2. Worodria William (WW), MB ChB, MMED (Internal Medicine), PhD (Medicine) Mulago National Teaching and Referral Hospital, Uganda

Transcription

1 Running Head: A Systematic Review and Meta-analysis of Evidence on Same Day Diagnosis and Treatment Initiation of Tuberculosis in Resource Limited Peripheral Settings: Smear Microscopy versus New Technologies (Real Time-PCR/GeneXpert) Reviewers: 1. Ekwaro A Obuku (EAO), MB ChB, MSc (Clinical Trials), PhD (c) Joint Clinical Research Centre, Uganda 2. Worodria William (WW), MB ChB, MMED (Internal Medicine), PhD (Medicine) Mulago National Teaching and Referral Hospital, Uganda 3. Akena Dickens (AD), MB ChB, MMED (Psychiatry), PhD (c) Makerere University College of Health Sciences, Uganda Corresponding Reviewer: Ekwaro A Obuku, Fogarty International Clinical Research Scholar, Uganda-Case Western Reserve University Collaboration, Joint Clinical Research Centre, Plot 101 Lubowa Estates, Off Entebbe Road, P.O Box 10005, KAMPALA ekwaro@gmail.com Start Date: July 2010 Expected Completion Date: July 2013 International Prospective Register of Systematic Reviews number: CRD Version 1: 03 rd July 2010 Version 5: 29 th July 2011 Version 6: 01 st June 2012 List of abbreviations: AIDS Acquired Immune Deficiency Syndrome CWRU Case Western Reserve University, USA Page 1 of 14

2 DOTS Directly Observed Treatment Short Course EQA External Quality Assurance/Assessment FIC/NIH Fogarty International Centre/National Institutes of Health FM Fluorescent Microscopy GCP Good Clinical Practice GRADE Grading Recommendations Assessment, Development and Evaluation HIV-1 Human Immunodeficiency Virus Type 1 HMIS Health Management Information System IAF Impact Assessment Framework JCRC Joint Clinical Research Centre LMICs Low and Middle Income Countries MOH Ministry Of Health Mtb Mycobacterium tuberculosis NTLP National Tuberculosis and Leprosy Programme NTRL National Tuberculosis Reference Laboratory QUADAS Quality Assessment of Diagnostic Accuracy Studies SDV Source Data Verification SOPs Standard Operating Procedures STARD Standards for Reporting Diagnostic Accuracy Tests STATA-IC Intercooled STATA TB Tuberculosis TBRU Tuberculosis Research Unit WHO World Health Organisation Definition of terms for the Systematic Review on Same Day Tuberculosis: Page 2 of 14

3 Case of Tuberculosis The World Health Organisation criteria states thus; a patient in whom tuberculosis has been confirmed by bacteriology or diagnosed by a clinician. DOTS Strategy an approach by the WHO adopted in 1993 after declaring TB a global emergency that encompasses political commitment, quality assured diagnosis by smear microscopy, standardized TB treatment, uninterrupted supply of quality assured TB drugs and an effective monitoring and evaluation system for patient outcomes. The World Health Assembly Targets were to detect 70% and treat 85% of the TB cases in the community by Frontloading/Same Day Diagnosis - completing microscopy examination of serial smears of sputum on the same day the patient reports to the health facility and provides specimen to declare diagnosis of TB. In this review, this has been broadened to include issuing of same day results & the use of new rapid diagnostic technique (GeneXpert) recommended by the World Health Organisation. GeneXpert: MTB/RIF a new technology that utilizes real-time PCR to diagnose TB from various specimens. So far, this has been approved by the World Health Organisation using sputum only. Intensified Case Finding a strategy recommended by the WHO to routinely screen HIV/AIDS patients for TB symptoms at first contact with the health system and regularly there after using a simple set of questions, followed by evaluation of the TB suspects by sputum, radiography etc Peripheral HIV/AIDS care centre the first stop where patients are provided a comprehensive HIV/AIDS package i.e. testing, prevention, palliative care, antiretroviral therapy, laboratory and community support commonly at health centre level IV and or III STOP TB Strategy In 2006 the WHO revised DOTS to reach the 2015 Millennium Development Goals and encompasses: Pursue high quality DOTS expansion and enhancement; address TB/HIV, MDR & other challenges; health systems strengthening; engage all care providers; empower people with TB & communities; promote research. Source Data Verification following up a data trail from source documents e.g. a sputum request and results slip is a source document that can be traced back to the patients file and laboratory register, check for correctness, completeness and thereby assuring quality. Three I s Intensified Case Finding, Infection Control and Isoniazid Preventive Therapy is are interventions recommended by the WHO-TB/HIV collaboration and integration activities to reduce the burden of TB among Persons with HIV/AIDS in health facilities and congregate settings Table of Contents: 1.0 Background and Rationale The problem of Tuberculosis in Sub-Saharan Africa and Uganda Page 3 of 14

