcomes in early childhood.15 nally transferred sCD14, both pre- and postnatally.25 Meanwhile, in rural Africa, parasitic infestation with European investigators of farm/non-farm communities schistosomiasis16 or ascaris/hookworm17 has been asso- have recently reported a collective of important associa- ciated with less allergen sensitization and asthma. In the tions between endotoxin exposure and outcomes in chil- schistosomiasis study, peripheral blood cells from nonal- dren: (1) farm children were exposed to more endotoxin lergic patients demonstrated greater schistosome-specif- (as measured in house dust, barn dust, and mattress ic IL-10 production in vitro,16 raising interest in the dust)26,27; (2) greater endotoxin exposure was associated potential disease-mitigating role of IL-10–producing with less allergen sensitization, hay fever symptoms, and cells.18 Mechanistically, IL-10 can differentially regulate atopic asthma, in a dose-dependent manner26; (3) farm IL-4–stimulated B cells to produce IgG4 instead of IgE, children’s blood expressed higher amounts of CD14 and block mast cell degranulation, and downregulate IL-4 Toll-like receptor 228; (4) early life exposures to farm and IL-5 production. “Regulatory” IL-10–producing barns and unpasteurized milk had strong associations CD4+ CD25+ T lymphocytes, capable of abrogating with low asthma and allergy prevalences29; and (5) high autoimmunity and transplant rejection in some animal levels of endotoxin exposure were associated with an models, may also have a role in alleviating and prevent- increased prevalence of nonatopic wheeze.26 This is a set of hypothesis-generating observations for future longitu- Indeed, a recent study of Finnish medical registries dinal, prospective and interventional studies, on the role revealed asthma prevalence to be higher in children with of noninfectious and naturally occurring endotoxin expo- autoimmune diseases (ie, celiac disease, rheumatoid sure to mitigate allergic manifestations, including the arthritis, type 1 diabetes).19 Similarly, a study of the common allergy-associated asthma. At high levels of prevalence of childhood asthma and type 1 diabetes in 28 endotoxin exposure, asthma in endotoxin-sensitive indi- different countries found a strong positive correlation of viduals, similar to that seen in occupational forms of the prevalence of these 2 conditions.20 These reports sug- endotoxin-mediated asthma, will be manifest.
gest that the immune processes underlying childhood Because animals in homes is associated with greater asthma and autoimmune diseases might be similar, and endotoxin content in dust,30 it is intriguing to find that 2 that the hygiene hypothesis may also be relevant to recent longitudinal, prospective birth cohort studies in US metropolitan communities have found less asthma in Liu and Szefler S787
children raised with pet dogs,31 and less allergen sensiti- Several prospective studies in the past year have zation with increasing numbers of pet cats, dogs, or both helped to clarify the development of allergen sensitiza- in early life.32 Two studies have recently associated high tion in the early childhood years and its relationship to levels of cat allergen in dust with less allergen sensitiza- asthma development. Two studies found that food aller- tion33,34 and have suggested an allergen-specific mecha- gen sensitization in the first 2 years of life was associat- nism. However, the Ownby study, strengthened by its ed with asthma at ages 7 and 22 years.46,47 For allergen prospective study design, found that pet cat and dog sensitization to egg, milk, or both in the first year of life, exposures were associated with less allergen sensitiza- sensitivity and specificity for asthma at age 22 years was tion to all tested common inhalant allergens (ie, dog, cat, 57% and 89%, respectively.48 At age 7, food allergen mite, alternaria, grass, ragweed), suggesting a more gen- sensitization was not associated with asthma; however, eralized mechanism of protection against atopy. Thus, the combination of food allergen sensitization by age 2 endotoxin exposure may have an atopy-mitigating role in and inhalant allergen sensitization by age 7 (“persistent sensitization”) was associated with a significantly higher The hygiene hypothesis research is evolving from the prevalence of asthma and bronchial hyperresponsive- association-type “ecological” studies to longitudinal ness.46 For seasonal inhalant allergens, a group of infants prospective studies with biomarkers of immune response born in Stockholm, Sweden during an unusually high and development, providing greater validity to this natu- birch pollen season (in 1993, birch pollen counts were 10 rally occurring phenomenon. The movement of hygiene to 50 times higher than in 1992 and 1994) were com- hypothesis-related concepts to clinical interventions is pared with those born in relatively low birch pollen also underway. The use of “immunostimulatory DNA years.49 At age 5, those born in 1993 had higher preva- sequences (ISS)” as Th1-inducing adjuvants is conceptu- lences of allergen sensitization to birch and allergic asth- ally derived from unmethylated CpG motifs in bacterial ma. For example, for allergic asthma at age 5, the preva- DNA. ISS conjugates to allergen (ie, Amb a1) are being lence for children born during birch pollen season in developed as immunotherapy for allergic asthma and hay 1992 (low pollen counts), 1993 (high), and 1994 (low) fever, with promising results.35-37 Recently, ISS-allergen was 8.4%, 12.2%, and 8.8%, respectively.
