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The Natural History of Asthma and Early Intervention 2002

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The natural history of asthma and early intervention Stanley J. Szefler, MD Denver, Colo The understanding of the natural history of asthma has changed significantly during the last 4 decades, with the view that asthma is a disease of chronic inflammation and varying degrees of severity replacing that of it being a disease of reversible airway obstruction. Treatment has progressed in accordance with the growing knowledge about the pathophysiologic mechanisms of asthma. Nevertheless, much remain
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  The understanding of the natural history of asthma haschanged significantly during the last 4 decades,with the viewthat asthma is a disease of chronic inflammation and varyingdegrees of severity replacing that of it being a disease of reversible airway obstruction. Treatment has progressed inaccordance with the growing knowledge about the pathophysi-ologic mechanisms of asthma. Nevertheless,much remainsunknown,especially about how to treat asthma effectively.Pharmacogenetics,an emerging field in which the knowledgeof the genetic basis of a disease is applied to its treatment,mayultimately lead investigators to define many unanswered ques-tions about asthma therapy. Asthma occurs early in childhood,but the ideal time for intervention and the most effective treat-ment strategy are yet unknown for young patients. The lack of response to a therapy may indicate the course of the disease asmuch as a lack of treatment efficacy. It may be that includingsuch variables as airway hyperresponsiveness in treatmentgoals will not only become routine but will result in improvedlong-term asthma treatment as well. The progress in definingasthma and targeting treatment toward specific pathophysio-logic mechanisms should lead to better-defined optimal strate-gies for treating asthma in children. (J Allergy Clin Immunol2002;109:S549-53.)  Key words: Asthma, natural history, inflammation, early interven-tion The understanding of the pathophysiology of asthmahas evolved significantly during the last 4 decades,andtreatments have progressed in accordance with the grow-ing knowledge about the natural history of the disease. Inthe 1960s,asthma was perceived to be an episodic disease,and the therapeutic objectives were to relieve symptoms,primarily bronchospasm. Epinephrine partly achieved thisgoal,and efforts ensued to develop an oral formulation of this drug and to prolong its duration of action.During the next 2 decades,concerns shifted toward theprogression of the disease and how its evolution could bemanaged. In the 1970s,when medications such asalbuterol and theophylline were in use,the emphasis of asthma treatment was bronchospasm prevention ratherthan simply the relief of symptoms. The introduction of theophylline resulted in improved control of nocturnalasthma,and in the 1980s,cromolyn sodium was used tocontrol allergen-induced bronchospasm during the earlyand late phases of asthma.Then,in the 1990s,bronchoscopy and endobronchialbiopsy specimens revealed inflammation in the airwaysof asthmatics. The definition of asthma changed frombeing a reversible disease of airway obstruction to that of a chronic inflammatory disease with varying degrees of severity. Researchers focused attention on the cellularand molecular mechanisms of the disease (such ascytokines,chemokines,and leukotrienes,immuneresponse,remodeling,and inflammation) and how thesefactors may predict the severity or progression of the dis-ease. Figure 1 summarizes the evolution of asthma as ithas been viewed since the late 1990s.The development,refinement,and increased use of assessment tools including bronchoscopy,endobronchialbiopsy,bronchoalveolar lavage,and induced sputumwere instrumental in quantifying and qualifying inflam-mation in asthmatic patients. Inhaled glucocorticoidsbecame the agents of choice to prevent and resolve air-way inflammation in adults and older children. 