Epidemiology, Clinical and Economic Burden, and Natural History of Chronic Obstructive Pulmonary Disease and Asthma

Supplements and Featured Publications, Treatment and Management Options for Reversible Airway Disease, Volume 10, Issue 5 Suppl

Chronic obstructive pulmonary disease (COPD)and asthma are conditions that exact a tremendoustoll on patients, providers, and society. The substantialincrease in the prevalence of both conditions inrecent decades has generated sizable concern fromboth domestic and global perspectives. The underlyingcharacteristics of both conditions involve inflammationof the respiratory tract, although the specificnature and reversibility of these processes differaccording to each illness. Within the context of diseasemanagement, acute exacerbations are importantclinical events that contribute to an increase inmorbidity and mortality, and may occur in anypatient suffering from the disease. Because theseconditions are highly important to clinical practiceand healthcare systems, this article will highlight keyaspects of epidemiology, burden of illness, and clinicalpresentation of COPD and asthma. A review ofthe definition, classification, and natural history isalso offered, emphasizing the role of acute exacerbations.In general, the natural history of both COPDand asthma is highly variable and not preciselydefined because of their heterogeneous clinicalcourses. Continued inquiry concerning the epidemiology,etiology, classification, and prognosis of eachcondition and related exacerbations may offer cliniciansimproved decision-making information to optimizeinterventions for affected patient populations.

(Am J Manag Care. 2004;10:S129-S138)

In 2001, approximately 12.1 millionadults older than 25 years of age werereportedly diagnosed with chronic obstructivepulmonary disease (COPD) in theUnited States. Another 24 million presentedwith impaired lung function that may suggesta marked underdiagnosis of the disease.1,2 COPD has been identified as thefourth leading cause of morbidity and mortalitydomestically, and projections estimatethat the condition will rise globally to be thefifth most common cause for morbidity andthe third most frequent cause of mortalityby the year 2020.2-4 Asthma is estimated toaffect 300 million people worldwide and 11%of the US population. By 2025, 400 millionpeople are expected to suffer from the illnessglobally.5 In the United States, more than 11million individuals reported having an asthmaattack in 2000; more than 5% were childrenunder 18 years of age.6

The economic burden of COPD is considerable,with direct medical costs in theUnited States estimated at $18 billion in2002, and indirect costs associated withmorbidity and mortality were approximately$14.1 billion.7 In asthma, direct medicalcosts were estimated to be $9.4 billion, withindirect costs comprising an additional $4.6billion.7 Hospital costs are a large single contributorto expenditures in both illnesses. In2002, costs of hospitalization constituted40.6% ($7.3 billion) of direct COPD costsand 33.0% ($3.1 billion) of direct asthmacosts.7 Prescription drugs constituted 20.6%($3.7 billion) of direct COPD costs and39.4% ($3.7 billion) of direct asthma costs.7Recent findings from The Epidemiologicaland Natural History of Asthma: Outcomesand Treatment Regimens (TENOR) studyhave also found a significantly higher burdenand resource utilization (eg, higher absenteeismrates, increased healthcare visits) inpatients with more severe or difficult-to-treatcases of asthma.8

Exacerbations in COPD and asthma are aprimary contributor to morbidity, mortality,and cost of illness in both hospital and outpatientsettings.5,9 An estimated 25% of casespresenting in emergency departments fordyspnea have been attributed to COPD-relatedexacerbations.10 In 2000, 16 millionphysician office visits and 1.5 million COP-Drelatedemergency department visits werereported; 726 000 hospitalizations and119 000 deaths also occurred secondary tothe disease.11,12 Approximately 2 millionemergency department visits, 478 000 hospitalizations,and 4400 deaths were attributedto asthma in 1999; 10.8 million physicianoffice visits placed asthma as a primarydiagnosis in the same year.6,13,14 Beyond thediscussion of the epidemiology and burdenof illness, the purpose of this article is topresent the definition, classification, clinicalpresentation, and natural history ofCOPD, asthma, and related exacerbationsin each condition.

