CURRICULUM VITAE Martin Roy First Division of Nephrology & Hypertension MARITAL STATUS: Married - 2 children CITIZENSHIP: University of Witwatersrand, M.B., B.Ch., 1966 House Surgeon, Johannesburg General Hospital Johannesburg, South Africa, January – June, 1967 House Physician, Johannesburg General Hospital Johannesburg, South Africa, July - December, 1967 Medical Officer, S
Doi:10.1016/j.jaci.2005.08.034Spirometric criteria for asthma: Adding furtherevidence to the debate Sarah L. Appleton, BSc (Hons),a Robert J. Adams, MBBS, MD,a David H. Wilson, PhD,a Anne W. Taylor, MPH,b and Richard E. Ruffin, MBBS, MD,a on behalf of the North West Adelaide Cohort Health Study Team Woodville and Adelaide, Australia Background: Objective assessments of pulmonary function are Key words: Asthma, spirometry, bronchodilator response, asthma considered essential for the diagnosis of asthma. The degree of reversibility of FEV1 considered supportive of asthma variesbetween international asthma guidelines.
Objective: We sought to compare the relative performance of Asthma-like symptoms in adults can be explained international guideline reversibility criteria for identifying by differential diagnoses, including cardiac, neurologic, impairment in persons with a significant bronchodilatorresponse (SBR) without an asthma diagnosis.
and drug-related causes.The diagnosis of asthma in Methods: The North West Adelaide Health (Cohort) Study, adults can be difficult and confounded by comorbidities.
a population biomedical study of 4060 subjects, conducted A gold standard test would simplify the diagnosis of spirometry according to American Thoracic Society criteria.
asthma and perhaps reduce the frequency of underdiag- SBR was defined as postbronchodilator FEV1 responses of at nosed asthmhowever, no gold standard existsAirway least 12% or 15% of baseline values, 9% of predicted values, responsiveness is considered a hallmark of asthma.
or 400 mL. A self-completed questionnaire assessed current Although it has been suggested that airway hyperrespon- asthma (CA), respiratory symptoms, and participant siveness testing in primary practice might reduce the problem of delayed diagnosis and inappropriate Results: The prevalence of CA was 9.4% (n 5 380), whereas the test is complex, invasive, and conducted by pulmo- 1.3% ($400 mL) to 4.5% ($9% of predicted value) ofparticipants demonstrated an SBR in the absence of CA.
nary function laboratories.Epidemiologic studies have With the exception of the 9% predicted criterion, shown that the specificity of the test for an asthma diag- nosis (derived by physician or questionnaire) is high; demonstrating an SBR but no CA was significantly worse however, the sensitivity is poor,limiting its positive than that in the CA group. Significantly more respiratory predictive value. Furthermore, there is a continuum of symptoms were experienced by the SBR groups than the bronchial responsiveness in the normal population that group without asthma. Logistic regression analyses identified overlaps with that in the asthmatic population, clearly pre- different characteristics of those classified by the following venting a discriminatory cutoff separating the asthmatic criteria: 12% and 15%, age of 40 years or greater and household income of less than $40,000; 9% predicted, struction also display a broad range of airway responsive- household income of less than $40,000; 400 mL, male sex(odds ratio, 4.5; 95% CI, 2.1-9.3).
nessfrom normal to asthmatic, which is dependent on Conclusions: Different criteria identify different persons, but SBR by any criteria was associated with significant The National Asthma Education and Prevention respiratory impairment, some of which might be attributable Programidentifies the importance of spirometry for to asthma. Postbronchodilator change as a percentage of the diagnosis of asthma, given that physicians have a predicted value was the least biased of the criteria. (J Allergy limited ability to estimate the degree of obstructionor predict reversibility of the obstruction.The NationalAsthma Education and Prevention Program report alsorecommends spirometry over peak expiratory flow mea-surements because of the wide variability in peak expira-tory flow reference values. International asthma guidelines From aThe Health Observatory, Department of Medicine, University of recommend that reversibility of FEV1 in response to in- Adelaide, The Queen Elizabeth Hospital Campus, Woodville, and bthe halation of short-acting bronchodilators is indicative of Population Research and Outcome Studies Unit, South Australian De-partment of Health, Adelaide.
asthma; however, the degree of reversibility considered Supported by the University of Adelaide and the South Australian Department significant varies between guidelines. The British Thoracic Societyrecommends at least 15% of baseline FEV1, Received for publication March 29, 2005; revised August 2, 2005; accepted Reprint requests: Robert J. Adams, MBBS, MD, The Health Observatory, Initiative for Asthma recommend at least 12% Department of Medicine, University of Adelaide, The Queen Elizabeth of baseline FEV1, and others recommend 9% of the pre- Hospital Campus, Woodville Rd, Woodville, South Australia, 5011.