1 Although steroids were used extensively,a new class of drugs,the leukotriene (LT) modifiers,was being devel-oped. The LT modifiers targeted the cysteinyl LT media-tors present in asthma inflammation that are not neces-sarily or consistently controlled by corticosteroids.Leukotrienes are associated with airway edema,smooth muscle contraction,and altered cellular activityin the inflammatory process. The LT modifiers weredesigned either to inhibit LT synthesis (5-lipoxygenaseinhibitor) or to prevent the LTs from binding to their spe-cific receptors on airways and inflammatory cells. In1995,two medications of this new class of drugs,zileu-ton (Zyflo; Abbott Laboratories,North Chicago,Ill),anLT synthesis inhibitor,and zafirlukast (Accolate; The natural history of asthma and earlyintervention Stanley J.Szefler,MD  Denver, Colo S549 From the Department of Pediatrics,National Jewish Medical and ResearchCenter,Denver,Colo,and the Department of Pediatrics and Pharmacolo-gy,University of Colorado Health Sciences Center,Denver,Colo.Dr Szefler is the Helen Wohlberg and Helman Lambert Chair in Pharmacoki-netics/Divisions of Clinical Pharmacology and Allergy and Immunology.Supported in part by National Institutes of Health grants HL-36577 and HD-37237 and General Clinical Research Center Grant 5M01-RR00051 fromthe Division of Research Resources.Dr Szefler serves on pedatric advisory panels for childhood asthma forMerck,AstraZeneca,and GlaxoSmithKline.Reprint requests:Stanley J. Szefler,MD,Division of Clinical Pharmacology,National Jewish Medical and Research Center,1400 Jackson St,RoomJ209,Denver,CO 80206.©2002 Mosby,Inc. All rights reserved.0091-6749/2002 $35.00 + 0 1/0/124569 doi.10.1067/mai.2002.124569  Abbreviations used  BHR:Bronchial hyperresponsivenessECP:Eosinophilic cationic proteinICS:Inhaled corticosteroid(s)LT:LeukotrieneLTRA:Leukotriene receptor antagonist  S550 Szefler J ALLERGY CLIN IMMUNOLJUNE 2002 AstraZeneca Pharmaceuticals,Wilmington,Del),aleukotriene receptor antagonist (LTRA),were approvedfor the treatment of asthma in the United States. AnotherLTRA,montelukast sodium (Singulair; Merck & Com-pany,Inc,West Point,Pa),subsequently received FDAapproval in 1998. Approved for adults,only two of thesemedications are approved for young children:zafirlukast,for children as young as 5 years of age,and montelukast,for children as young as 2 years of age. Although firstmet with skepticism,the LT modifiers have been incor-porated rapidly into the physician’s armamentarium forasthma treatment. DISCERNING THE STATUS OF THE DISEASE An understanding of the natural history of asthma cancontribute substantially to optimal,early treatment. Withchronic inflammation,there is an element of progression,but asthma progression has not been defined clearly. Theonly indication in the literature regarding progression isa decline in FEV 1 . Other factors,such as intensifying fre-quency or severity of symptoms,increasing the need formedication to control symptoms and hyperexpansion,may also be important indicators of disease progression.In the past,clinicians used pulmonary function testingprimarily to gauge the severity of a patient’s asthma andto monitor response to therapy. Several questions remain,however,regarding how best to use the pulmonary func-tion tests. Among these questions are:Does spirometryprovide information that peak flow does not? Whichpatients might benefit from the measuring of lung volumeand hyperexpansion (with body plethysmography)? Theanswers may not always be complete enough to provide afull appreciation of the disease for a particular patient. Itmay also be important,therefore,to evaluate patientsusing exercise-induced asthma or methacholine chal-lenge,particularly in those who participate in sports or forwhom regular participation in exercise is important.In recent years,measurements for markers of inflam-mation have become more accessible. These new toolsinclude induced sputum cytology to assess the presenceof inflammatory cells in the lungs (eosinophils,neu-trophils,and others),and blood tests to determine levelsand activation states of inflammatory cells (mainlyeosinophils),along with the presence of inflammatorymarkers such as the eosinophilic cationic protein (ECP).Other measurements are used only in research settings,such as the level of exhaled nitric oxide as a marker of inflammation. New techniques are being developed tomeasure other mediators. There are,however,no para-meters that relate findings of such measurements to a risk profile. Defining the clinical relevance of measurementswould allow them to be incorporated into routine prac-tice. Similarly,the best methods for measuring theresponse