Definitions and Classifications

COPD is a disease state characterized byprogressive airflow obstruction that is oftenaccompanied by airway hyperreactivity.15The development of COPD has been suggestedto be linked to several systemic sequelae,especially in advanced stages.16,17 Bothchronic bronchitis and emphysema areincluded within the definition of COPD;bronchitis involves a definition relating toclinical presentation (eg, long-term cough orsputum production extending over 3 monthsfor a period of at least 2 years) whereasemphysema centers on the pathology of thelung itself.18 In 2001, chronic bronchitisaccounted for 76% (9.2 million) of COPDcases whereas emphysema accounted for17% (2 million); the remainder involved bothconditions.1,19

Following the endorsement of theAmerican Thoracic Society, the NationalHeart, Lung, and Blood Institute of theNational Institutes of Health, and the WorldHealth Organization's (NHLBI/WHO) GlobalInitiative for Chronic Obstructive LungDisease (GOLD) identified COPD as "characterizedby airflow limitation that is notfully reversible. The airflow limitation is inmost cases both progressive and associatedwith an abnormal inflammatory response ofthe lungs to noxious particles or gases."20,21Typical symptomatic manifestations of COPDinclude cough, increased sputum production,and dyspnea on exertion. Although thecondition is often considered to be irreversiblebecause a complete remission of airflowlimitation does not typically occur,reversible components may also be present.

COPD is often associated with a history oftobacco smoking and occasionally with apredisposition to respiratory illness in childhood;approximately 10% to 15% of smokersdevelop the illness.16,22,23 As such, the mostcritical risk factor of COPD is considered tobe smoking, although genetic factors (eg, α1-antitrypsin deficiency) have been linked tothe condition.24 In older populations, mucushypersecretion, respiratory infections, andconcomitant cardiovascular conditions (eg,ventricular or atrial arrhythmias) are also ofimportance in the prognosis of COPD.25COPD is classified according to severityand often emphasizes pulmonary functionbased on forced expiratory volume in 1 second(FEV1), although symptoms and otherfactors are of importance. The staging ofCOPD offered by GOLD appears in Table 1.21

Asthma is a chronic inflammatory diseasewherein airflow obstruction is reversible andbronchial hyperresponsiveness is often manifestedsymptomatically by increased sputumproduction, shortness of breath,wheezing, coughing, and chest tightness.26-28The most universally accepted definition ofasthma was proposed by the NationalInstitutes of Health National AsthmaEducation and Prevention Program (NAEPP)at the NHLBI and has been subsequentlyused by the NHLBI/WHO Global Initiativefor Asthma (GINA):

"Asthma is a chronic inflammatorydisorder of the airways in which manycells and cellular elements play a role, inparticular, mast cells, eosinophils, T lymphocytes,neutrophils, and epithelialcells. In susceptible individuals, thisinflammation causes recurrent episodesof wheezing, breathlessness, chest tightness,and cough, particularly at night andin early morning. These episodes are usuallyassociated with widespread but variableairflow obstruction that is oftenreversible either spontaneously or withtreatment. The inflammation also causesan associated increase in the existingbronchial hyperresponsiveness to a varietyof stimuli."26,27

Asthma often develops in childhood,although adult onset is not infrequent, especiallybecause of occupational exposure topotential irritants. In children, risk factors forasthma have been identified as wheezing notrelated to rhinovirus infection, male sex, parenteralhistory of asthma, atopy, obesity,peripheral eosinophilia, severe infections ofthe lower respiratory tract, and increasedserum immunoglobulin E (IgE).29,30 Key riskfactors for asthma in adults include cigarettesmoking, rhinitis, atopy, family history ofasthma, and female sex.30 The susceptibilityto asthma that may be attributable to geneticpredisposition has been estimated to be ashigh as half of all cases.31

