Relationship of the Arabic version of the asthma control test with ventilatory function tests and levels of exhaled nitric oxide in adult asthmatics Syed S. Habib, MBBS, FCPS, Mohammed A. Alzoghaibi, BSc, PhD, Abdullah A. Abba, FRCP (Glas), FRCPI, Mujtaba Hasan, FCPS.
ABSTRACT يهدف هذا املشروع إلى حتديد العالقة بني اختبار التحكم:األهداف أكسيد،باستخدام النسخة العربية،)ACT مبرض الربو (اختبار الـ ) ووظائف الرئة؛ وذلك للحصول على النقاطFENO( النيتريك املزفر مع املستويات املعتمدة لدى جمعية الصدرACT الفاصلة لهذا االختبار .األمريكية للتحكم بااللتهابات مريض ًا53 مريض بالربو من البالغني بينهم59 قمنا بدراسة:الطريقة م2012 م إلى يونيو2011 أنهوا الدراسة بالكامل خالل الفترة من يوليو ومت حساب. اململكة العربية السعودية، الرياض،في جامعة امللك سعود ) ومتNIOX MINO( بطريقة النايكس مينوFENO مستويات الـ .تسجيل وظائف التهوية بالطرق القياسية >20 أعلى إحصائي ًا في مرضى الربو بدرجةFENO كانت قيم الـ:النتائج ≥ طبق ًا20 ) مقارنة باملرضى ذوي الدرجة65.5 ± 35.4( ACT طبق ًا لـ ) من ضمن املشاركني األصحاء27.4 ±10.5، p>0.001( .ACT لـ ،عاليFENO ) حاالت كان لديها مستوى الـ25%( 6 ،ACT طبق ًا لـ ) حاله كان لديها79.3%( 23 ،بينما مجموعة األصحاء األقل مستوى الفترة الثابتة: p>0.0001:11.5 عالي (نسبة فرديةFENO مستوى الـ ودرجة اختبارFENO هناك عالقة واضحة وأكيده بني.)3.16-41.72 20 عند النقطة الفاصلة العاملية.)r=-0.581، p>0.0001( ACT الـ أن أعلى درجة للخصوصيةROC وضح.من اخلصوصية واإلحساسية كنقطة19 كانت عندACT واإلحساسية مت تسجيلها في اختبار الـ .)81.2 و90.5( فاصلة ، عالقة سلبيةACT ودرجة اختبار الـFENO تربط كال من الـ:اخلامتة إن. ووظائف الرئةFENO بينما تظهر عالقة غير هامة إحصائي ًا بني الـ لهوACT و درجة اختبار الـFENOالعالقة الهامة والقوية بني مستوى الـ .مؤشر واضح على استمرارية االلتهاب في مرضى الربو ضعيفي التحكم Objectives: To determine the relationship between the asthma control test (ACT) score using the Arabic version, fractional exhaled nitric oxide (FENO), and lung functions, and to derive the cutoff points for the ACT score with the American Thoracic Society recommended FENO standard levels of inflammation control.
Methods: We recruited 59 adult asthmatics out of which 53 subjects completed the study between July 2011 and June 2012 at King Saud University, Riyadh, Saudi Arabia. The FENO levels were measured by NIOX MINO (Aerocrine AB, Solna, Sweden), and ventilatory functions were recorded by standard techniques. Results: The FENO values were significantly higher in patients with an ACT score <20 (65.5±35.4) compared with those patients with an ACT score ≥ 20 (27.4±10.5, p<0.001). Among the well-controlled group based on the ACT score criteria, 6 (25%) cases had high FENO levels, while among the poorly controlled group, 23 (79.3%) cases had high FENO levels (odds ratio: 11.5; p<0.0001; confidence interval: 3.16-41.72). There was a significant negative correlation between FENO and ACT score (r=-0.581, p<0.0001). At the international cutoff point of 20, the sensitivity was 95.2, and the specificity was 68.8. The receiver operating curve (ROC) showed that maximum sensitivity and specificity were observed at an ACT score cut off point of 19 (sensitivity: 90.5, and specificity: 81.2). Conclusions: The FENO levels correlate negatively with ACT scores however, the relationship between FENO and lung function is not significant. A significant relationship between ACT score and FENO levels indicate that there is an ongoing inflammatory state in patients with poor asthma control. Saudi Med J 2014; Vol. 35 (4): 397-402 From the Departments of Physiology (Habib, Alzoghaibi), and Medicine (Abba, Hasan), College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia. Received 10th November 2013. Accepted 11th March 2014. Address correspondence and reprint request to: Dr. Syed S. Habib, Professor & Consultant, Department of Physiology (29), College of Medicine, PO Box 2925, King Saud University, Riyadh 11461, Kingdom of Saudi Arabia. Tel. +966 (11) 4671604. Fax. +966 (11) 4672567. E-mail: [email protected]
Saudi Med J 2014; Vol. 35 (4)
FENO and ACT score ... Habib et al
t present airflow obstruction in asthma is routinely monitored by history, physical examination, and spirometry. There is airway inflammation in asthma, which is central to its pathogenesis and there is recent evidence that its monitoring should be part of patient management.1,2 Monitoring inflammation in asthmatic patients with fractional exhaled nitric oxide (FENO) is not yet included in current asthma guidelines, despite upcoming evidence that this may improve control.3,4 It is well known that atopy is a significant factor associated with raised levels of FENO, in patients with or without asthma.5,6 Research has suggested that the noninvasive FENO testing may be a useful tool in the diagnosis as well as in prognosis to