conjugates were shown to induce stronger antibody and A bronchoalveolar lavage (BAL) study of infants and Th1-type immune responses, while reducing mast cell children necessitating bronchoscopy for “unusual” asthma degranulation, anaphylactogenic potential, and delayed found that allergic asthmatics had increased BAL arthus-type reactions than either allergen alone or aller- eosinophils, associating eosinophilic airway inflammation gen mixed with ISS but not conjugated.35 Using a differ- with the allergic asthmatic phenotype even in early child- ent approach, a randomized controlled birth cohort trial hood.50 BAL eosinophils, however, were at low levels in of oral lactobacillus supplementation for mothers of infants younger than age 30 months. Furthermore, exclusively breast-fed infants in the first 6 months of life increased BAL neutrophils were found in childhood asth- found that the prevalence of atopic dermatitis by age 2 ma of greater persistence and longer duration. Finally, the was reduced 3-fold in those receiving supplementation effect of infant breast-feeding on asthma outcomes was (15% vs 47%, P = .01).38 Lactobacillus supplementation well studied in the past year, but with inconsistent find- was associated with higher concentrations of the anti- ings. A prospective birth cohort study of about 2,600 Aus- inflammatory cytokine TGF-β2 in breast milk.
tralian children found that exclusive breast-feeding for With these and other private sector initiatives in devel- longer than 4 months was associated with less doctor-diag- oping microbe-derived products for immune modulatory nosed asthma at age 6, regardless of maternal asthma his- therapies, combined with studies to better understand if tory.51 However, a longitudinal study of about 1,000 New and how naturally occurring microbial exposures might Zealand children to age 26 found that infants breast-fed for lower the likelihood of asthma and allergies, a clearer 4 weeks or longer had a higher prevalence of allergen sen- picture is likely to emerge in the near future. In the mean- sitization and asthma that was independent of maternal time, for general pediatrics, it is important to note that asthma or hay fever history.52 Considering this lack of current epidemiologic evidence finds that neither child- consensus on the relationship between infant breast-feed- hood immunizations39,40 nor antibiotic use41-43 are asso- ing and asthma, general pediatrics should continue to favor ciated with a greater prevalence of allergy and asthma.
infant breast-feeding for its many other benefits.
Rasmussen et al53 sought to determine the risk factors THE NATURAL HISTORY OF ASTHMA
for single and multiple hospitalizations for asthma. Froma population-based, unselected birth cohort of 1,037 New New directions in the management of childhood asth- Zealanders who answered questionnaires and underwent ma include early recognition and early intervention with lung function, airway responsiveness, and allergy testing environmental control and administration of long-term on 7 occasions, the authors identified frequent respirato- control therapy.1,9 Hopefully, this movement will result ry symptoms, airway hyperresponsiveness, atopy, and in improved methods to diagnose and alter the natural low lung function as indicators of high risk for hospital- history of asthma. Inhaled glucocorticoid therapy ization for asthma, especially in relation to multiple hos- improves asthma control, but it is not clear whether this pitalizations. Another feature of asthma associated with treatment can prevent progression of asthma.44,45 significant morbidity is nocturnal symptoms. Strunk et S788 Liu and Szefler
al54 examined the database of the National Heart, Lung The preferred additive therapy for inadequate control and Blood Institute’s (NHLBI) Childhood Asthma Man- with low-medium dose ICS is a long-acting β-adrenergic agement Program obtained during the 28-day period agonist.5,6 Leukotriene antagonists, as well as cromolyn, before randomization to study treatment. They noted that nedocromil, and theophylline, are considered alternative nocturnal awakenings occurred in one third of these chil- first-line therapy to ICS and alternative additive therapy dren with mild-to-moderate asthma. A nocturnal awak- to long-acting β2-adrenergic agonists once ICS has been ening was an indicator of increasingly severe asthma in the 3 days after a nocturnal episode. In addition, those One of the first steps in alleviating symptoms related with a positive skin test response to dog and a high level to persistent asthma is to identify the patient’s allergen of dog allergen in the home had a greater risk of night sensitivity, assess exposure in the patient’s environment, awakening caused by asthma, as did those with a positive and make attempts to limit the allergen exposure. As this skin test response to cat and a high level of cat allergen recommendation has never been adequately tested, in the home. These studies added to the available litera- Carter et al57 assessed the efficacy of allergen avoidance ture are beginning to help us profile the patient at risk for as a treatment for asthma among inner city children in persistent asthma, and for significant morbidity.