to asthma treatment remain unclear. It is notknown which indicators are best:the control of symp-toms,FEV 1 ,airway hyperresponsiveness,the level of exhaled mediators such as nitric oxide,or a combinationof these markers. Regulatory agencies need to addressquestions raised regarding the application of surrogatemarkers in terms of which are suitable as short-termmarkers and which indicate long-term response. DEFINING A GENETIC BASIS FOR ASTHMAAND APPLYING IT TO TREATMENT Atopy is the single most important risk factor for asth-ma 2 and,in genetically predisposed patients,environ-mental stimuli produce inflammation and ultimately canaffect airway structure. Pharmacogenetics is an emerging FIG 1. Natural history of asthma. Schematic of the natural history of asthma demonstrates several possiblefeatures of the disease that may be amenable to preventive or therapeutic intervention. (From Holgate ST.The cellular and mediator basis of asthma in relation to natural history. Lancet 1997;350(Suppl 2):5-9. © byThe Lancet Ltd, 1997.)  J ALLERGY CLIN IMMUNOLVOLUME 109, NUMBER 6 Szefler S551 field that may help to incorporate several different treat-ment aspects (for old therapies and new therapies indevelopment) into a schematic such as drug response (ata cellular receptor level),drug metabolism,and risk foradverse effects of medications. Research has focused onidentifying the genes associated with asthma,whichwould allow for the recognition of patients at risk and formore proactive management,prevention,and selection of therapeutic options. Distinguishing genetic markers forasthma from those for allergy is a challenging task; how-ever,several candidate genes and their functions havebeen identified. 2 RECOGNIZING INDIVIDUAL DIFFERENCES INASTHMA Asthma is heterogeneous. Elucidation and examina-tion of the variables in asthma could add valuable diag-nostic and treatment information. The National AsthmaEducation and Prevention Program (NAEPP) guidelinesprovide a limited classification of asthma as mild inter-mittent,mild persistent,moderate persistent,and severepersistent. By adding other categories,more epidemio-logic information could be retrieved (Table I). 3,4 The differences among patients with asthma also pres-ent other important implications. For example,specificand distinguishing differences occurring during thecourse of the disease may alter the initial prognosis,andadditional information regarding these variables mightbetter define risk features. Patients’responses to therapyvary,however,and the impact of such variance isunknown. A key question,then,is do these distinctionsreflect varying modifications of a common pathophysio-logic process or varying processes? CHILDHOOD ASTHMA:CURRENTKNOWLEDGE AND ISSUES Asthma often occurs in early childhood. Because theincidence of asthma in children younger than 5 years of age is the highest compared with that of older childrenand adults,it is important to identify the disease in thesevery young patients. 5 Owing to the growing understand-ing of the natural history of asthma,treatment can be tar-geted toward specific pathophysiologic mechanisms thatcan lead to better defined optimal strategies for treatingasthma in children. Current asthma therapy is based onthe concept that chronic inflammation is a key feature of the disease; however,there is neither enough informationabout the time of onset of inflammation nor precisemechanisms for asthma initiation,progression,and per-sistence,especially in children.Although asthma often starts early in life,wheezingresolves by 6 years of age in many children. Among 277children with wheezing before the age of 3 years,164(59.2%) had not wheezed during the previous year whenexamined at 6 years of age. Children with persistentwheezing were twice as likely to have wheezed often orvery often ( P = .001) or to have wheezed without coldsduring infancy ( P = .05),compared with children whohave transient early wheezing. Although children withpersistent wheezing at 6 years of age had significantlyreduced pulmonary function,compared with nonwheez-ers at 6 years (1069.7 vs 1262.1 mL/s,respectively, P <.01). When younger than 1 year of age,they had a pul-monary function similar to the children who neverwheezed at age 6 (104.6 vs 123.3 mL/s,respectively).These data suggest that in these children,the persistentwheezing is not caused by poor initial pulmonary func-tion but instead may be the result of the chronic diseaseprocess in the bronchi. 