indicate persistence of asthma and the severity of airway inflammation.7,8 Recent reports also suggest that FENO can identify patients with difficult-to-treat asthma, and indicates the potential to respond to high doses of inhaled corticosteroids or systemic steroids.9 The asthma control test (ACT) score was devised by Nathan et al in 2004,10 and is recommended by the National Heart Lung and Blood Institute (NHLBI), and other organizations in the Asthma Guidelines 200711 as a validity tool to assess asthma control. The conventional measures of asthma severity include symptoms, amounts of b2-agonist used, and lung function. These measures do not assess airway inflammation. Therefore, they may not provide optimal assessment for guiding therapy, and are correlated poorly with eosinophilic inflammation on bronchial biopsies, or with FENO. Hence, FENO may be a quick and simple inflammatory marker to assess the impact of treatment changes on inflammation and to guide asthma therapy. Still, large long-term outcome trials are necessary to validate its usefulness. Although evaluation of asthma control using the ACT has been performed in the Saudi population in a previous study,12 to investigate the prevalence of uncontrolled asthma, which was very high at 64%, still the relationship between the ACT score and FENO needs further elaboration, especially using the Arabic version of the ACT score questionnaire, since FENO is becoming a useful marker of airway inflammation. Therefore, this study aimed to determine the relationship between the scores computed from the ACT using the Arabic version, FENO targets according
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company. This project was supported by grant from College of Medicine Research Center (CMRC).
Saudi Med J 2014; Vol. 35 (4)
to the recent American Thoracic Society guidelines,13 and ventilatory lung functions. Additionally, we tried to determine the best cutoff points for the ACT score with the recommended standard levels of inflammation control determined by measuring FENO levels. Methods. This cross-sectional study was carried out at the Departments of Physiology and Medicine, College of Medicine and King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia between July 2011 and June 2012. The Research Ethics Committee of the College of Medicine Research Center approved the study protocol. The study was performed according to the principles of the Helsinki Declaration. All subjects studied were known asthmatic patients who had asthma for at least one year duration with mild to moderate symptoms. Patients with allergic rhinitis, chest cage, or spinal deformities, current smokers, chronic obstructive pulmonary disease, bronchiectasis, and emphysema interstitial lung diseases, or tumors were excluded. Asthmatic patients were recruited from the chest clinic in KKUH. Measurements of fractional exhaled nitric oxide. The FENO measurements were performed according to the present recommendations of the American Thoracic Society using handheld NIOX MINO Airway Inflammation Monitor (Aerocrine AB, Solna, Sweden). A FENO level of >47 ppb was used to indicate inflammation and uncontrolled asthma.13 Ventilatory function parameters. Spirometry was performed after recording FENO values and included forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), percentage of forced expiratory volume in the first second (FEV1%), peak expiratory flow (PEF), and forced expiratory flow at 25 (FEF25), 50 (FEF50), and 75% (FEF75) of vital capacity. Ventilatory functions were measured using an electronic spirometer (Vitalograph Co, Clare, Ireland), which was calibrated daily. Statistical analysis. Statistical analysis was performed using the Statistical Package for Social Sciences version 20 (SPSS Inc., Chicago, IL, USA). Data were expressed as mean ± SD for continuous variables. Categorical data were expressed as absolute numbers and percentages. The test applied for statistical analysis was Student’s t-test and Pearson’s correlation coefficient. Different groups were compared by chi-square test for categorical variables. The receiver operating curve (ROC) was used to detect control of inflammation in asthma by FENO and identify cutoff points with a higher sensitivity (true positive rate) and specificity (true negative rate). Positive
FENO and ACT score ... Habib et al
predictive values (PPV) and negative predictive values (NPV) were also calculated and compared for proposed and standard ACT score cutoff points. Spearman’s correlation was calculated to determine the relation between age, height, weight, asthma duration, FENO, FVC, FEV1, and FEV1%. A p≤0.05 was considered statistically significant.
