SYSTEMATIC REVIEW ON THE EFFECTS OF ANTI- INFLAMMATORY ASTHMA MEDICATION ON FENO VALUES Class 19 FMUP 2008/2009 Adviser: Dr. João Fonseca

INDEX Statement of the Problem Background Main Problem Aims Methods Expected Results References

▫ Asthma is a disease with high prevalence and morbidity 1 ; ▫ There are different types of Asthma Medication, some have anti-inflammatory effects; ▫ FENO is a biomarker of airways’ inflammation. What are the effect of anti-inflammatory asthma medication on FENO values? STATEMENT OF THE PROBLEM 1 GLOBAL INITIATIVE FOR ASTHMA

BACKGROUND WHAT IS ASTHMA? Asthma is a chronic inflammatory disorder of the airways. 1 1 GLOBAL INITIATIVE FOR ASTHMA 2006

BACKGROUND o ASTHMA MEDICATION 2 : Anti- inflammatory Agent Drugs Leukotriene Antagonists Montelukast Zafirlukast Zileuton Inhaled Glucocorticoids Fluticasone Budesonide Triamcinolone Flunisolide Beclomethasone Mometasone Oral Glucocorticoids Prednisone Methylprednisolone Hydrocortisone 2 National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program

BACKGROUND WHAT IS NITRIC OXIDE? - It’s a gas produced by cells that line the inner wall of the airways; - The amount of nitric oxide exhaled shows how much inflammation there is in the lungs. 3 3 JONGSTE J.C. 2005

MAIN PROBLEM Normal values of FENO aren’t clearly defined; FENO values are influenced by demographic and biological factors; Some effects of anti-asthma medication on FENO values have been reported.

AIMS Evaluate the effect of anti-inflammatory asthma medication and its magnitude on FENO values, namely: ▫ Leukotriene modifiers; ▫ Inhaled Corticosteroids; ▫ Oral Corticosteroids;

METHODS STUDY DESIGN: SYSTEMATIC REVIEW Phases of a systematic review: 1. Formulation of the Question 2. Search and inclusion of primary studies 3. Quality assessment of included studies 4. Data Extraction 5. Statistical Analysis and synthesis of study results 6. Interpretation of the results and report writing

2. Search and Inclusion of primary studies: DATA SOURCE: PUBMED SCOPUS ISI Web of Knowledge Conduction of separate, sensitive searches using different combination of multiple and alternative key- words METHODS

SearchPUBMEDSCOPUSISITotal : asthma AND exhaled nitric oxide AND (glucocorticoids OR Leukotriene antagonists) 2: asthma AND exhaled nitric oxide AND (glucocorticoids OR Leukotriene antagonists); limits: since : exhaled nitric oxide AND (glucocorticoids OR Leukotriene antagonists); limits: since : exhaled nitric oxide AND (glucocorticoids OR leukotriene antagonists OR Montelukast OR Zafirlukast OR Zileuton OR Fluticasone OR Budesonide OR Triamcinolone OR Flunisolide OR Beclomethasone OR Mometasone OR Prednisone OR Methylprednisolone OR Hydrocortisone); limits: since : exhaled nitric oxide AND (glucocorticoids OR leukotriene antagonists OR Montelukast OR Zafirlukast OR Zileuton OR Fluticasone OR Budesonide OR Triamcinolone OR Flunisolide OR Beclomethasone OR Mometasone OR Prednisone OR Methylprednisolone OR Hydrocortisone); limits: since 1990, HUMANS 6: exhaled nitric oxide AND (glucocorticoids OR leukotriene antagonists OR Montelukast OR Zafirlukast OR Zileuton OR Fluticasone OR Budesonide OR Triamcinolone OR Flunisolide OR Beclomethasone OR Mometasone OR Prednisone OR Methylprednisolone OR Hydrocortisone); limits: since 1990, HUMANS, CLINICAL QUERY - Teraphy and sensitive search 7: (exhaled nitric oxide OR FENO OR ENO) AND (glucocorticoids OR leukotriene antagonists OR Montelukast OR Zafirlukast OR Zileuton OR Fluticasone OR Budesonide OR Triamcinolone OR Flunisolide OR Beclomethasone OR Mometasone OR Prednisone OR Methylprednisolone OR Hydrocortisone); limits: since 1990, HUMANS, CLINICAL QUERY - Therapy and sensitive search 2. Selection and Inclusion of primary studies: INCLUSION OF PRIMARY STUDIES ACCORDING TO THE INCLUSION AND EXCLUSION CRITERIA:

METHODS 2. Selection and Inclusion of primary studies: ▫ Selection of the Query: (Exhaled Nitric Oxide OR FENO OR ENO) AND (Leukotriene Antagonists OR Glucocorticoids OR Montelukast OR Zafirlukast OR Zileuton OR Fluticasone OR Budesonide OR Triamcinolone OR Flunisolide OR Beclomethasone OR Mometasone OR Prednisone OR Methylprednisolone OR Hydrocortisone)  LIMITS: articles published since 1990 (except on ISI); data collected on HUMANS - PUBMED, [AND (humans OR patients OR volunteers) – SCOPUS and ISI; Clinical Queries: Therapy and Sensitive Search – PUBMED, [AND clinical trial OR therapy OR “therapeutic use”] – SCOPUS and ISI.