The diagnostic value of reversibility to separate asthma from chronic obstructive pulmonary disease (COPD) has Ó 2005 American Academy of Allergy, Asthma and Immunologydoi:10.1016/j.jaci.2005.08.034 been debated for some time.Lack of response to a information on sociodemographic factors was obtained in this ques- tionnaire and the telephone interview. Of the 8213 eligible house- BTS/SIGN: British Thoracic Society/Scottish Intercollegiate holds contacted, 71.2% (n 5 5850) were interviewed. The clinic participation rate as a proportion of eligible selected households was 49.4% (n 5 4060). Demographic data on persons who refused participation were also obtained to compare with participants and COPD: Chronic obstructive pulmonary disease allow for appropriate weighting in the analyses.
Self-reported current confirmed asthma (CA) was defined as a NICE: National Institute for Clinical Excellence positive response to all 3 of the following questions: (1) ‘‘Have you ever had asthma?,’’ (2) ‘‘Was your asthma confirmed by a doctor?,’’and (3) ‘‘Do you still have asthma?’’ SBR was defined as reversibility according to the criteria in the absence of CA (ie, ‘‘yes’’ or ‘‘no’’ to question 1, but if ‘‘yes,’’ then ‘‘yes’’/‘‘no’’/‘‘don’t know’’ in response single bronchodilator reversibility test is not indicative of to question 2 and then ‘‘no’’/‘‘don’t know’’ in response to question 3.
long-term response to treatment.However, patients with Spirometry was conducted in 2 hospital-based clinics (Microlab 3300spirometer; Micro Medical LTD, Kent, United Kingdom), according to American Thoracic Society criteria.Each subject performed at reversibility testing, have demonstrated subsequent re- least 3 acceptable and reproducible forced vital capacity maneuvers.
sponses to long-term therapy for objective and subjective Reversibility of airway obstruction was defined by using several cri- outcomes only half as great as those of patients classified teria for the increase in FEV1 after inhalation of 400 mg of salbutamol as This lends some validity to the use of of at least 12% (American Thoracic Society/GINA)or 15% of base- a reversibility test to predict the outcomes of treatment.
line values or 9% of predicted FEV1 (assuming the Recently in the United Kingdom, the National Institute increase exceeded 200 mL) and 400 mL (NICE).Reversibility as for Clinical Excellence (NICE) guidelines for COPD a volume of FEV1 (in liters; REVFEV1) was defined as follows: recommended a change of at least 400 mL of FEV1 in re- sponse to an acute bronchodilator test or a short course of oral or inhaled corticosteroids for an increase in FEV1 Reversibility as a percentage of baseline was calculated as follows: to demonstrate asthma. The danger in an older populationwith an age-related decrease in lung volumes is that the ½REVFEV1=Prebronchodilator FEV1 ðLÞ 3 100: 400 mL reversibility criterion might misclassify personswith significant reversibility that is amenable to treatment.
If participants’ reversibility was equal to or exceeded 12% or 15%,then participants were classified as reversible according to the 12% Alternate reversibility criteria might generate false- and 15% criteria, respectively. Nine percent of the predicted prebron- positive results, but this could be preferable to the alterna- chodilator FEV1 (in liters) was calculated for each participant with the tive of underdiagnosis, given the potential poor health The aim of this study was to determine the prevalence of 0:09 3 ½Prebronchodilator FEV1 ðLÞ=ðPrebronchodilator FEV1 % asthma according to self-report in the North West Adelaide Health (Cohort) Study, a biomedical population study of4060 persons. We also sought to determine the prevalence If the FEV1 reversibility (L) was equal to or exceeded this volume, of a significant bronchodilator response (SBR) in those then the participant was considered to be reversible according to without an asthma diagnosis according to international the 9% predicted criterion. Participants were considered to be revers- guideline reversibility criteria. This enabled us to charac- ible according to the 400 mL criterion if the FEV1 reversibility (L) terize those identified by the criteria in terms of impairment and demographics. To our knowledge, this is the first Analysis of the performance of the reversibility criteria in terms of examination of the performance of the NICE reversibility identifying impairment was limited to persons who were classified bythe reversibility criteria but without a diagnosis of current asthma and criterion in a representative population sample.
therefore were steroid naive. This was to demonstrate unmodifiedeffects on the respiratory health attributable to unrecognized (signif-icant) bronchodilator responsiveness.