6 Furthermore,certain patients with bronchial hyperre-sponsiveness (BHR) were more predisposed to a declinein pulmonary function over time. 7 This has led to specu-lation that if BHR occurs early in children,their lungdevelopment may be compromised and could be at risk for more rapid decline and chronic obstructive pul-monary disease. If so,one would expect patients withsevere asthma to have a decline in pulmonary functioncontinuously over time,but data from long-term studiesdo not support that hypothesis. 8 Certainly,patients withsevere asthma have diminished pulmonary function andairway hyperresponsiveness. What is not clear is whethersuch deficits in pulmonary function occur suddenly andthen continue or whether there is a “window of opportu-nity”for intervention.Including the reduction of airway hyperresponsivenessin treatment goals might result in more effective controlof asthma,fewer exacerbations,less variable airflowobstruction,and a more effective decrease of airwayinflammation and remodeling compared with the use of conventional measures. Data showing the degree of BHRin asthma have provided relevant information on theexacerbation rate,which appeared to be highest inpatients with relatively severe BHR. 9 These data alsosuggested that a step-up of doses of inhaled corticoste-roid (ICS) therapy could be tailored more easily to theneeds of each individual according to the severity of BHR. Including the BHR reduction in the therapeuticgoals allowed for a reduced exacerbation rate,anincreased FEV 1 (bronchodilation) and a decreased thick-ness of the subepithelial reticular layer (decrease in col-lagen,a surrogate marker for airway remodeling) in thebronchial wall,indicating a reversal of airway remodel-ing. The drawback to including BHR reduction in thetreatment goal results,however,is an approximate dou- TABLE I. Differences based on patterns of symptoms 1. NAEPP guidelines:mild intermittent,mild persistent,moderatepersistent and severe persistent2. Persistent asthma,obstructed asthma,episodic asthma,asthmain remission,potential asthma,trivial asthma*3. Cough-variant asthma4. Asthmatic bronchitis5. Brittle asthma:“chaotic”or “sudden-onset”6. Potentially fatal asthma *Adapted from data in Barnes and Woolcock. 4  S552 Szefler J ALLERGY CLIN IMMUNOLJUNE 2002 bling of the ICS dose 9 (Fig 2) and the consequent risk of adverse effects. Further study may define better the clin-ical use of this approach,particularly in children. It maybe that earlier intervention negates the need for increaseddoses of ICS.The suggestion that the measurement of BHR beincluded in the long-term treatment of asthma highlightsthe fact that an adequate response to therapy has not beendefined clearly. Studies tend to focus on the averageresponse,often neglecting important aspects,including FIG 2. Daily doses of inhaled steroids. Actual daily doses of ICS ( µ g: mean ±SEM) according to the AHRstrategy and the reference strategy. AHR strategy necessitated the use of higher mean doses than did thereference strategy throughout the 2-year study. Median difference in treatment and ICS was ±400 µ g dur-ing the 2-year follow-up. Treatment requirement decreased with both strategies; however, the decrease withthe AHR strategy was somewhat greater than with the reference strategy. (From Sont JK, Willems LN, BellEH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsivenessas an additional guide to long-term treatment in the AMPUL Study Group. Am J Respir Crit Care Med1999;159:1043-51. With permission.) FIG 3. Variability of response to asthma therapy. The response distribution according to FEV 1 shows a bell-shaped curve for both montelukast and beclomethasone and indicates that there may be a spectrum ofresponse, at least as measured by FEV 1 to drug therapy for asthma. In this study, all patients benefited frommandatory use of spacers, enforced compliance, and the rigorous monitoring of patients. Black bars, Patientsreceiving 10 mg/d montelukast; white bars, patients receiving inhaled 200 µ g beclomethasone twice daily.(From Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone andplacebo for Montelukast/Beclomethasone Study Group. Ann Intern Med 1999;130:487-95. With permission.) Image available in print only
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