4 1.2 Diagnosis of Tuberculosis in Low and Middle Income Countries; smear microscopy and access to new technology Recent developments on same day diagnosis of Tuberculosis & the need to evaluate the evidence Overview of Sputum Microscopy studies on same day diagnosis Techniques other than Sputum Microscopy Why a Systematic Review on same day diagnosis of Tuberculosis? Goal: Research Questions and Objectives Review Methods Criteria for selecting studies for this review Types of outcome measures Search strategy for identification of studies Search terms Data Collection and Analysis Results Administration of the Review References Background and Rationale: 1.1 The Problem of Tuberculosis in Sub-Saharan Africa and Uganda: At the end of million people were estimated to suffer from tuberculosis (TB) globally and 1.72 million Page 4 of 14

5 men, women and children died (WHO, 2009). Africa which has 14% and 2.5% of the global population and Gross Domestic Product respectively (IMF, 2009) contributes 35% of all global TB cases (WHO, 2009). Although there has been progress since the 1993 WHO DOTS (Directly Observed Treatment Short Course) and 2006 STOP-TB strategies with a decrease in the incidence, prevalence and mortality of TB globally; a heightened awareness of the three I s (Intensified Case Finding, Isoniazid Preventive Therapy, Infection Control) as well as increased financing through multilateral partnerships (WHO, 2009); developing an efficient and reliable TB diagnostic strategy for tuberculosis in LMICs remains a significant challenge (Tiwariae, 2007). 1.2 Diagnosis of Tuberculosis in Low and Middle Income Countries; smear microscopy and access to new technology Mycobacterium tuberculosis (Mtb) was isolated as a human pathogen over a century ago (Koch R, 1882) yet it remains a significant global health challenge particularly in LMICs. The common diagnostic technology by sputum microscopy has low sensitivity and high user variability requiring several sputum samples from each patient, increasing the turn-around time (Mase, 2007). This raises provider, patient and household costs let alone increasing the chance of drop out of PTB suspects (Squire, 2005; Kemp, 2007; Keeler, 2006). Results from field evaluation of some rapid point-of- care techniques like the recently reported Gene-Xpert which can detect drug susceptible Mtb and Mtb resistant to Rifampicin in 2 hours have been impressive but the cost too prohibitive for routine use in developing countries (Boehme, 2010) whilst serological techniques have been disappointing with inconsistent specificity (Steingart, 2007). Therefore, sputum microscopy remains crucial in evaluating the most infectious PTB suspects and augmenting Intensified Case Finding efforts in LMICs. The WHO reduced the number of sputum specimen required for diagnosis of PTB from three to two and revised the case definition to at least one smear positive result on initial examination within a robust External Quality Assurance system (EQA) (WHO, 1994; WHO, 2001; WHO, 2008). Studies including a systematic review found less efficient additional value of the third smear (Katamba, 2007; Mase, 2007). However, this shift did not account for time, cost and effort reduction as the patient still makes repeat visits to the health facility to complete PTB diagnosis. In one study in Uganda an estimated 32% of TB suspects dropped out without returning a second sputum specimen on the next day (Semitala, 2010). 1.3 Recent developments on same day diagnosis of Tuberculosis & the need to evaluate the evidence: Page 5 of 14

