THE ROLE AND UTILITY OF CURRENT DIAGNOSTIC TESTS FOR ASTHMA IN THE ELDERLY

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1 Journal of Experimental Medical & Surgical Research Cercetãri Experimentale & MedicoChirurgicale Year XVII Nr.3/2010 Pag JOURNAL Experimental Medical of Surgical R E S E A R C H THE ROLE AND UTILITY OF CURRENT DIAGNOSTIC TESTS FOR ASTHMA IN THE ELDERLY S. Macesanu 1 C. Vernic 2 R. Timar 1 C. Tudor 3 SUMMARY: Asthma (AB) is a common disorder in the general population, with a high prevalence, asthma diagnosis is difficult to establish in the elderly and very often it is overlooked. The aim of the study: the evaluation and comparison of modern diagnostic tests for asthma elderly. Material and methods: We evaluated 66 elderly patients over 60 years, with chronic cough, they were divided in 2 groups: 32 patients in group A, diagnosed with asthma and 34 patients in group B, with other chronic obstructive diseases. We used 5 methods of investigations: the best FEV1 by Spirometry, bronchodilation test (BDtest), exhaled nitric oxide measurement (FeNO) value, Airway hyperresponsiveness measuring(ahr), corticosteroids oral test, and best FEV1 value after corticosteroid inhaler treatment and statistical correlations between these tests. Results: spirometry and measurements FeNO were undertaken in all patients. In group A, FeNO values were significantly high in 19%, and mild in 59% of the cases, BDtest results were positive in 71.8% from group A. In those patients with negative results of BDtest, additional tests were undertaken: AHR test (positive in 12.5%), oral CStest (positive in 15.6%) and ICS inhaler after 3 monthstreatment (positive in 15.6%).In group A, the best FEV1(V1) and FeNO values were highly statistically significant (p<0.001). Conclusions: Bronchoreversibility was higher in group A, the FeNO value was helpful on diagnosis, and both tests were easy and cheap to apply on elderly. If FeNO is normal at baseline, it cannot be used in the diagnosis of asthma as single test and it should be well correlated with BDtest, AHR or CS test. Key Words: asthma, elderly, asthma diagnosis, modern tests for investigation. ROLUL ªI UTILITATEA METODELOR MODERNE DE DIAGNOSTIC ALE ASTMULUI BRONªIC LA VÂRSTNICI Received for publication: Revised: Rezumat: Astmul bronºic (AB) este o boalã cronicã frecventã în populaþia generalã, însã diagnosticul la vârstnici este dificil de efectuat ºi adesea omis.scopul studiului este de a evalua ºi compara metodele moderne de diagnostic al AB la vârstnici. Material ºi metode: Am evaluat un lot de 66 pacienþi cu tuse cronicã, divizaþi în 2 loturi: lot A au fost diagnosticaþi cu AB, lotul B, cu alte boli obstructive cronice. Sau folosit 5 metode curente de diagnostic al astmului: spirometrie forþatã (cel mai bun FEV1), test de bronhodilatare inhalator (BDtest), mãsurarea hiperresponsivitãþii bronºice cu metacholinã (AHR), mãsurarea valorii FeNO din aerul exhalat, test cu corticosteroizi oral(csoral) ºi corticosteroizi inhalator(ics) timp de 3 luni ºi corelaþii statistice între metodele utilizate.rezultate: la toþi pacienþii sa efectuat spirometrie fortaþã ºi dozarea FeNO.In lotul A, 19% valori FeNO crescute, 59% prezente dar uºoare iar tesul BD a fost pozitiv la 71,8% cazuri.la pacienþii cu BDtest negativ sau efectuat teste suplimenatare:cu metacholinã(12,5% pozitivi),test cu corticosteroizi orali(15,6% pozitivi), test cu ICS 3 luni (15,6% pozitivi). In lotul A, au avut corelaþie semnificativã statistic testele FeNOFEV1(V1), (p<0,001). Concluzii: bronhoreversibilitatea este demonstratã la un numãr mare de pacienþi din lotul A, dozarea FeNO ajutã la diagnosticarea AB, ambele teste sunt accesibile ºi uºor de efectuat la vârstnici. Dacã valoarea FeNO este intermediarã iniþial, nu trebuie consideratã ca singurul marker pozitiv al inflamaþiei bronºice, ci trebuie corelatã cu celelalte teste, AHR sau CS test. Cuvintecheie: astm bronºic, vârstnici, teste diagnostice. 1. Emergency County Hospital, Timisoara; 2 University of Medicine and Pharmacy V Babes, Timisoara; 3 University of Medicine and Pharmacy V Babes, Timisoara Correspondence to: Simona Orieta Mãceºanu, Ambulatory I, Emergency County Hospital, Timiºoara, 194