Atlanta. They documented a significant decrease in acutevisits (P < .001) for asthma among children whose MANAGEMENT OF CHILDHOOD ASTHMA
homes were visited. However, there was no significantdifference between the active and placebo homes either Asthma guidelines currently recommend intervention in the effect on asthma visits or in allergen concentra- at several points.1,5,6 First, there is intervention with bron- tions. When the children with mite allergy were consid- chodilators for treating symptoms with addition of sys- ered separately, there was a significant correlation temic glucocorticoids for significant exacerbations. Sec- between decreased mite allergen and change in acute vis- ond, intervention with long-term control therapy is its (P < .01); however, the avoidance measures for cock- recommended when symptoms occur more than twice per roach allergen appeared to be ineffective.
week, when nocturnal symptoms occur more than twice Several new classes of medications were introduced per month, and when pulmonary function with either over the last 5 years, including the long-acting β2-adren- FEV1 or peak expiratory flow is less than 80% predicted ergic agonists and the leukotriene modifiers. The long or if within-day peak flow variability exceeds 20%. In acting β2-adrenergic agonists, salmeterol and formoterol, addition, when significant acute exacerbations recur in have a 12-hour duration of action and are currently young children within 6 weeks, then intervention with approved for use in children age 4 and older. One of the long-term controller therapy should be considered.
oral leukotriene antagonists, montelukast, has emerged Another opportunity for intervention with long-term ther- as a popular first-line, long-term control therapy in chil- apy is in the young child at risk of persistent asthma with dren with asthma because of the availability of dosage frequent exacerbations—for example, more than 3 within guidelines and the demonstration of safety in children as a 1-year period.5 Castro-Rodriguez et al55 introduced the concept of an Asthma Predictive Index, suggesting that Arguments against the use of leukotriene receptor frequent wheezing during the first 3 years of life, along antagonists have centered around the limited evidence with either 1 major risk factor (parental history of asthma for anti-inflammatory effect. Phipatanakul et al58 evalu- or eczema in the child) or 2 of 3 minor risk factors ated the effect of montelukast on upper and lower airway (eosinophilia >4%, wheezing without colds, and allergic responses to intense cat allergen exposure in a double- rhinitis), was associated with the persistence of asthma.
blind, placebo-controlled, randomized, crossover trial in The National Asthma Education and Prevention Pro- 18 participants ages 6 to 14 with cat-induced asthma. The gram’s guidelines update addressed the needs of child- participants were treated for 1 week and then exposed for hood asthma through a careful evidence-based review of 1 hour to cat allergen in an environmental exposure unit.
critical issues, such as the time of intervention, the safe- Montelukast was significantly more effective than place- ty and limitations of ICS, and the preferred medication bo in attenuating lower respiratory responses and extend- for additive therapy to ICS.5,6 Information related to ing challenge length when cat-sensitive children with asthma management for children younger than age 5 is mild persistent asthma were exposed to high levels of cat weak because of the small number of studies. Therefore, allergen. To examine the anti-inflammatory properties of many assumptions for treatment recommendations for leukotriene modifiers and their effect on bronchial hyper- young children are based on studies in adults.
responsiveness, Stelmach et al59 in a double-blind, ran- Current studies substantiate the role of ICS as first-line domized, placebo-controlled trial, evaluated 39 children therapy in the management of persistent asthma, but they with mild-to-moderate atopic asthma. They were ran- also identify some limitations in the efficacy of ICS, such domly allocated to receive montelukast or placebo for 6 as failure to eradicate acute exacerbations or to prevent the weeks, and then inflammatory markers along with pul- recently described loss in pulmonary function.45,56 Treat- monary function and airway responsiveness to histamine ment strategies must now address the limitations of ICS in was measured. They found that montelukast resulted in a preventing asthma progression and reversing pulmonary significantly decreased serum concentration in cytokine, function in long-standing, poorly controlled asthma.
intercellular cell adhesion molecule 1 (ICAM-1), and Liu and Szefler S789
eosinophilic cationic protein (ECP) and peripheral blood dren with frequent symptoms, a family history of asthma, eosinophils, along with improvement in FEV1 and reduc- or both showed the greatest response to this treatment.
tion in histamine PC20 over the treatment period.