The Chronic Lung Disease (CLD) Indexwas administered to de- The methods of the North West Adelaide Health (Cohort) Study termine the severity of respiratory symptoms in the population. This have been described previously.Briefly, all households in the is a 6-item questionnaire scored out of 100, with subscales relating to northwest region of Adelaide that were listed in the electronic the frequency and intensity of dyspnea and wheezing and frequency ‘‘White Pages’’ telephone directory were eligible for selection. A of coughing and volume of sputum production. Categories of severity letter of introduction was sent to the household of each randomly are as follows: mild, 43 or less; moderate, 44 to 62; and severe, 63 or selected telephone number. Selected households received a tele- greater. These categories have demonstrated discriminative value be- phone call inviting the person with the most recent birthday and tween different levels of chronic lung disease that affect quality of life who was at least 18 years of age to participate in the study. Up to 5 across physical and mental health scales.The CLD Index has been callbacks were made to interview the selected person, and there validated in US and Australian population studies.It has shown a was no replacement for nonresponse. The validity of these methods high level of agreement with clinical data, including peak flow of selection criteria to achieve an unbiased sample has been described Those agreeing to participate were sent an information Institutional ethics committee approval was obtained for the packet that included a self-administered questionnaire. Self-reported TABLE I. Population prevalence of significant bronchodi- CI, 25.2 to 12.0), and as a percentage of predicted FEV1, lator reversibility according to various FEV1 the mean response was 3.2% of predicted value (95% CI, 24.5 to 10.9). In those with SBR and no CA, the medianreversibility as a percentage of baseline ranged from 12.8% (9% predicted criterion) to 19.5% (15% criterion).
As an absolute volume (in liters), the median reversibility ranged from 0.34 (9% predicted criterion) to 0.48 (400 mL disparity in the performance of the criteria to identify re- versibility, which was related to the number identified by each criterion. For example, of the 153 participantswith FEV1 reversibility of at least 12% of baseline value,97% were also reversible according to the 9% of predicted Data presented here were analyzed with the Statistical Package value criterion (k 5 0.73). Conversely, of the 248 revers- for Social Sciences (SPSS Inc, Chicago, Ill), version 10.0 for ible according to the 9% of predicted value criterion, only Windows and were weighted to the Australian Bureau of Statistic’s 59% were reversible according to the 12% criterion. The k 1999 estimated resident population by region (west and north), values show the highest agreement between the 12% and age groups, sex, and probability of selection in the household.
15% criteria (k 5 0.77) and the 12% and 9% of predicted Agreement between the reversibility criteria in the classification of value criteria (k 5 0.73). The lowest agreement occurred an SBR was determined by using the k test ratio. Multiple analysisof variance was used to calculate mean prebronchodilator and post- between the 400 mL criterion and the other standard crite- ria, reflecting the large lung volumes in this group of pre- 1 absolute and percent predicted values, adjusting for baseline covariates, including age and sex. Statistically significant dominantly young male subjects identified by the 400 mL differences in proportions were determined by using the x2 test (Epi criterion. Importantly, the 9% of predicted value crite- Info Version 6). The Student t test was used to determine statistically rion identified nearly all patients who were classified by significant differences in mean values (GraphPad Instat, version the standard criteria (12%, 15%) and the 400 mL 2.02). Odds ratios were calculated with Epi Info version 6.
Variables significant in univariate analysis at a P value of less than Respiratory function for those with CA or a SBR with .25were included in logistic regression analyses (enter method) to determine the best set of explanatory variables to describe those adjusted prebronchodilator and postbronchodilator FEV demonstrating an SBR without a diagnosis of CA. Tests for colinear- ity were conducted before the logistic regression analyses, and none of the CA group was significantly worse than that of the group without asthma; however, postbronchodilatorvalues (percent predicted) returned to near-normal levels.
Mean prebronchodilator and postbronchodilator FEV1 (absolute and percent predicted) of those classified bythe 12% and 15% reversibility criteria were significantly Complete spirometric and self-reported CA data were worse than the values for the CA group and the group available for 4002 (98.5%) participants. Current asthma without asthma. The exception to this was that the post- was reported by 9.4% (n 5 380) of the study participants.
bronchodilator values of those classified by the 12% crite- shows that the prevalence of reversibility in the rion were similar to the values for the CA group. Those population according to differing criteria ranged from classified by the 9% of predicted value criterion also dem- 2.0% for the 400 mL or greater criterion to 6.2% for the onstrated significantly worse respiratory function than the 9% of predicted value or greater criterion. The prevalence group without asthma, and the postbronchodilator FEV1 of significant bronchodilator responsiveness (ie, revers- returned to normal values with significantly less impair- ibility without a CA diagnosis) ranged from 1.3% to ment than that seen in the subjects with current asthma.