2. Selection and Inclusion of primary studies: INCLUSION OF PRIMARY STUDIES ACCORDING TO THE INCLUSION AND EXCLUSION CRITERIA:  Screen of articles independently by two reviewers and selection of those appropriate for inclusion. Assessing Title/Abstract When there isn’t sufficient information, the article will proceed to the next phase When the reviewers disagree on the inclusion or exclusion of an article, the article is automatically included Assessing Full-text When the two reviewers disagree on the inclusion or exclusion of a specific article, the disagreement will be solved by consensus or request of a third reviewer; The articles which don’t accomplish the criteria will be excluded and the reasons for that exclusion will be registered. METHODS

 Inclusion Criteria: - Explicit comparison of FENO values in patients treated with anti- inflammatory medication with the values in the same patients not on treatment; -related to the effects of Oral Corticosteroids, Inhaled Corticosteroids or Leukotriene modifiers on FENO values; - a experimental longitudinal study; - primary data; - published since  Exclusion Criteria: - in a language either than English, Portuguese or Spanish; - studies without a rigorous definition about the existence or not of asthma in the patients, at the beginning of the treatment. - Not analyzed on humans; METHODS 2. Selection and Inclusion of primary studies: INCLUSION OF PRIMARY STUDIES ACCORDING TO THE INCLUSION AND EXCLUSION CRITERIA:

3. Quality Assessment of included studies Quality refers to internal validity of the studies (i.e. lack of bias). This task should also be performed independently by two reviewers basing on a list with selection criteria. The quality criteria used will depend on the study design, in our case, selection criteria are, for example, “Were patients randomized?”, “Was follow up complete?”, etc. METHODS

Reviewers will extract information on the characteristics of the study, such as its methodology, population, interventions and outcomes. Variables extracted from each article will be: Study Identification - Author; - Year; - Nationality. Type of Study (Longitudinal – Retrospective or Prospective) Study’s Objective 4. Data Extraction:

Study Variables:  Patients: - Number of participants; - Age (children, adults); - Sex (Male or Female); - Health Condition;  Intervention: -Type of anti-inflammatory treatment (Leukotriene Antagonists or Glucocorticoids) - Treatment duration (0-4 weeks; or 4 weeks to 6 months; or 6 to 12 months; or more then a year) - Use of Control or Placebo Groups.  Comparation : - Of evolution of FENO values: Between two or more different asthma medication; Between treated and not treated groups of patients.  Outcomes: - Treatment influence on FENO values (FENO values before and after the treatment); - Development of new sensitivities in patient groups and type of sensitivity developed (if developed). METHODS 4. Data Extraction:

5. Statistical Analysis and synthesis of study results Tabulation of study characteristics and results. It will made a statistical analysis and it will be used SPSS for the descriptive statistics proportion. Meta-analysis : combination of the results of previous studies to achieve at summary conclusions. 6. Interpretation of the results and report writing: Interpretation of results, discussion of issues and limitations of primary studies included and the conduction of the review; Writing of the manuscript for publication. METHODS

EXPECTED RESULTS Find enough data that relates the different drugs that compose the three types of anti-inflammatory asthma medication (Leukotriene modifiers, inhaled Corticosteroids and oral Corticosteroids) to variations in FENO values; Literature will show a decrease in the FENO values of patients treated with anti-inflammatory asthma medication.

REFERENCES 1) Global Initiative for Asthma, A Pocket Guide for Physicians and Nurses, ) National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma ) Jongste J.C. Yes to NO:The First Studies on Exhaled Nitric Oxide-Driven Asthma Treatment, 2005, ERS Journal Ltd, 26: ) Madhukar P, Systematic reviews and meta-analyses: An illustrated, step-by-step guide, The National Medical Journal of India VOL. 17, NO. 2, ) Oddera S., Silvestri M, Balbo A, Jovovich BO, Penna R, Crimmi E, Rossi GA, Airway eosinophilic inflammation, epithelial damage, and bronchial hiperresponsiveness in patients with mild-moderate, stable asthma, 1996, 51(2): ) Consumers Union, Steroid Inhalers Used to Treat Asthma and Chronic Lung Disease, Consumer Reports Best Buy Drugs, Abril ) Smith AD, Cowan JO, Brasset KP, Herbison P, Taylor DR, Use of exhaled nitric oxide measurements to guide treatment in chronic asthma, N Engl J Med, 2005; 352(21): ) Buchvald F, Baraldi E, Carraro S, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years, J Allergy Clin Immunol 2005;115:1130–1136 9) Pijnenburg W., Hofhuis W., Hop C., Jongste J. C., Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission, Thorax 2005;60:215–218 10) Stirling RG, Kharitonov SA, Campbell D, Robinson DS, Durham SR, Chung KF, Barnes PJ, Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group, Thorax Dec; 53(12): Stirling RGKharitonov SACampbell DRobinson DSDurham SRChung KFBarnes PJ 11) National Heart Lumb and Blood Institute, Asthma, September 2008, 12) MEDLINE Plus, Asthma,