35.4 ppb) compared with those patients with an ACT score ≥20 (27.4 ±10.5 ppb, p<0.001). Linear regression analysis revealed a significant negative correlation of FENO with ACT score (r=-0.581, p<0.0001) (Figure 1). There was no significant correlation of FENO with age, height, weight, asthma duration, and ventilatory function tests (Table 3). Twenty-four cases (45.3%) had an ACT score ≥20, and 29 cases (54.7%) had an ACT score <20. Among the well-controlled group, based on ACT score criteria, 18 (75%) cases had desirable FENO levels while 6 (25%) cases had high FENO levels. Among the poorly controlled group, 6 (20.7%) cases had desirable FENO levels while 23 (79.3%) cases had high FENO levels (odds ratio 11.5; 95% confidence interval [CI]: 3.16-41.72, p<0.0001). Table 4 shows sensitivity, specificity, PPV, NPV for the different ACT cutoff points for uncontrolled asthma. The highest area under the curve (91%) corresponded to the ACT cutoff point of 19. We observed that the best pair of sensitivity and specificity was observed at the cutoff point of 19, at which sensitivity was 90.5% (95% CI: 76.2-100%) and specificity was 81.2% (95% CI: 65.6-93.7%). At the international cutoff point of 20, although sensitivity was high (95.23) the specificity was low (68.75). The total area under ROC curve was 91% with 95% CI: 83.5-98.5%, where the maximum sensitivity and specificity was observed at cutoff point of 19 as shown in Figure 2.
Results. We recruited 59 adult asthmatics out of which 53 participants completed the study. Clinical and demographic characteristics of all asthmatics are shown in Table 1. Table 2 summarizes the history of medications in the patients. Mean FENO values were significantly higher in patients with an ACT score <20 (65.5 ± Table 1 - Clinical and demographic characteristics of all asthmatics included in a study at the Departments of Physiology and Medicine, College of Medicine and King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia (n=53). Variables n (%) Gender Male 42 Female 11 Age, years 36.1 ± 14.3 Height, cm 167.3 ± 8.6 Weight, kg 80.3 ± 11.0 FEV1 L 3.2 ± 0.8 (% predicted) (84.4%) FVC L 3.8 ± 0.7 (% predicted) (81.2%) FEV1% 83.8 ± 7.7 ACT Score 17.6 ± 4.9 FENO, ppb 48.9 ± 33.3 Asthma duration, years 12.0 ± 10.3 Family history 32 (60.4) Ex-smokers 23 (43.4) Atopy 35 (64.8) Allergic conjunctivitis 22 (41.5) Eczema 15 (28.3) FEV1 - forced expiratory volume in the first second, FVC - forced vital capacity, ACT - Asthma Control Test, FENO - fractional exhaled nitric oxide
Table 2 - History of medications in all patients included in a study at the Departments of Physiology and Medicine, College of Medicine and King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia. Variables None Bronchodilators Steroids Leukotriene inhibitors Mixed
Frequency 8 21 15 3 6
Valid percent 15.1 39.6 28.3 5.7 11.3
Table 3 - Pearson’s correlations coefficients age, height, weight, asthma duration, FENO, FVC, FEV1 and FEV1%. Variables
Height Weight Duration FENO
FEV1 - forced expiratory volume in first second, FVC - forced vital capacity, FEV1% - percentage of forced expiratory volume in the first second, *correlation is significant at the 0.05 level (2-tailed), †Correlation is significant at the 0.01 level (2-tailed)
Saudi Med J 2014; Vol. 35 (4)
FENO and ACT score ... Habib et al
Figure 1 - Linear regression analysis between fractional exhaled nitric oxide (FENO) and asthma control test (ACT) Score.
Figure 2 - A receiver operating curve (ROC) analysis showing the total area under ROC of approximately 91% with 95% confidence interval ([CI]: 83.5-98.5%). The maximum sensitivity and specificity was observed at cutoff point of 19. As shown in the figure sensitivity was 90.47% (CI: 76.2-100%), and specificity was 81.2% (CI: 65.6-93.7%).