The classification of asthma is based onseverity, which considers general symptoms(eg, intermittent, long term), nighttimesymptoms, and pulmonary function. NAEPPuses the following schema relating to stepwisetherapy, beginning with the mildestforms and building in terms of severity:Step 1–Mild intermittent; Step 2–Mild persistent;Step 3–Moderate persistent; andStep 4–Severe persistent.6,27 Specific casesof asthma may also be described as seasonal,allergic, nocturnal, or cough variant and mayinvolve exercise-induced bronchospasm.6,27Further classification may include an indicatorof the severity of an acute exacerbation.Table 2 presents more detailed informationconcerning the general classification of asthmabased on severity that was developed byNAEPP.27

Although COPD and asthma similarlyinvolve airflow limitation and chronicinflammatory processes, the pathophysiologyof COPD contrasts with asthma concerningthe exact nature of inflammation. Theobstruction of airflow in COPD occurs secondaryto hypertrophy of smooth muscle,decreased elastic recoil pressure in emphysema,and peribronchiolar fibrosis.19 Thepresence of neutrophils, macrophages, andCD8+ T lymphocytes is considered to be ofprimary importance in COPD.32 In contrast,asthma predominantly involves eosinophils,mast cells, and CD4+-related mechanisms;IgE antibodies play a key role in immuneresponses associated with asthma.33


An exacerbation is a clinical event ofboth COPD and asthma that may result inhospitalizations, treatment within intensivecare units, or death. Although theseepisodes are most commonly associatedwith uncontrolled or severe conditions, allindividuals with COPD or asthma are atrisk.34 To illustrate the morbidity and mortalityassociated with exacerbations inCOPD, patients with an FEV1 below 50%predicted (ie, moderate-to-severe COPD)have been reported to experience 1 to 2exacerbations on a yearly basis.35,36Furthermore, exacerbations in COPD worsenthe natural history of disease and lowerquality of life to a greater degree than theaccompanied decreased lung functionbased on clinical function parameters.36-38Complete recovery in pulmonary functiondoes not occur quickly, with an estimated25% of patients reported not to haveregained preexacerbation lung function 35days after the event, and approximately halfof patients have been found to be readmittedwithin 6 months after discharge.39-41Although many investigations have foundinpatient mortality rates associated withCOPD exacerbations to be between 2.5%and 4%, GOLD has reported an overall rateof 10%, which increases to 40% in 1year.21,42 In patients older than 65 years ofage, the 1-year mortality rate has beenobserved to be as high as 59%.43 In emergencydepartments in the United States,asthma constitutes the eleventh most diagnosedcondition, and mortality for acuteasthma in intensive care settings was foundin one investigation to be as high as 22%,although rates are most often observed to bebetween 0% and 6%.44-46

Although no clear consensus currentlyexists across guidelines defining acute exacerbationin COPD, one definition offered is"a variation in symptoms above the normalday-to-day variation that causes a change ina patient's medications."47-49 More recently,this definition has been expanded to be a"sustained worsening of the patient's condition,from the stable state and beyond normalday-to-day variations that is acute inonset and may warrant additional treatmentin a patient with underlying COPD."34,48Because of discrepancies in definitions, theactual number of exacerbations in COPD ispresumed to be substantially underestimatedin the population.36,48 Furthermore, it hasbeen reported that approximately half of allCOPD exacerbations are not reported to clinicians.36,48 Despite a lack of standardization,most experts offer the 3 following clinical criteriafor changes beyond baseline that defineCOPD exacerbation: (1) increased sputumvolume, (2) increased sputum purulence,and (3) worsened dyspnea.50 Acute exacerbationsin COPD may also be associated withfever, chest tightness, and systemic symptoms.19 Although no explicit standardized orvalidated system is in use today, and numerousother methods have been proposed, thecommonly adopted grading method of COPDexacerbation severity appearing in Table 3 isbased on research presented by Anthonisenand colleagues.34,48,50,51 According to this stagingmethod, 3 groups are established ofincreasing severity: type I (mild), type II(moderate), and type III (severe).51