Szefler et al64 compared the efficacy of switching from Evidence for the role of ICS on improving asthma con- chlorofluorocarbon (CFC)-beclomethasone dipropionate trol was largely based on the results of the long-term (BDP) to a hydrofluorocarbon (HFA)-based BDP inhaler NHLBI Childhood Asthma Management Program.45 This in children ages 5 to 11. They concluded that asthma con- study also demonstrated significant improvement in asth- trol can be well maintained in children with switching ma control and reduction in airway responsiveness; how- from CFC-BDP plus spacer to an HFA-BDP Autohaler at ever, there was no significant long-term effect on pul- monary function and airway responsiveness. This Also, renewed interest has developed in the combina- observation, combined with similar losses in asthma con- tion of medications in one formulation, such as an ICS trol measures, indicate that long-term outcomes of asthma and a long-acting β-adrenergic agonist, based on evi- may not be altered by even our best form of treatment.
dence of additive effects, convenience for the patient, and An area that requires additional research centers the potential to further reduce the risk for significant around the appropriate time to intervene with either envi- exacerbations.65 However, combination therapy as a sin- ronmental control, pharmacotherapy, or immune modu- gle entity is currently only approved for use in children lation.5,6 Stevenson et al60 examined the national preva- lence and demographic correlates of sensitivity to indoor To limit the adverse effects of short-acting β-agonists, allergens related to asthma in a cross-sectional survey of the stereoisomer of albuterol, levalbuterol, was devel- a representative sample of 4,164 US children aged 6 to oped. Milgrom et al66 studied the comparative safety and 16 years who participated in the Third National Health efficacy of levalbuterol and albuterol in asthmatic chil- and Nutrition Examination Survey from 1988 to 1994.
dren ages 4 to 11 in a multicenter, randomized, double- The main outcome measures were sensitivity reactions to blind study over a 21-day treatment period with medica- cockroach, dust mite, cat, and Alternaria alternata by tion administered 3 times a day. Levalbuterol was skin prick testing. The authors reported that African clinically comparable to 4- to 8-fold higher doses of American and Mexican American children were substan- racemic albuterol with a more favorable safety profile.
tially more likely than white children to be sensitized to Pharmacotherapy in young children can also be a chal- allergens important in asthma. These differences in lenge because of limitations in the route of administra- indoor allergen sensitivity were consistent with racial tion for inhaled medication administration and depen- differences in asthma morbidity. These observations, dence on patient cooperation.67 Information regarding along with other reports, demonstrate racial disparity in the appropriate dose of medications for children younger housing and community, or that the 2 combined environ- than age 5 is available for some medications, but not all.
mental factors play a role in determining national pat- Revised dosing guidelines for asthma medications in terns of asthma morbidity. As indicated by Wahn and von children appear in the recent update to the NAEPP guide- Mutius,61 cross-sectional studies can only generate lines.5,6 The updated guidelines suggest that first-line hypotheses, which must be supported by prospective, therapy could begin with low-dose inhaled glucocorti- longitudinal, cohort studies. Well-controlled intervention coid by nebulizer or alternatively, by a spacer/holding studies should identify which nutritional, environmental, chamber and face mask.5 As indicated previously, a neb- or lifestyle factors to consider for early intervention.
ulized budesonide preparation recently was approved for Because allergen exposure is difficult to control, we use in children as young as age 1.7 Comparative studies then turn to pharmacotherapy. John Warner and the Early are needed to determine whether an ICS administered by Treatment of the Atopic Child (ETAC) Study Group62 pressurized metered dose inhaler and spacer/face mask is examined the effect of an antihistamine, cetirizine, in pre- equivalent to nebulized ICS administration. Other alter- venting the onset of asthma in children ages 1 and 2 with natives include the use of montelukast that is now avail- atopic dermatitis in a double-blinded, randomized, place- able in a formulation that can be administered to children bo-controlled trial. The authors completed 18 months of treatment and followed the participants 18 months off A recent study that compared nebulized budesonide to treatment. Cetirizine delayed or, in some cases, prevented inhaled cromolyn by nebulizer clearly demonstrated the development of asthma in a subgroup of infants with superior asthma control with the nebulized budesonide atopic dermatitis sensitized to grass pollen and, to a less- formulation in measures of asthma exacerbations, symp- er extent, house dust mite. Egg sensitization was also tom control, and time for supplementary medication.
noted as a high-risk factor for development of asthma.
However, hospitalizations and emergency department Studies focused specifically on sensitized groups are now visits were similar in both treatment groups.68 needed to substantiate this observation.