Discussion. The present study shows the relationship of the ACT score with FENO and pulmonary functions. At present the conventional measures of asthma severity do not assess airways inflammation,
Saudi Med J 2014; Vol. 35 (4)
and thus may not provide optimal assessment for guiding therapy. Moreover, they correlate poorly with eosinophilic inflammation on bronchial biopsies. The best paired sensitivity and specificity were observed at a cutoff point of 19 (90.5 and 81.2), with the highest area under the curve. Although the sensitivity was high (95.2) at a cutoff point of 20, yet the specificity was low (68.75). There was no significant correlation between FENO and ventilatory function tests As an ‘‘inflammometer,’’ FENO provides the clinician with severity of airway inflammation; thus, complementing conventional physiological testing. At present, measuring FENO in our clinical settings remains unpopular, although current studies are revealing that it runs in parallel to inflammation in a wide range of patients. The same methodology was used by Schatz et al14 to test the reliability and validity of the ACT in a longitudinal study of asthmatic patients. They reported the same cutoff point of 19 to identify patients with poor asthma control. Similarly, a Spanish questionnaire validation study carried out by Vega et al15 and also Thomas et al16 showed the same results. However, they compared the ACT score with the levels of control according to GINA (Global Initiative for Asthma) to establish the best cutoff points for the ACT. A similarly designed study by Alvarez-Gutiérrez et al17 reported ACT cutoff points of ≥21 for controlled asthma, 19-20 for partially controlled asthma, and ≤18 for non-controlled asthma. They based their gold standard criteria on the Global Initiative for Asthma, which was not yet ratified. This may be the reason that our results differed from their observations. We used FENO cutoffs based on ATS recent guidelines.17 They also observed significant but slight correlation between levels of FEV1, FENO, and ACT. They included smokers in their study, whereas, we excluded smokers as smoking is known to reduce FENO values.18 However, there was no significant correlation between FENO and ventilatory function parameters in our study. There was a significant correlation between FENO and ACT score. The FENO was independently related to the ACT score and spirometric functions. In our report, the relationship of FENO with ventilatory functions was not significant.19 In the Greek asthmatic population,20 the ACT score was found to significantly reflect lung function and inflammation. In contrast to our study, Melosini et al21 reported that ACT scores significantly correlated with symptoms, but not with ventilatory functions reversibility and FENO. In another study, the ACT score was correlated better with treatment decisions made by asthma specialists compared with
FENO and ACT score ... Habib et al Table 4 - Asthma Control Test (ACT) score, and validity of different cut-off points for the classification of control of asthma. Cut-off points <25 <24 <23 <22 <21 <20 <19 <18 <17 <16 <15 <14 <13 <12 <11 <10 <9 <8
Sensitivity Specificity PPV 100 9.4 42.0 100 15.6 43.7 100 31.2 48.8 100 37.5 51.2 100 53.5 58.3 95.2 68.7 66.7 90.5 81.2 76.0 85.7 81.2 75.0 80.9 84.4 77.3 61.9 87.5 76.5 57.1 93.7 85.7 47.6 93.7 83.3 38.1 96.9 88.9 33.3 100 100 28.6 100 100 23.8 100 100 14.3 100 100 4.8 100 100 PPV - positive predictive values, NPV - negative predictive values
spirometry and FENO levels. An ACT score of ≤20 best correlated with uncontrolled asthma (sensitivity 70.5%, specificity 76.0%, PPV 76.2%, and NPV 70.2%) for predicting the plan for asthma therapy. In an ROC analysis, the ACT score had the highest prediction for changing asthma therapy when compared with FENO or ventilatory functions.22 Shirai et al23 also reported a significant relationship between levels of FEV1, FENO, and ACT scores. The limitations of our study are its cross sectional design and small sample size. Further prospective follow up studies with a larger sample size are needed to elucidate proper monitoring of asthma control and management. In conclusion, the FENO levels correlated negatively with the Arabic version of the ACT scores. Patients with low ACT scores had significantly higher levels of FENO compared with those with a higher ACT score. A significant strong relationship between ACT scores and FENO levels indicated that there was an ongoing inflammatory state in patients with poor asthma control. Acknowledgment. The authors are thankful to Mr. Timhar Amlih for performance of lung functions and collection of data.
References 1. Leung TF, Ko FW, Wong GW. Recent advances in asthma biomarker research. Ther Adv Respir Dis 2013; 7: 297-308. 2. Hamid Q, Tulic M. Immunobiology of asthma. Annu Rev Physiol 2009; 71: 489-507.