Primary factors associated with triggeringexacerbations in COPD may involve bacterialor viral infections and exposure to air pollution.21,52 Other causes include inappropriateuse of certain medications (eg, sedatives,narcotics, beta blockers), temperature orweather changes, and numerous comorbidities(eg, pulmonary embolism, pneumothorax,heart failure or arrhythmia).21,52Although the role of bacterial infections isconsidered to be somewhat controversial,colonization has been found to appear in46% to 53% of cases of chronic bronchitisexacerbation; other research has indicatedthat an estimated one third of COPD exacerbationsare of unknown origin or can beattributed to viral infections.53-56

In asthma, exacerbations range from mildcases to those that develop into life-threateningemergencies characterized by increasedmucus accumulation, severebronchospasm, airway edema, and markedinflammation.27,57 Generally, exacerbationsin asthma are classified as mild, moderate,or severe (Table 4) and are based on apatient's risk factors for asthma-relateddeath, pulmonary function (ie, <50% predictedpeak expiratory flow [PEF] is suggestiveof severe exacerbations), signs,symptoms, and response to initial treatment.27 Depending on the severity, exacerbationsin patients with asthma maysynonymously be referred to as simply anasthma attack, acute asthma, or severeacute asthma.58 Status asthmaticus is oftenreserved to describe cases of severe, acuteasthma wherein the chief concerns areimpending respiratory failure or asthma-relateddeath.46 Although most exacerbationsare associated with a somewhat slowprogression over time, a rapid onset has alsobeen observed.57,58 Exacerbations in asthmaare frequently related to environmentalexposure to allergens or irritants (eg, pollen,cigarette smoke) and viral infections (eg,rhinovirus).27,59,60 Other triggers may includenonspecific stimuli (eg, weather changes)and aspirin or certain nonsteroidal antiinflammatoryagents. History of suddensevere exacerbations, the use or recent withdrawalof systemic corticosteroids, andexcessive use of inhaled &#945;2-agonists (>1 canisterper month) have also been identified asmajor risk factors for severe exacerbationsor asthma-related death.27 Clinicians mustremain cognizant that patients who presentto emergency departments with severeexacerbations may be using inadequatetherapeutic regimens for chronic asthma.61

Natural History

The natural history of COPD may be lifethreateningand involve changes in symptoms,quality of life, utilization of healthcareresources, and the function or pathology ofthe lung.62,63 Lung function peaks in healthyindividuals in the early-to-mid 20s anddeclines with age.62 In smokers, the declinefollows a more curvilinear relationship, withfaster rates of decline noted in patients withincreased smoking patterns or in those withmore advanced COPD at initial diagnosis.61Age and FEV1 have been considered thestrongest predictors for mortality in COPDpatients.64 Although numerous other terminalevents may occur, mortality in COPDpatients often occurs as a result of respiratoryfailure, cor pulmonale, or pulmonaryinfection; acute respiratory failure in COPDmost often occurs because of acute exacerbationsof the disease.61,62,65

The prognosis of COPD is highly variablebetween patients, and more is understoodconcerning the clinical course of the conditionwhen symptoms become observable.61A patient's initial presentation to clinicalsettings typically involves more advanceddisease, with an acute exacerbation oftenbeing the first event to precipitate a medicalintervention. It is not uncommon forpatients who are first diagnosed with COPDto be in a moderate or severe stage, giventhat both clinical and physiologic observationstypically occur simultaneously in thesecategories.63,66 Chronic bronchitis typicallyprogresses with a decline in respiratoryfunction, increased frequency of exacerbations,and the development of potentiallylife-threatening complications, such as corpulmonale or hypercapnia. Patients withemphysema often develop worsening dyspnea,whereas exacerbations may be lesslikely to be associated with sputum productionas seen in bronchitis. Consistentwith bronchitis, however, complications inemphysema including cor pulmonale andhypercapnia are important clinical eventsthat may lead to increased morbidity andmortality. The Figure presents a hypotheticalrepresentation of the natural history ofCOPD, assuming that biochemical and cellularevents result in changes detectable withspirometry and clinical and radiographicchanges appearing as the disease progressesin severity and over time.63