Recent studies from the Tucson Children’s Respirato- Roorda et al63 sought to determine whether there are ry Study that have followed respiratory patterns in chil- subgroups of young children with recurrent asthma dren for the first 15 years of life now indicate that chil- symptoms who are most likely to respond to ICS. They dren who wheeze during lower respiratory tract illnesses examined pooled data from 2 similar 12-week studies in the first 3 years of life and who still wheeze at age 6 with inhaled fluticasone propionate and placebo. Chil- (“persistent wheezers”) have the lowest levels of lung S790 Liu and Szefler
TABLE II. Key advances in pediatric asthma over the last
The area of pharmacogenetics could provide informa- tion on the relationships of genetics to medication response.74 Advances in this area could help define rele- • Associations of microbial exposures with less atopy-associated vant asthma phenotypes and genotypes associated with a favorable response to medications and assist in defining • Associations of animal exposures in early life (farm animals individualized treatment approaches.
and pet cats and dogs) with less asthma, atopy, or both in chil-dren CONCLUSION
• No associations of childhood immunizations or antibiotic use Based on the results of the long-term Childhood Asthma • Refinement of early childhood patterns of allergen sensitization Management Program clinical trial in childhood asthma, to inhalants and foods, as risk factors for asthma the benefits of continuous long-term ICS on asthma con- Management of asthma in children• Presentation of a profile of risk features for the development of trol in children are clear. Studies are in progress to evalu- asthma in a young child with frequent wheezing ate whether early intervention with ICS can alter the nat- • Introduction of medications approved for use in young children ural history of asthma. Indicators are rapidly being defined to identify the patient at risk for persistent asthma • Identification of the limitations of inhaled corticosteroids in and thus identify the appropriate candidates for early intervention. Given the right medication and the patientprofile, it may be possible to induce remission or even a *Based on literature available between October 2001 and September 2002.
“cure.” It will also be very important to recognize patientsat risk for severe asthma and to intervene more effective-ly to prevent asthma progression to severe levels and the function in later childhood.56 Based on limited evidence, consequent irrecoverable loss of pulmonary function.
it is thought that a loss of pulmonary function over time The key advances in pediatric asthma over the last is associated with airway remodeling.69 It is also project- year are summarized in Table II. The goal should now be ed that the consequent alteration in lung growth could to strive for a reduction in asthma morbidity and mortal- have an overall effect on long-term outcomes. It has been ity. A high proportion of asthma morbidity among inner proposed that early intervention with ICS therapy can be city children appears related to nonadherence. Therefore, effective in preventing the progression of the disease and targeting management approaches to improve adherence the risk for irreversible changes in the airways; however, or to derive more effective therapies could reduce mor- this remains to be proven. There is no doubt that inter- vention with ICS offers the best opportunity to improve We thank Gretchen Czapla for assistance in the manuscript The NHLBI Asthma Clinical Research Network described the significant variability in response to ICS inadults with reduced pulmonary function and persistent REFERENCES
asthma.70 It will be important to determine whether this 1. Spahn JD, Szefler SJ. Childhood asthma: new insights into management.
variability in response to ICS is also present in children J Allergy Clin Immunol 2002;109:3-13.
undergoing early intervention. A review by Payne and 2. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma—United States, 1980-1999. MMWR Balfour-Lynn provides a summary of our current under- standing of the management of severe persistent asthma 3. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, in children.71 They proposed that tools to measure airway health care utilization, and mortality. Pediatrics 2002;110:315-322.
inflammation, such as exhaled nitric oxide, induced spu- 4. National Institutes of Health, National Heart, Lung, and Blood Institute.
Global Initiative for Asthma. Global strategy for asthma management and tum, BAL, and biopsy could assist in decisions centered prevention, NHLBI/NIH workshop report. 2002.
around pursuing more aggressive forms of anti-inflam- 5. National Asthma Education and Prevention Program Report: Guidelines matory therapy or bronchodilator therapy. Other mea- for the Diagnosis and Management of Asthma Update on Selected Top- sures of airway inflammation, such as IL-4 and interfer- ics—2002. J Allergy Clin Immunol 2002;110:S141-S219.
on gamma, can be measured in exhaled condensates.72 6. Busse WW, Lenfant C, Lemanske RF. Asthma guidelines: a changing par- adigm to improve asthma care. J Allergy Clin Immunol 2002;110:703-5.