NPV 100 100 100 100 100 95.6 92.8 89.6 87.1 77.8 76.9 73.2 70.4 69.6 68.1 66.7 64.0 61.5
3. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67: 199-208. 4. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715-1721. 5. Steerenberg PA, Janssen NA, de Meer G, Fischer PH, Nierkens S, van Loveren, et al. Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children. Thorax 2003; 58: 242-245. 6. Franklin PJ, Turner SW, Le Souef PN, Stick SM. Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children. Thorax 2003; 58: 1048-1052. 7. Ricciardolo FL. Revisiting the role of exhaled nitric oxide in asthma. Curr Opin Pulm Med 2014; 20: 53-59. 8. Ozier A, Girodet PO, Bara I, Tunon de Lara JM, Marthan R, Berger P. Control maintenance can be predicted by exhaled NO monitoring in asthmatic patients. Respir Med 2011; 105: 989-996. 9. Pérez-de-Llano LA, Carballada F, Castro A-ón O, Pizarro M, Golpe R, Baloira A, et al. Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma. Eur Respir J 2010; 35: 1221-1227. 10. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113: 59-65. 11. National Heart, Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma (EPR-3). Available from: http://www.nhlbi.nih.gov/guidelines/asthma 12. Al-Jahdali HH, Al-Hajjaj MS, Alanezi MO, Zeitoni MO, Al-Tasan TH. Asthma control assessment using asthma control test among patients attending 5 tertiary care hospitals in Saudi Arabia. Saudi Med J 2008; 29: 714-717.
Saudi Med J 2014; Vol. 35 (4)
FENO and ACT score ... Habib et al 13. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An Official ATS Clinical Practice Guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184: 602-615. 14. Schatz M, Sorkness CH, Li J, Marcus PH, Murray JJ, Natham RA, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006; 117: 549-556. 15. Vega JM, Badia X, Badiola C, López-Vi-a A, Olaguíbel JM, Picado C, et al. Validation of the Spanish version of the asthma control test (ACT). J Asthma 2007; 44: 867-872. 16. Thomas M, Kay S, Williams A, Carranza Rosenzweig JR, Hillyer EV, Price D. The asthma control test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey. Prim Care Resp J 2009; 18: 41-49. 17. Alvarez-Gutiérrez FJ, Medina-Gallardo JF, Pérez-Navarro P, Martín-Villasclaras JJ, Martin Etchegoren B, Romero-Romero B, et al. Comparison of the Asthma Control Test (ACT) with lung function, levels of exhaled nitric oxide and control according to the Global Initiative for Asthma (GINA). Arch Bronconeumol 2010; 46: 370-377.
18. Habib SS, Ahmed SM, Al Drees AM, Husain A. Effect of cigarette smoking on fractional exhaled nitric oxide in Saudi medical college students. J Pak Med Assoc 2011; 61: 120-123. 19. Schatz M, Zeiger RS, Zhang F, Chen W. Development and preliminary validation of the Asthma Intensity Manifestations Score (AIMS) derived from Asthma Control Test, FEV(1), fractional exhaled nitric oxide, and step therapy assessments. J Asthma 2012; 49: 172-177. 20. Papakosta D, Latsios D, Manika K, Porpodis K, Kontakioti E, Gioulekas D. Asthma control test is correlated to FEV1 and nitric oxide in Greek asthmatic patients: influence of treatment. J Asthma 2011; 48: 901-906. 21. Melosini L, Dente FL, Bacci E, Bartoli ML, Cianchetti S, Costa F et al. Asthma control test (ACT): comparison with clinical, functional, and biological markers of asthma control. J Asthma 2012; 49: 317-323. 22. Ko FW, Leung TF, Hui DS, Chu HY, Wong GW, Wong E et al. Asthma Control Test correlates well with the treatment decisions made by asthma specialists. Respirology 2009; 14: 559-566. 23. Shirai T, Furuhashi K, Suda T, Chida K. Relationship of the asthma control test with pulmonary function and exhaled nitric oxide. Ann Allergy Asthma Immunol 2008; 101: 608-613.
Related Articles Assiri AM, Saeed A. Incidence and diagnostic features of eosinophilic esophagitis in a group of children with dysphagia and gastroesophageal reflux disease. Saudi Med J 2014; 35: 292-297. Adham TM, Tawfik SA. Dermatophagoides in childhood asthma. Allergy to dermatophagoides associates more severe childhood asthma with a potential role for acaricides. Saudi Med J 2012; 33: 292-297. Liu QQ, Chen SH, Liang MB, Feng LY. Induced sputum eosinophil count for the diagnosis of bronchial asthma. Saudi Med J 2010; 31: 710-712.
Saudi Med J 2014; Vol. 35 (4)