2 INTRODUCTION Asthma is a common disorder in the general population with an overall prevalence of up to 7 8%.(1) Despite this high prevalence, asthma diagnosis is difficult in the elderly and very often it is overlooked. At elderly asthmatics patients, the diagnostic and therapy problems are inadequately treated. The diagnosis of asthma was based on patient history and clinical examination, in addition to objective evidence of specific pulmonary function testing, with the demonstration of reversible airway obstruction, but there are unique problems in performing these tests in older patients and in their often wrong interpretation.(2) The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guide criteria show that a 70% ratio of FEV1/FVC as value for the airway obstruction, may not necessarily be true in older people and can result in overdiagnosis of obstructive lung disease in older patients. Severity of pulmonary function decline in elderly people with asthma is multifactorial: clinical condition, age, time before diagnosis, history of cigarette smoking and clinical phenotype, all can contribute to disease severity. When there are diagnostic difficulties, objective tests are needed. Abnormal spirometry at diagnosis of asthma in older patients is a common phenomenon, and relationship between delay in diagnosis and commencement of appropriate therapy, is likely due to nonspecific presentation of symptoms and the diagnostic difficulties highlighted above.(3) Spirometry has been used as a gold standard in diagnosis and monitoring treatment in asthma. Forced Expiratory Volume in 1 second (FEV1) begins to decline from approximately the middle of the third decade at the rate approximately 30 ml/year for men and 25 ml/year for women. Most longitudinal studies suggest an accelerated decline in FEV1 (to 38 ml/year).(4) Definitions of the bronchial obstructive reversibility, controversial in COPD, are more clearly for asthma. An improvement in FEV1 of at least 12% after administration of bronchodilators is accepted for positive AB diagnosis.(5) In asthmatics elderly, a negative bronchodilator response to a shortacting beta2 agonist does not rule out a diagnosis of asthma because they have a fixed airflow obstruction from many causes. Often, treatment with ICS over time will improve lung function and, when documented by spirometry, a diagnosis of asthma can be confirmed.6 Differentiation of COPD in order to perform the test with oral cortisone ( mg/kg bw/day), for 714 days. Because of possible CS oral side effects, are used recently, ICS test for 6 weeks3 months, it s simple test, without possible side effects.7 In last years, measuring exhaled nitric oxide (FeNO) has been proposed as a marker of airway inflammation, an easier and cheaper method, but is less accessible. Routine use of FeNO for the diagnosis and management of asthma requires standardization and agreed reference ranges, which vary as a function of age and height. Exhaled NO is increased during exacerbations of asthma, and reduced in subjects taking inhaled corticosteroids.(8) Airway hyperresponsiveness (AHR), a specific feature of asthma, is considered to be related to airway inflammation and are changes of severity after ICS treatment. AHR may be measured using challenge tests with direct agonists such as histamine or metacholina.9 MATERIAL AND METHODS The authors have proposed the investigation of 64 elderly patients with chronic cough, using modern and available diagnostic tests for asthma, using functional criteria for asthma diagnosis and the markers of airway inflammation. Between 2007 and 2009 we selected for our study from the physician s office in the Ambulatory Care of Emergency County Hospital, Timisoara, Medicali s Clinic and from Clinic Hospital Timisoara sixtysix consecutive elderly patients, over 60 years of age. The patients were divided into two groups, Group A included 32 asthmatic patients and Group B included 34 patients with other chronic respiratory diseases. Patient s main symptoms was chronic cough, history of cough lasting over 6 months; moreover patients were recently diagnosed with asthma, and had no previous treatment with steroids or antileukotriens. As exclusion criteria were febrile respiratory tract infection within 4 weeks, incompliance, severe respiratory or cardiovascular failure, alcoholism and active tuberculosis. Protocol: 1. Evaluation of basal pulmonary function with spirometry, using easytach spirometer with color screen (KOKO Legend model). 2. Bronchodilation test (BDtest), with measurement the best FEV1 out before and 15 min after short action beta2agonists inhalation (salbutamolum 400ìg or 195

