1. 1 A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Introdução à Medicina 2006/2007 Class 3, First Year João Almeida Lopes Fonseca Altamiro Manuel Rodrigues da Costa Pereira

2. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 2 Summary Introduction Current Tests Inflammatory Biomarkers Aim Methods Study Design Data source Study Selection Why Were Articles Not Included? Search Results Included Articles: Quality Criteria and Statistical Analysis Agreement Between Reviewers Results Description of Included Studies Quality Assessment Data Analysis Fe(NO) Induced Sputum Eosinophilia Discussion Limitations Conclusion Authors

3. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 3 Introduction Asthma is an inflammatory disorder Asthma diagnosis: Mostly based on the clinical observation complemented with lung function tests Bronchodilatation and hiperreactivity tests (methacholine) There is growing interest in exhaled nitric oxide (Fe(NO)) and induced sputum eosinophilia

4. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 4 Introduction Introduction Current Tests GINA. 2006 Nov Dundas I. Thorax. 2005 Jan Busse WW. Am J Respir Crit Care Med. 2005 Oct Lung function BronchodilatationMethacholine Bronchial Biopsy Safe  Non-Invasive  Quick and Easy  Sensitive  Specific  Tests Parameters

5. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 5 Introduction Introduction Inflammatory Biomarkers Lemiere C et al. Can J Physiol Pharmacol. 2006 Jan Joos GF et al. Curr Opin Pharmacol. 2003 Jun Dinakar C et al. Curr Allergy Asthma Rep. 2004 Nov Kim CK et al. Ann Allergy Asthma Immunol. 2004 Aug Fe(NO) Induced Sputum Eosinophilia Safe Non-Invasive Quick and Easy  Sensitive ?? Specific ?? Tests Parameters

6. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 6 Introduction Introduction Aim To evaluate the sensitivity and the specificity of Fe(NO) and induced sputum eosinophilia in asthma diagnosis

7. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 7 Methods Methods Study Design A meta-analysis of the published studies on the sensitivity and specificity of measurements of Fe(NO) and induced sputum eosinophilia.

8. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 8 Methods Methods Data Source Research was made using Medline, Scopus and references of used articles. Query of Medline was: (("Asthma"[MeSH] OR Asthma OR Asthm*)AND (("Nitric Oxide"[MeSH] OR feno OR ENO OR exhaled air) OR ((Eosinophil[MeSH] OR Eosinophil* OR Eosinophilia[MeSH]) AND (Sputum[MeSH] OR Sputum))) AND ((sensitiv*[Title/Abstract] OR sensitivity and specificity[MeSH Terms] OR diagnos*[Title/Abstract] OR diagnosis[MeSH:noexp] OR diagnostic * [MeSH:noexp] OR diagnosis,differential[MeSH:noexp] OR diagnosis[Subheading:noexp] OR (Diagnosis[MeSH] OR Diagnosis OR Diagnos*))

9. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 9 Methods Methods Data Source Query of Scopus was: (((asthma OR asthm) AND ((nitric oxide OR feno OR eno OR exhaled air) OR (eosinophil OR eosinophilia) AND sputum)) AND (((sensitiv OR sensitivity) AND specificity) OR (diagnostic OR differential diagnosis OR diagnosis)))

10. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 10 Methods Methods Study Selection Six groups of two reviewers - titles/abstracts Six groups of two reviewers - full text Articles atributted randomly using Microsoft Excel Checked inclusion and exclusion criteria to select the articles 1st stage: titles/abstracts ( non-agreement: article included) 2nd stage: full text ( non-agreement solved by consensus or a third reviewer)

11. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 11 Methods Methods Study Selection Inclusion criteria 1. Studies the use of exhaled nitric oxide or eosinophil levels in induced sputum for the diagnosis of asthma in humans 2. Reports original data on the sensitivity and specificity of the application of inflammatory biomarkers Exclusion criteria 3. Not written in English, Portuguese, French or Spanish 4. Full text not available via Medline, Scopus, FMUP library or through contact with authors 5. Does not describe the criteria used for the diagnosis of asthma After the 2nd stage of selection, the articles repeated in both data bases were excluded

12. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 12 Methods Methods Why Were Articles Not Included? Criteria 1. Does not study the use of exhaled nitric oxide or eosinophil levels in induced sputum for the diagnosis of asthma in humans 2. Does not report original data on the sensitivity and specificity of the application of inflammatory biomarkers 3. Not written in English, Portuguese, French or Spanish 4. Full text not available via Medline, Scopus, FMUP library or through contact with authors 5. Does not describe the criteria used for the diagnosis of asthma 6. Article repeated in both data bases

13. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 13 MEDLINE SCOPUS 1671 articles 732 articles 1 st stage: 284 articles included 2 nd stage: 18 articles included Methods Methods Search Results After applying inclusion and exclusion criteria, 9 articles from Medline and 9 from Scopus were included. However, 5 articles were repeated 544

14. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 14 Methods : Methods Included Articles: Quality Criteria and Statistical Analysis STARD Checklist (1) to evaluate the articles regarding their methodological quality – mean of two reviewers Meta-Disc 1.4 and SPSS 14.0 to extract relevant information ( 1) BOSSYUT, PM, et al; The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. The Standards for Reporting of Diagnostic Accuracy Group; Croat Med J.; 2003; 44(5):639-50

15. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 15 Methods Methods Agreement Between Reviewers Kappa = 0,899 Agreement Between Reviewers 238232385 11819 2383212404 Excluded Included 1st Reviewer Total ExcludedIncluded 2nd Reviewer Total

16. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 16 Results Results Description of Included Studies 10 1 2

17. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 17 Results Results Quality Assessment

18. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 18 Results Results Data Analysis – Fe(NO) Summary sensitivity There is no evidence of heterogeneity

19. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 19 Summary specificity There is evidence of heterogeneity Results Results Data Analysis – Fe(NO)

20. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 20 Summary sensitivity There is no evidence of heterogeneity Results Results Data Analysis – Induced Sputum Eosinophilia

21. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 21 Summary specificity There is no evidence of heterogeneity Results Results Data Analysis – Induced Sputum Eosinophilia

22. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 22 Discussion Fe(NO): The sensitivity is around 83%, the specificity ranges from 60% to 90% Induced Sputum Eosinophilia: Although only 3 studies were analysed, the sensitivity was 76% and specificity was 85% Fe(NO) Induced Sputum Eosinophilia Safe Non-Invasive Quick and Easy  Sensitive (83%)? (76%) Specific ?? (85%) Parameters Tests

23. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 23 Discussion Sensitivity and specificity for both biomarkers were: High Similar Therefore other characteristics may be relevant for the choice

24. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 24 Discussion Discussion Limitations Research only in Medline and Scopus databases Published data not assessed by the queries Language restriction Full texts not available Articles with missing data Heterogeneity among population and conditions of the studies Few articles on induced sputum eosinophilia in asthma diagnosis

25. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 25 Induced Sputum Eosinophilia and ENO are two sensitive and specific methods There are few studies concerning Induced Sputum Eosinophilia On evaluating the quality of this biomarkers, other items should be considered Conclusion

26. A Meta-analysis on the Sensitivity and Specificity of Exhaled Nitric Oxide and Induced Sputum Eosinophilia for the Diagnosis of Asthma Class 3; 2006-7 26 Authors Ana Luísa Marçal Andreia Coelho Carolina Rodrigues Delfim Duarte Diogo Costa Inês Falcão João Paulo Castro Mariana Rocha Marina Eichmann Pedro Sousa Sara Ranchordás Vânia Guedes João A. Fonseca, PhD MD Class 3