4.5%. The proportion of current asthmatic subjects dem- Compared with the other criteria, the FEV1 values of onstrating SBR was low and ranged from 6.7% (400 mL those classified by the 400 mL criterion showed a differ- criterion) to 17.9% (9% of predicted value criterion).
ent pattern. Unlike the other criteria, the unadjusted pre- Of those classified as having SBR with no CA, only bronchodilator absolute FEV1 of this group (3.14 L) was 19.6% (9% of predicted value) to 26.4% (400 mL not significantly different from that of the group without criterion) responded that they had ever had physician- asthma; however, this value equated to 84% of predicted confirmed asthma but no longer believed they had asthma.
value. After adjustment for age and sex, prebronchodilator In addition, of those classified as having ‘‘no asthma,’’ values were significantly worse than those in the CA group 9.6% responded they had ever had physician-confirmed and the group without asthma. Postbronchodilator values returned to near normal and were similar to those in the In the population with no CA and no airways obstruc- CA group and the group classified by the 9% of predicted tion, the mean bronchodilator response, as an absolute volume, was 0.10 L (95% CI, 20.15 to 0.35). As a per- Mean CLD Index scores for respiratory symptoms in centage of baseline, the mean response was 3.4% (95% the population are also shown in indicating that TABLE II. Ability of FEV1 reversibility criteria to capture cases of significant bronchodilator reversibility and agreementaccording to k ratio TABLE III. Mean FEV1 (absolute and percent predicted) and CLD Index scores according to significant bronchodilator NB, No asthma: n range, 3458 (9% of predicted value and 200 mL criteria) to 3481 (400 mL criterion).
*CLD Index40 is a 6-item questionnaire with subscales of dyspnea, wheezing, and cough-sputum and scored out of 100 as follows: mild, 43 or less; moderate,44 to 62; severe, 63 or greater.
Significantly different from CA, P < .001.
àSignificantly different from no asthma, P < .001.
§Significantly different from CA, P < .05.
the SBR groups experienced significantly less respiratory discordance between different criteria. Both the frequency symptoms than the CA group but significantly worse and the characteristics of individuals classified with an symptoms than the group without asthma after adjustment SBR but without a diagnosis of CA varied. The logistic regression analyses identified a significant sex bias in Among those with CA, 14% demonstrated airways the ability of the NICE criterion to detect SBR, which obstruction, whereas among those with SBR and no CA, might be asthma. This criterion was established to avoid the prevalence ranged between 7% (400 mL criterion) and the misclassification of persons with COPD who have 21% (15% criterion). Less than 2% of the group without reversibility of their airway obstruction as having asthma.
However, women with airways obstruction with a large re- The best sets of sociodemographic variables to describe versible component but less than 400 mL are more likely the various SBR (no CA) groups as determined by logistic to be classified as having COPD by using this criterion.
regression are presented in The 12% and the Given the possible diverging therapeutic strategies for 15% reversibility criteria consistently identified individ- asthma and COPD and the associated long-term outcomes, uals who were likely to be older than age 40 years with this has implications for such patients if inhaled steroid lower levels of income. The 9% of predicted value and 400 mL criteria were not age specific; however, the 400 However, all criteria have the potential to misclassify mL criterion was selective in its identification of men.
patients. In our study the GINA and BTS/SIGN criteriamissed patients with an SBR who were identified by theNICE criterion of 400 mL or greater reversibility. These subjects were almost exclusively young male subjectsaged less than 35 years with large lung volumes such that It is clear from this study that the 4 reversibility criteria reversibility of 400 mL was less than 12% of their classify quite different persons, which, although intuitive, prebronchodilator FEV1. The standard criteria (12% has not been previously demonstrated in a large repre- and 15%) appear biased in their ability to detect cases sentative population sample. This has considerable impli- among younger persons, indicating a potential need for cations for clinical practice and for the interpretation of age-specific cutoffs. This might be achieved by using epidemiologic studies examining asthma prevalence.
reversibility as a percentage of predicted FEV1, as recom- Consistent with previous studies in COPD,bron- mended by Quanjer et al.However, the 9% predicted chodilator reversibility was normally distributed in the criterion also missed 6% of cases (n 5 5) among those population. Consequently, there is likely to be a large identified as having at least 400 mL of FEV1 reversibility.