3 Ipratropium bromide, 20 ìg x 24 doses), according to the American Thoracic Society guidelines. 3. Evaluation of bronchial responsiveness (AHR): Bronchial challenge tests to Methacholine if FEV1>80%, (PC20, methacholine concentration inducing 20% fall in FEV1), on corticosteroid naive patients. 4. Measurement fraction of nitric oxide (FeNO) in exhaled air with electrochimical analyzer (NIOX MINO ), noninvasive, quick and easy FeNO measurement, repeatable and reproducible results, detection limit: 5 ppb, interpretable value 2550 ppb, significant value over 50 ppb. 5. Oral corticosteroid test (CStest) with Prednisone 0.4mg /kg bw/day, during 7 days, and repetable the best FEV1 (positive test post bronchodilation over 500ml). 6. In dynamics, best FEV1 after 3 months therapy with the CS inhaler treatment (for patients nonresponsiveness to other tests), using a dose of budesonide µg/day or beclomethasone. The Table.1. Baseline characteristics of the study: Associated respiratory comorbidities inhaled corticosteroids test is considered positive when FEV1 value increases with 500ml, before and after administration of beta2 agonists. Data were analyzed with Pearson s correlation coefficient (r), chisquare test, unpaired ttest and test of linear regression. According to current asthma management guidelines, the level of severity and adjustment of antiinflammatory asthma treatment are guided by symptoms and lung function.(10) RESULTS Classification of asthma control level was performed according to guidelines GAMA (11), show that most patients had forms of partially controlled or uncontrolled disease at initial visit (V1), before treatment CS inhaler. Associated respiratory comorbidities in the both groups had higher prevalence, especially smoking history, table 1. Group A Group B P value Allergic rhinitis 25% Chronic respiratory failure 9.3% 32.35% p = S TB disabling 6.2% 11.7% p = NS Smoking current history 34.3% 76.47% p = ES Bronchiectasis 3.1% 14.7% p = NS COPD 79.4% Chronic bronchitis 26.4% Best FEV1 initial visit(v1) 66.69± ± p = S Best FEV1 post BDtest 71.53± ± p = FS Functional test performed BD test(beta2 agonists) Metacholine test (AHR) Oral corticosteroids(cstest) Measuring FeNO Best FEV1 after 3months ICS Levels of asthma control in V1 AB uncontrolled AB partially controlled AB controlled FeNO value FeNO significant (over 50ppb) FeNO present, but mild(2550ppb) FeNO unlikely( under 24ppb) 12.5% 15.6% 15.6% 28% 47% 25% 19% 59% 22% Negative 14.47% p= S p<0.001 ES 196

4 Fig.1 FeNO value Value NO Fig.1 FeNO value in group A. The value of NO test should be interpreted in clinical context and it may have a high diagnostic value (Fig.1).In group B, all the patients had insignificant FeNO value. The bronchodilation test was negative in all patients from group B, with low variation below 12 % of predicted FEV1, statistically insignificant. In those patients who had negative BDtest, AHRtest was performed, which had hit 4 of 7 patients. Among patients with uncertain positive result BDtest, or We calculated Pearson Correlation Coefficients (r), and we found a strong inverse correlation value between NO FEV1 (V1), (r = 0.614, p < 0.001), which was highly statistically significant, in group A, Fig 3. We founded low correlation between the values FEV1BDtest and FeNO valuesstatistically insignificant and also, moderate correlationstatistically significant, between AHR valuesfev1(v1), (r=0.383, p= 0.031), in group A. Fig.2.Positive tests distribution in group A. negative/not taken AHR test; an additional CS oral test was positive in 5 patients. Distribution tests with positive results obtained in group A (Fig.2). Our evaluations were predictable, % of the asthmatic patients who had fixed airflow obstruction, after 3 months treatment with CSI+BDLA (medication was recommended as guide GAMA 2008 )(11), achieved normal FEV1. In group B, CStest was performed in patients with uncertain diagnosis of asthma or COPD (41.47 %), and the results were negative in all patients. The average FEV1 (V1) value of group A (66.69± ) compared with FEV1 (V1) value of group B (57.62 ± ), was statistically significantly increased (p<0.012). Comparing the average FEV1 value after BDtest between 2 groups, we found that FEV1 value from group A was statistically significantly higher (p<0.0006). Comparing the FeNO value between the two groups, FeNO value in elderly asthmatics was highly statistically significantly increased (p<0.001). 197