The natural history of asthma remainspoorly defined.67 The condition has beendescribed as being a syndrome rather than aspecific illness because of its broad and heterogeneousetiology and clinical presentation.63 Relative to COPD, mortality is lowerfor asthma; it has been suggested that anestimated 80% to 90% of asthma-relateddeaths may have been prevented.27 Inflammationprogresses throughout the airwaysand parenchyma and affects the mechanicsof the lung, also manifesting with airwaynarrowing and airflow limitation. Asthma isnot generally classified as a disease that isprogressive or irreversible like COPD; however,a process termed airway remodelingdescribes irreversible physiologic changes inthe airways that occur secondary to observedchronic inflammatory processes.68 Estimatesindicate that 28% to 78% of young childrenwith asthma ultimately have symptom resolutiononce adulthood is reached, with 6% to19% continuing with severe forms of thedisease.69

The clinical course of asthma does notgenerally follow the same relationshipbetween time and severity as with COPD,although it has been suggested that cliniciansshould remain aware of any possibilitythat patients with persistent asthma maydevelop fixed airway obstruction.70 The long-termprognosis of asthma may often be bestcharacterized relative to the number andseverity of exacerbations, because theseacute episodes contribute substantially tomorbidity and mortality associated with thedisease. A patient's atopic status (ie, IgE-relatedimmune responses to environmentalstimuli) has been stated as being the mostimportant risk factor for predicting persistentasthma and the strongest predictor of apoor prognosis.30,61 To more fully understandthe natural history of asthma, the ongoingTENOR study was initiated and remains thelargest cohort of patients with severe or difficult-to-treat asthma that has been empiricallyobserved to date.8

Discussion and Conclusion

An accurate and differential diagnosis ofeither COPD or asthma is crucial regardlessof which disease state the exacerbationoccurs. Patients often present with shortnessof breath, wheezing, or other symptomsconsistent with congestive heart failure (eg,mitral stenosis, left ventricular failure),small pulmonary emboli, hyperventilationsyndrome, or numerous upper airwayobstructions (eg, laryngeal spasm, superiorvena cava syndrome, foreign body aspiration).58,71-73 Furthermore, symptoms may notdiffer substantially between exacerbations ofCOPD and asthma.72,74 Severity must beappropriately gauged to guide clinical interventionsand to ensure that no delay inemergent care or hospitalization occurs thatmay result in patient morbidity or mortality.75 Quantitative assessments of lung functionwith FEV1 and PEF are helpful indiagnosis, monitoring, and treatment.Comprehensive assessments should be conductedconcerning any risk factors or exposure,time of onset and severity of thepresenting exacerbation and of previousattacks, medication use, comorbidities,prior hospitalizations, history of respiratoryfailure, and other information in the courseof a differential diagnosis.20,58 Specific componentsin assessing medical history, physicalexamination, spirometry, pulse oximetry,arterial blood gases, chest radiography, andcardiac rhythm are described elsewhere.6,21,26,27,58,76 In COPD, other useful informationcollected from a chest roentgenogram,electrocardiogram, and laboratory tests (eg,white blood cell count with differential,hemoglobin/hematocrit, sputum, &#945;1-antitrypsin)may assist in establishing an overalldiagnosis, in differentiating emphysemafrom bronchitis, or in assessing complicationssuch as cor pulmonale.61

Overall, COPD and asthma are diseasesthat have a tremendous impact relating toepidemiology and burden of illness forpatients, healthcare systems, and society.The underlying characteristics of both conditionsinvolve inflammation of the respiratorytract, although the specific nature andreversibility of these processes differ accordingto each illness. Within COPD and asthma,acute exacerbations represent clinicalevents that are associated with relativelyhigh levels of mortality and morbidity, andmay occur in any patient suffering from thedisease. In general, the natural history ofboth COPD and asthma is highly variableand not precisely defined because of theirheterogeneous clinical courses. Continuedinquiry concerning the epidemiology, etiology,prognosis, and classification of each conditionand related exacerbations may offerclinicians improved decision-making informationto offer optimal interventions foraffected patients.

1. National Center for Health Statistics. National Health Interview Survey. Hyattsville, Md: USDepartment of Health and Human Services; 2001.