Zanconato et al73 examined the effect of oral prednisone 7. Szefler SJ, Eigen H. Budesonide inhalation suspension: a nebulized corti- treatment on expired nitric oxide (FENO) and carbon costeroid for persistent asthma. J Allergy Clin Immunol 2002;109:730-42.
monoxide (ECO) in 30 asthmatic children before and 8. Szefler SJ (ed). Meeting the needs of the modernization act: challenges after a 5-day course of oral prednisone therapy for an in developing pediatric therapies. J Allergy Clin Immunol 2000;106 (3Suppl):115-7.
acute asthma exacerbation. They reported a significant 9. Naspitz C, Szefler SJ, Tinkelman D, Warner JO (eds). Textbook of Pedi- decrease in FENO but no significant change in ECO, sug- atric Asthma. London: Martin-Dunitz; 2001.
gesting this measure is less sensitive than FENO. Unfor- 10. Broadfield E, McKeever TM, Scrivener S, Venn A, Lewis SA, Britton J.
tunately, there is very little evidence in children that these Increase in the prevalence of allergen skin sensitization in successive indicators of airway inflammation can be reliably applied birth cohorts. J Allergy Clin Immunol 2002;109:969-74.
11. Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. Hay fever to asthma management decisions, especially for patients and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol 2002;110:381-7.
Liu and Szefler S791
12. McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, et oligodeoxynucleotide conjugates with retained immunogenicity and min- al. Identification of Tapr (an airway hyperreactivity regulatory locus) and imal anaphylactogenicity. J Allergy Clin Immunol 2002;110:413-20.
the linked Tim gene family. Nat Immunol 2001;2:1095-6.
36. Santeliz JV, Van Nest G, Traquina P, Larsen E, Willis-Karp M. Amb a 1- 13. Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development linked CpG oligodeoxynucleotides reverse established airway hyperre- and the intestinal microflora during the first year of life. J Allergy Clin sponsiveness in a murine model of asthma. J Allergy Clin Immunol 14. Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E.
37. Tighe H, Takabayashi K, Schwartz D, van Nest G, Tuck S, Eiden JJ, et Distinct patterns of neonatal gut microflora in infants in whom atopy was al. Conjugation of immunostimulatory DNA to the short ragweed aller- and was not developing. J Allergy Clin Immunol 2001;107:129-34.
gen amb a 1 enhances its immunogenicity and reduces its allergenicity. J 15. Benn CS, Thorsen P, Jensen JS, Kjaer BB, Bisgaard H, Andersen M, et Allergy Clin Immunol 2000;106:124-34.
al. Maternal vaginal microflora during pregnancy and the risk of asthma 38. Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and hospitalization and use of antiasthma medication in early childhood. J breast-feeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol 2002;109:119-21.
16. van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, 39. Anderson HR, Poloniecki JD, Strachan DP, Beasley R, Bjorksten B, Kremsner PG, et al. Decreased atopy in children infected with Schisto- Asher MI, et al. Immunization and symptoms of atopic disease in chil- soma haematobium: a role for parasite-induced interleukin-10. Lancet dren: results from the international study of asthma and allergies in child- hood. Am J Public Health 2001;91:1126-9.
17. Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun D, Girma S, Ali S, 40. DeStefano F, Gu D, Kramarz P, Truman BI, Iademarco MF, Mullooly JP, et al. Independent effects of intestinal parasite infection and domestic et al. Childhood vaccinations and risk of asthma. Pediatr Infect Dis allergen exposure on risk of wheeze in Ethiopia: a nested case-control 41. Celedon JD, Litonjua AA, Ryan L, Weiss ST, Gold DR. Lack of association 18. Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the between antibiotic use in the first year of life and asthma, allergic rhinitis, hygiene hypothesis. Science 2002;296:490-4.
or eczema at age 5 years. Am J Respir Crit Care Med 2002;166:72-5.
19. Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases 42. Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, Sommerfeld C, coexist? Evaluation of asthma incidence in children with coeliac disease, et al. Early childhood infectious diseases and the development of asthma type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin up to school age: a birth cohort study. Br Med J 2001;322:390-5.
43. McKeever TM, Lewis SA, Smith C, Collins J, Heatlie H, Frischer M, et 20. Stene LC, Nafstad P. Relation between occurrence of type 1 diabetes and al. Early exposure to infections and antibiotics and the incidence of aller- gic disease: a birth cohort study with the West Midlands General Practice 21. Liu AH. Endotoxin exposure in allergy and asthma: reconciling a para- Research Database. J Allergy Clin Immunol 2002;109:43-50.
dox. J Allergy Clin Immunol 2002;109:379-92.
44. Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity 22. Gehring U, Bolte G, Borte M, Bischof W, Fahlbusch B, Wichmann HE, and mortality. J Allergy Clin Immunol 2001;107:937-44.
et al. Exposure to endotoxin decreases the risk of atopic eczema in infan- 45. The Childhood Asthma Management Program Research Group. Long- cy: a cohort study. J Allergy Clin Immunol 2001;108:847-54.
term effects of budesonide or nedocromil in children with asthma. N Engl 23. Park JH, Gold DR, Spiegelman DL, Burge HA, Milton DK. House dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med 46. Illi S, von Mutius E, Lau S, Nickel R, Niggemann B, Sommerfeld C, et al. The pattern of atopic sensitization is associated with the development 24. Vercelli D. The functional genomics of CD14 and its role in IgE respons- of asthma in childhood. J Allergy Clin Immunol 2001;108:709-14.
es: an integrated view. J Allergy Clin Immunol 2002;109:14-21.
47. Rhodes HL, Sporik R, Thomas P, Holgate ST, Cogswell JJ. Early life risk 25. Jones CA, Holloway JA, Popplewell EJ, Diaper ND, Holloway JW, Vance factors for adult asthma: a birth cohort study of subjects at risk. J Aller- GHS, et al. Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, 48. Rhodes HL, Thomas P, Sporik R, Holgate ST, Cogswell JJ. A birth cohort or both. J Allergy Clin Immunol 2002;109:858-66.
study of subjects at risk of atopy. Am J Respir Crit Care Med 26. Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, et al.
Environmental exposure to endotoxin and its relation to asthma in 49. Kihlstrom A, Lija G, Pershagen G, Hedlin G. Exposure to birch pollen in school-age children. N Engl J Med 2002;347:869-77.
infancy and development of atopic disease in childhood. J Allergy Clin 27. Gereda JE, Leung DYM, Liu AH. House-dust endotoxin is higher in rural homes in developing countries and farm homes, where asthma is less 50. Just J, Fournier L, Momas I, Zambetti C, Sahraoui F, Frimfeld A. Clini- cal significance of bronchoalveolar eosinophils in childhood asthma. J 28. Lauener RP, Birchler T, Adamski J, Braun-Fahrlander C, Bufe A, Herz U, et al. Expression of CD14 and Toll-like receptor 2 in farmers’ and non- 51. Oddy WH, Peat JK, de Klerk NH. Maternal asthma, infant feeding, and farmers’ children. N Engl J Med 2002;347:869-77.
the risk of asthma in childhood. J Allergy Clin Immunol 2002;110:65-7.
29. Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Malsch S, 52. Sears MR, Greene JM, Willan AR, Taylor DR, Flannery EM, Cowan JO, et al. Exposure to farming in early life and development of asthma and et al. Long-term relation between breastfeeding and development of allergy: a cross-sectional survey. Lancet 2001;358:1129-33.
atopy and asthma in children and young adults: a longitudinal study.
30. Gereda JE, Klinnert MD, Price MR, Leung DYM, Liu AH. Metropolitan home living conditions associated with indoor endotoxin levels. J Aller- 53. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbi- son GP, et al. Risk factors for hospital admission for asthma from child- 31. Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, Wright AL.
hood to young adulthood: a longitudinal population study. J Allergy Clin Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol 2001;108:509-15.
54. Strunk RC, Sternberg AL, Bacharier LB, Szefler SJ. Nocturnal awaken- 32. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the ing caused by asthma in children with mild-to-moderate asthma in the first year of life and risk of allergic sensitization at 6 to 7 years of age.
childhood asthma management program. J Allergy Clin Immunol 33. Custovic A, Hallam CL, Simpson BM, Craven M, Simpson A, Woodcock 55. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical A. Decreased prevalence of sensitization to cats with high exposure to cat index to define risk of asthma in young children with recurrent wheezing.
allergen. J Allergy Clin Immunol 2001;108:537-9.
Am J Respir Crit Care Med 2000;162:1403-6.
34. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitiza- 56. Martinez FD. Development of wheezing disorders and asthma in tion, asthma, and a modified Th2 response in children exposed to cat aller- preschool children. Pediatrics 2002;109:362-7.
gen: a population-based cross-sectional study. Lancet 2001;357:752-6.