5 Value NO FEV1 (V1) DISCUSSIONS Fig.3. Correlation between FeNO value and FEV1(V1) in group A. In subjects thought to be at risk, spirometry should be obtained first. With this evidence, in the case of patients without airway obstruction but still at risk, methacholine challenge testing can be used to further refine the probability that asthma is present. However, this test is not sensitive or specific for asthma, and as a measure of airway hyperresponsiveness, it may not be predictably accurate in the elderly population (may have positive results also in other diseases), but in correlation with other investigation methods may be helpful, if this test it is expensive.(12) Many respiratory comorbidities were associated in elderly, but the differential diagnosis with COPD was the main problem at elderly patients with chronic cough.(13) The impact of smokinginduced lowering of pulmonary function might explain a lower FEV1 in some older smoking patients. In fact, the actual prevalence of current smokers in our study it s higher, smoking cessation is a method to decrease FEV1 decline.(14) The data had reported increase level NO in other airway diseases, the use of FeNO as only asthma diagnosis it is insufficient but is useful. In some asthmatic groups of patients (with main symptom the cough), FeNO could be normal, using the hypothesis: bronchial epithelial damage can lead to decreased synthesis of NO in the airways. Also in smokers FeNO value may was low, and this explain the lower values of FeNO in patients with chronic obstructive diseases and smoking (from group 2), our results was comparable with data.(1516 ) CONCLUSIONS 1. The positive AHR test is a better marker of disease and useful too, when the forced spirometry and BDtest is normal. 2. If FeNO is normal at baseline, it cannot be used in the diagnosis of asthma as a single marker of airway inflammation, and should be well correlated with BDtest, AHR or CS test, if possible. 3. Our records show that BDtest (with positive test) and FeNO measurement are accessible, rapid and inexpensive diagnostic tests for AB in the elderly. 4. Study shows that if these modern methods of investigation for asthma diagnosis have been available and two out of five tests have been positive, they are sufficient to establish an accurate asthma diagnosis and to make a differential diagnosis easier. REFERENCES: 1. Evans R, Mullaly DI, Wilson RW, et al. National trends in the morbidity and mortality of asthma in the US.Chest.1987;91: Chotirmall SH, Watts M, et al. Diagnosis and Management of Asthma in Older Adults. JAGS. 2009;57: Burrows B, Lebowitz MD, Barbee RA, et al. Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol.1991;88: Crapo RO. The ageing lung. Pulmonary Disease in the Elderly Patient.1993;63: American Thoracic Society. Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis.1991;144: Mannino DM, Gagnon RC, Petty TL, et al. Obstructive lung disease and low lung function in adults in the United States, NHNE Survey , Arch Intern Med. 2000;160: Tudorache V, Mihaiescu T, Mihaltan F. Pulmonary elderly pathology. Ed.Didactica. 2004:

6 8. Junpei S, Suguru S. et al. OffLine Fractional Exhaled Nitric Oxide Measurement Is Useful to Screen Allergic Airway Inflammation in an Adult Population, J of Asthma. 2007;44: Leuppi JD, Salome CM, Jenkins CR, et al. Predictive Markers of Asthma Exacerbation during Stepwise Dose Reduction of Inhaled Corticosteroids. Am. J. Respir. Crit. Care Med. 2001;163(2): GINA Report, The Global Strategy for Asthma Management and Prevention. Updated guide. dec GAMA, Update guide for asthma management, Romanian Society of Pneumology Cuttitta G, Cibella F, Bellia V, et al. Changes in FVC during methacholineinduced bronchoconstriction in elderly patients with asthma: bronchial hyperresponsiveness and aging. Chest. 2001;119(6): Fabbri L, Romagnoli M, Corbetta L et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;167: Quadrelli SA, Roncoroni AJ. Is Asthma in the Elderly Really Different? Respiration. 1998;65: Improving Diagnosis and Management of Asthma through FeNO Measurement. [Online] Available from URL: Silkoff PE, et al. ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, Am J Respir Crit Care Med. 2005;171:

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