2. National Heart, Lung, and Blood Institute. Data Fact Sheet: Chronic Obstructive Pulmonary Disease. NationalInstitutes of Health Publication 03-5229. Bethesda, Md: US Department of Health and Human Services; 2003.


3. Hurd S. The impact of COPD on lung health worldwide: epidemiology and incidence. . 2000;117(suppl):1S-4S.


4. Murray CJ, Lopez AD. Alternative projection of mortality by cause 1990-2000: global burden of diseasestudy. . 1997;349:1498-1504.

5. Masoli M, Fabian D, Holt S, Beasley R. Global Burden of Asthma. Global Initiative for Asthma (GINA).Wellington, New Zealand; Medical Research Institute of New Zealand, Southampton, United Kingdom; Universityof Southampton; 2003.

6. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program (NAEPP).Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. National Institutes of HealthPublication 02-5074. Bethesda, Md: US Department of Health and Human Services; 2003.

7. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chartbook on Cardiovascular, Lung,and Blood Diseases. Bethesda, Md: US Department of Health and Human Services; 2002.

Ann Allergy Asthma Immunol

8. Dolan CM, Fraher KE, Bleecker ER, et al, for the TENOR Study Group. Design and baseline characteristicsof The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: alarge cohort of patients with severe or difficult to treat asthma. . 2004;92:32-39.

9. Management of acute exacerbations of chronic obstructive pulmonary disease. Summary, EvidenceReport/Technology Assessment: No. 19. Agency for Healthcare Research and Quality Publication 00-E020.Rockville, Md: Agency for Healthcare Research and Quality; 2000.

Nurs Res

10. Parshall M. Adult emergency visits for chronic cardiorespiratorydisease: does dyspnea matter? .1999;48:62-72.

11. National Center for Health Statistics. National Hospital Ambulatory Medical Care Survey. Hyattsville,Md: US Department of Health and Human Services; 1995-2000.

12. National Center for Health Statistics. National Hospital Discharge Survey. Vital and Health StatisticsSeries. Hyattsville, Md: US Department of Health and Human Services; 1995-2000.

N Engl J Med

13. Weiss KB, Gergen PJ, Hodgson TA. An economicevaluation of asthma in the United States. . 1992;326:862-866.

MMWR Surveill Summ

14. Mannino D, Homa D, Akinbami L, et al. Surveillance for asthma-United States, 1980-1999.. 2002;51:1-14.

Am J Respir Crit Care Med

15. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonarydisease. . 1995;152(suppl):77S-121S.


16. Fletcher C, Peto R. The natural history of chronic airflow obstruction. . 1977;1:1645-1648.


17. Wouters EF, Creutzberg EC, Schols AM. Systemic effects in COPD. . 2002;121(suppl):127S-130S.


18. Calverley PMA, Walker P. Chronic obstructive pulmonary disease. . 2003;362:1053-1061.

Clin Cornerstone

19. Rennard SI. Pathogenesis of COPD. . 2003;5:11-16.

Am J Respir Crit Care Med

20. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS, on behalf of the GOLD Scientific Committee.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.NHLBI/WHO Global Initiative for Chronic ObstructivePulmonary Disease (GOLD) workshop summary. . 2001;163:1256-1276.

21. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis,Management, and Prevention of Chronic Obstructive Pulmonary Disease, Updated 2003. National Heart, Lung,and Blood Institute, World Health Organization; 2003.

22. US Surgeon General. The health consequences of smoking: obstructive lung disease. Washington, DC: USDepartment of Health and Human Services; 1984.

Am Rev Respir Dis

23. Gold DR, Tager IB, Weiss ST, Tosteson TD, Speizer FE. Acute lower respiratory illness in childhood as a predictorof lung function and chronic respiratory symptoms. . 1989;140:877-884.

J Clin Invest

24. Lomas DA, Mahadeva R. Alpha 1 antitrypsin polymerizationand the serpinopathies: pathobiology and prospects for treatment. . 2002;110:1585-1590.