TABLE IV. Logistic regression analysis of factors associ- that ‘‘an unambiguous bronchodilator response should ated with significant bronchodilator responsiveness in the exceed spontaneous variability and the response observed absence of CA, as classified by FEV1 reversibility criteria in healthy individuals.’’ The upper 95% CI of short-termvariability in persons with stable obstructive and restric- tive defects has been shown to be less than or equal to 0.19 L.The NICE criteria of an increase of at least 400 mL in FEV1 being necessary to demonstrate asthma appears to be derived from evidence from the ISOLDE study, in which 95% of nonasthmatic, nonbronchodilator- responsive (<10% of predicted value) ex-smokers with COPD demonstrated an FEV1 response to prednisolone of up to 412 Two large North American population samples, by Lorber et aland Dales et al,have demon-strated upper 95th percentile of FEV1 bronchodilator re- *Reference categories: age less than 40 years, not receiving a government sponse in healthy subjects in the range of 7.7% to benefit, annual household income of $40,000 or greater, and female sex.
9% respectively. Dales et alrecommended the use ofat least 9% of predicted value given its stability across There is a substantial burden of unidentified disease sex-age-height groups. The criteria specified by the in the community. Regardless of the criteria used, the BTS/SIGN and GINA guidelines are derived from these frequency of persons with significant reversibility and impairment without a diagnosis of asthma or COPD is Importantly, the SBR groups in the present study demon- considerable. Among these individuals, lung function and strated median bronchodilator reversibility far exceeding respiratory symptoms were significantly worse than in the spontaneous variability of the test and that seen in persons without asthma. However, in terms of symptoms our group without asthma. The North West Adelaide experienced, these persons are not as burdened as those Health (Cohort) Study cohort is currently undergoing with current asthma. Therefore the potential exists for clinic reassessment, and a proportion of the asthmatic gains to be made through identification and treatment of subjects are undergoing saline bronchial challenge testing, many of these individuals. This is particularly important induced sputum analysis, and measurements of exhaled when it is considered that by most of the criteria, such nitric oxide. This will permit validation of the original persons will tend to be older, where gains in quality of life asthma diagnosis and responder status to the extent that can be made with effective treatment. It is also of note that although lung function was worse in the SBR groups Third, our survey was limited to households with compared with the group with current asthma, this was not telephones. However, because 97% of the households in reflected in the level of symptoms experienced. This might the region have telephonesand the demographic charac- reflect the poorer perception of bronchoconstriction that teristics were representative of the population of profile has been observed in older persons.Detection of possi- of Adelaide overall,the extent of any bias is likely to ble asthma by means of screening with spirometry might need to be considered in older persons or in younger per- This study suggests that spirometry and, in particular, the bronchodilator response is not a very sensitive tool for Some of the impairment associated with bronchodilator the confirmation of current asthma, as shown by the 82% to responsiveness seen in this study is likely to be due to 93% of subjects with CA not demonstrating an SBR, COPD. According to the GOLD criteria, COPD requires depending on the criterion used. It is arguable, however, the presence of airflow limitation on postbronchodilator that asthma is well controlled and managed in these participants, given that moderate-to-severe respiratory obstruction was low in the SBR groups. Therefore it is symptoms (CLD Index) were reported by 29%. It is also unlikely that COPD is a dominant influence on our results.
possible that the group classified as having no asthma also Our study is limited by the use of self-report for a contained individuals with nondiagnostic spirometry (ie, diagnosis of asthma. However, it is unlikely that partic- bronchodilator nonresponsive). However, given that 94% ipants self-reporting CA do not actually have the condition of this group had respiratory symptoms rated as none to because it is used widely and has been shown to be a valid mild, a level significantly lower than that seen in the SBR group, this seems unlikely. The lack of a demonstrable Second, it is also important to acknowledge that SBR does not exclude asthma, however, and the broncho- given the controversy surrounding the diagnostic utility dilator reversibility test is therefore an imperfect tool for of bronchodilator reversibility test, this analysis was based screening the general population. Although it is difficult to on a single reversibility test. Calverley et have re- conjecture about the specificity of the bronchodilator cently demonstrated that in a group of patients with response in the absence of a gold standard, this does not COPD meeting the European Respiratory Society criteria detract from the central message of this study that an SBR, for irreversibility, 52% changed their responder status however classified, in the absence of a diagnosis of asthma using the 12% and 200 mL criteria. Quanjer et alstated was associated with significant avoidable morbidity.
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S t a d t B u r g - B e s c h l u s s v o r l a g e 2010/129 Amt für Stadtentwicklung, Bereich Wifö Beratungsfolge Sitzungstermin Enthaltung Stadtrat Betreff : Verlegung d. Veranstaltungsreihe „Grüner Markt“ ab 2011 auf den Magdalenenplatz Beschlussvorschlag Der Stadtrat beschließt die Weiterführung der sechs Innenstadtveranstaltungen „Grüner