57. Carter MC, Perzanowski MS, Raymond A, Platts-Mills TA. Home inter- 35. Horner AA, Takabayashi K, Beck L, Sharma B, Zubeldia J, Baird S, et al.
vention in the treatment of asthma among inner-city children. J Allergy Optimized conjugation ratios lead to allergen immunostimulatory S792 Liu and Szefler
58. Phipatanakul W, Nowak-Wegrzyn A, Eggleston PA, Van Natta M, Kesa- 67. Spahn JD, Covar RA, Gleason MC, Tinkelman DG, Szefler SJ. Pharma- van J, Schuberth K, et al. The efficacy of montelukast in the treatment of cologic management of asthma in infants and small children. In: Naspitz cat allergen-induced asthma in children. J Allergy Clin Immunol CK, Szefler SJ, Tinkelman D, Warner JO, editors. Textbook of pediatric asthma. Martin London: Dunitz Ltd; 2001. pp. 121-147.
59. Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the 68. Leflein JG, Szefler SJ, Murphy KR, Fitzpatrick S, Cruz-Rivera M, Miller effect of treatment with montelukast on bronchial hyperresponsiveness and CJ, Smith JA. Nebulized budesonide inhalation suspension compared serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor with cromolyn sodium nebulizer solution for asthma in young children: (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1) in results of a randomized outcome trial. Pediatrics 2002;109:866-72.
children with asthma. J Allergy Clin Immunol 2002;109:257-63.
69. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbi- 60. Stevenson LA, Gergen PJ, Hoover DR, Rosenstreich D, Mannino DM, son GP, Sears M. Risk factors for airway remodeling in asthma mani- Matte TD. Sociodemographic correlates of indoor allergen sensitivity fested by a low postbronchodilator FEV1/vital capacity ratio. Am J among United States children. J Allergy Clin Immunol 2001;108:747-52.
Respir Crit Care Med 2002;165:1480-8.
61. Wahn U, von Mutius E. Childhood risk factors for atopy and the impor- 70. Szefler SJ, Richard J. Martin RJ, et al, for the Asthma Clinical Research tance of early intervention. J Allergy Clin Immunol 2001;107:567-74.
Network of the National Heart, Lung, and Blood Institute. Significant 62. Warner JO, for the ETAC Group. A double-blinded, randomized, place- variability in response to inhaled corticosteroids for persistent asthma. J bo-controlled trial of cetirizine in preventing the onset of asthma in chil- Allergy Clin Immunol 2002;109:410-8.
dren with atopic dermatitis: 18 months’ treatment and 18 months’ post- 71. Payne DNR, Balfour-Lynn IM. Children with difficult asthma: a practi- treatment follow-up. J Allergy Clin Immunol 2001;108:929-37.
cal approach. J Asthma 2001;38:189-203.
63. Roorda RJ, Mezei G, Bisgaard H, Maden C. Response of preschool chil- 72. Shahid SK, Kharitinov SA, Wilson NM, Bush A, Barnes PJ. Increased inter- dren with asthma symptoms to fluticasone propionate. J Allergy Clin leukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 2002;165:1290-3.
64. Szefler SJ, Warner J, Staab D, Wahn U, Le Bourgeois M, van Essen- 73. Zanconato S, Scollo M, Zaramella C, Landi L, Zacchello F, Baraldi E.
Zandvliet EE, et al. Switching from conventional to extrafine aerosol Exhaled carbon monoxide levels after a course of oral prednisone in chil- beclomethasone dipropionate therapy in children: a 6-month, open-label, dren with asthma exacerbation. J Allergy Clin Immunol 2002;109:440-5.
randomized trial. J Allergy Clin Immunol 2002;110:45-50.
74. Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharmacogenetics of 65. Matz J, Emmett A, Rickard K, Kalberg C. Addition of salmeterol to low- asthma. Am J Respir Crit Care Med 2002;165:861-6.
dose fluticasone versus higher-dose fluticasone: an analysis of asthma 75. Bauman LJ, Wright E, Leickly FE, Crain E, Kruszon-Moran D, Wade SL, exacerbations. J Allergy Clin Immunol 2001;107:783-9.
Visness CM. Relationship of adherence to pediatric asthma morbidity 66. Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA.
among inner-city children. Pediatrics 2002;110(1 Pt 1):e6.
Low-dose levalbuterol in children with asthma: safety and efficacy in URL:http://www.pediatrics.org/cgi/content/full/110/1/e6 comparison with placebo and racemic albuterol. J Allergy Clin Immunol2001;108:938-45.
EXAMPLE PROTOCOL FOR ADMINISTRATION OF THE ‘NARCAN CHALLENGE’ B: General Exclusion Criteria for Community Detoxification. (i) Naltrexone as described in this protocol is for use • As for community lofexidine protocol. as adjunctive prophylactic therapy in the preventionof relapse to opioid drug misuse following planned(iv) The CDAT consultant should