Eur Respir J

25. Pistelli R, Lange P, Miller DL. Determinants of prognosis of COPD in the elderly: mucus hypersecretions,infections, cardiovascular comorbidity. . 2003;21(suppl):10S-14S.

26. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention,Updated 2003. National Institutes of Health Publication 02-3659. Bethesda, Md: US Department of Health andHuman Services; 2002.

27. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program (NAEPP),Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of HealthPublication 97-4051. Bethesda, Md: US Department of Health and Human Services; 1997.

Clin Chest Med

28. Sears MR. Consequences of long-term inflammation: the natural history of asthma. . 2000;21:315-329.

Am J Respir Crit Care Med

29. Castro-Rodriquez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma inyoung children with recurrent wheezing. . 2000;162:1403-1406.

Southern Med J

30. Roy SR. Asthma. . 2003;96:1061-1067.

Am J Respir Crit Care Med

31. Sandford A, Weir T, Pare P. The genetics of asthma. . 1996;153:1749-1765.

Am J Respir Crit Care Med

32. Saetta M, Turato G, Maestrelli P, et al. Cellular andstructural bases of chronic obstructive pulmonary disease. . 2001;163:1304-1309.

33. McFadden EF, Hejal RB. The pathobiology of asthma: implications for treatment. Clin Chest Med. 2002;21:213-224.

Eur Respir J

34. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. . 2003;21(suppl): 46S-53S.


35. Burge PS, Calverley PM, Jones PW, et al. Randomized, double blind, placebo controlled study of fluticasonepropionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. . 2000;320:1297-1303.

Am J Respir Crit Care Med

36. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronicobstructive pulmonary disease. . 1998;157:1418-1422.

Am J Respir Crit Care Med

37. Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patientswith chronic obstructive pulmonary disease. . 2000;161:1608-1613.

Respir Med

38. Doll H, Grey-Amante P, Duprat Lomon I, et al. Quality of life in acute exacerbation of chronic bronchitis:results from a German population study. . 2002;96:39-51.


39. Donaldson GC, Seemungal TA, Bohowmik A, Wedzicha JA. Relationship between exacerbation frequencyand lung function decline in chronic obstructive pulmonary disease. . 2002;57:847-852.

Am J Respir Crit Care Med

40. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronicobstructive pulmonary disease: the SUPPORT investigators (Study to Understand Prognoses and Preferencesfor Outcomes and Risks and Treatments). . 1996;154:959-967.

N Engl J Med

41. Weinberger M, Oddone EZ, Henderson WG. Does increased access to primary care reduce hospital readmissions?Veterans Affairs Cooperative Study Group onPrimary Care and Hospital Readmission. .1996;334:1441-1447.


42. Mushlin AI, Black ER, Connolly CA, Buonaccorso KM, Eberly SW. The necessary length of hospital stay forchronic pulmonary disease. . 1991;266:80-83.


43. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patientsadmitted to intensive care units with acute exacerbationof chronic obstructive pulmonary disease. . 1995;274:1852-1857.

Adv Data

44. Burt CW, Knapp DE. Ambulatory care visits for asthma: United States, 1993-1994. . 1996;277:1.

Am J Med

45. Mansel JK, Stogner SW, Petrini MF, et al. Mechanical ventilation in patients with acute severeasthma. . 1990;89:42-48.


46. Shapiro JM. Intensive care management of status asthmaticus. . 2001;120:115-119.


47. MacNee W, Calverley PMA. Chronic obstructivepulmonary disease: management of COPD. .2003;58:261-265.


48. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. . 2000;117(suppl):398S-401S.


49. Voelkel NF, Tunder R. COPD exacerbation. . 2000;117(suppl):365S-379S.

Ann Intern Med

50. Bach PB, Brown C, Gelfand SE, McCrory DC. Management of acute exacerbations of chronic obstructivepulmonary disease: a summary and appraisal of published evidence. . 2001;134:600-620.

Ann Intern Med

51. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructivepulmonary disease. . 1987;106:196-204.

Emerg Med Clin North Am

52. Palm KH, Decker WW. Acute exacerbations ofchronic obstructive pulmonary disease. . 2003;21:331-352.


53. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. . 2000;117(suppl):380S-385S.


54. MacFarlane JT, Colville A, Guion A, MacFarlane RM, Rose DH. Prospective study of aetiology and outcomeof adult lower-respiratory tract infections in the community. . 1993;341:511-514.

Clin Infect Dis

55. Codosh S, McCarty J, Farkas S, et al. Randomized double-blind study of ciprofloxacin and cefuroximeaxetil for treatment of acute bacterial exacerbations ofchronic bronchitis. The Bronchitis Study Group. . 1998;27:722-729.


56. Patel IS, Seemungal TA, Wilks M, et al. Relationship between bacterial colonization and the frequency, character,and severity of COPD exacerbations. .2002;57:759-764.

Am Rev Respir Dis

57. Strunk RC. Death due to asthma: new insights into sudden unexpected deaths, but the focus remains onprevention. . 1993;148:550-552.


58. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. . 2004;125:1081-1102.


59. Nicholson K, Kent J, Ireland D. Respiratory virusesand exacerbations of asthma in adults. . 1993;307:982-986.


60. Johnston SL, Pattermore PK, Sanderson G, et al. Community study of the role of viral infections in exacerbationsof asthma in 9-11 year old children. . 1995;310:1225-1229.

Pharmacotherapy: A Pathophysiologic Approach

61. Kelly HW, Sorkness CA. Asthma. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. . New York, NY: McGraw-Hill; 2002.

Eur Respir J

62. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. . 2001;17:982-994.


63. Petty TL. COPD in perspective. . 2002;121 (suppl):116S-120S.

Am J Respir Crit Care Med

64. Hansen EF, Phanareth K, Laursen LC, Kok-Jensen A, Dirksen A. Reversible and irreversible airflow obstructionsas predictor of overall mortality in asthma and chronic obstructive pulmonary disease. . 1999;159:1267-1271.

Mondali Arch Chest Dis

65. Zielinski J, MacNee W, Wedzicha J, et al. Causes of death in patients with COPD and chronic respiratoryfailure. . 1997;52:43-47.

Eur Respir J

66. Engstrom CP, Persson LO, Karson S, Sullivan M. Health-related quality of life in COPD: why both disease-specific and generic measures should be used. . 2001;18:69-76.

Current Diagnosis and Treatment in Pulmonary Medicine

67. Kaminsky DA. Asthma. In: Hanley ME, Welsh CH,eds. . New York, NY: Lange; 2003.

Am J Respir Crit Care Med

68. Busse W, Elias J, Sheppard D, Banks-Schlegel S.Airway remodeling and repair. . 1999;160:1035-1042.

Pediatric Asthma

69. Ahmed IH, Sarnet JM. The natural history of asthma. In: Murphy S, Kelly HW, eds. . NewYork, NY; Marcel Dekker; 1999.

Conn's Current Therapy 2004

70. Patel AC, Bacharier LB. Asthma in children. In:Rakel RE, Bope ET, eds. . Philadelphia, Pa: Saunders; 2004.

Obstet Gynecol Clin North Am

71. James AW. Asthma. . 2001;28:305-320.

Eur Respir J

72. Van Schayck CP, Chavannes NH. Detection of asthma and chronic obstructive pulmonary disease in primarycare. . 2003;21(suppl):16S-22S.

Eur Respir J

73. Weiss ST, DeMeo DL, Postma DS. COPD: problemsin diagnosis and measurement. . 2003;21(suppl):4S-12S.

Eur Respir J

74. Buist AS. Similarities and differences between asthma and chronic obstructive pulmonary disease: treatmentand early outcomes. . 2003;21(suppl):30S-35S.


75. Kolbe J, Vamos M, Fergusson W, et al. Determinantsof management errors in acute severe asthma. . 1998;53:14-20.

Med Clin North Am

76. Siwik JP, Nowak RM, Zoratti EM. The evaluationand management of acute, severe asthma. . 2002;86:1049-1071.