6 1.3.1 Overview of Sputum Microscopy studies on same day diagnosis: There have been several studies evaluating same day diagnosis of Tuberculosis by microscopy among persons with HIV/AIDS, persons without HIV/AIDS, children, in central referral laboratories and laboratories in district hospitals. These studies may have utilized single spot sputum specimen, two same day specimen one hour apart or more serial specimen on the same day. Additionally, in some studies, preparation of smears could have been as follows: one smear per specimen or two smears per specimen. Further, studies have examined the use of either direct light microscopy or fluorescent microscopy separately or concurrently to examine the same smear slides Techniques other than Sputum Microscopy: More recently, there has been fever-pitch excitement in the scientific world with the successful evaluation of DNA-PCR technology for diagnosis of Tuberculosis. Several studies have been conducted in TB High Burden Countries, central and peripheral laboratories, among HIV and non-hiv persons; children and adults using different specimen: blood, sputum and urine. The studies have demonstrated that with two hours a diagnosis of TB and no TB can be made with a good degree of confidence acceptable in medical practice Why a Systematic Review on same day diagnosis of Tuberculosis? The need to go beyond diagnostic accuracy in research laboratories has never been more important than today. If effective, same-day diagnosis of TB has the potential to significantly reduce patient drop outs. Studies on same-day diagnosis of TB have been done under different conditions and settings looking at different populations. This systematic review will summarize information whether, under routine conditions in a peripheral setting, same-day diagnosis sputum microscopy or other rapid diagnostic techniques is feasible and positively impacts on case detection and initiation of anti-tuberculous chemotherapy among TB only and TB/HIV coinfected persons by reducing the dropout rate whilst maintaining diagnostic accuracy comparable to or even better than serial spot and morning smears. 2.0 Goal: Page 6 of 14

7 To summarize the best evidence on the utility of same day diagnosis examining the comparative effectiveness of sputum microscopy versus new non-microscopy technologies for same day diagnosis of TB 2.1 Research Questions and Objectives: Question: Can sputum microscopy be successfully employed to achieve same day diagnosis of Tuberculosis in routine health care settings? Objective: To determine the effectiveness of sputum microscopy for same day diagnosis of Tuberculosis in routine health care settings Question: What is the utility of real-time Polymerase Chain Reaction by Gene Expert for same day diagnosis of Tuberculosis in routine health care settings? Objective: To determine the effectiveness of new rapid diagnostic technologies, real-time Polymerase Chain Reaction by Gene Expert, for same day diagnosis of Tuberculosis in routine health care settings Question: How does serial smear microscopy compare to real-time Polymerase Chain Reaction by Gene Expert for same day diagnosis of Tuberculosis in routine health care settings? Objective: To examine the comparative advantages and disadvantages of serial smear microscopy and new rapid diagnostic technologies, real-time Polymerase Chain Reaction by Gene Expert, for same day diagnosis of Tuberculosis in routine health care settings 3.0 Review Methods: 3.1 Criteria for selecting studies for this review: Types of studies: Studies comparing same-day diagnosis strategy to standard of diagnosis of Tuberculosis will be included. These may be cross-sectional or randomized designs but with a Gold Standard, solid or liquid culture for Mtb Types of participants: All categories of TB patients will be considered for review including those with confirmed multi- and extensively drug-resistance. Stratification will be by age: adults vs. children; HIV status - persons with HIV/AIDS and non-hiv infected persons; site of TB - Pulmonary and Extra-Pulmonary TB; new versus previously treated TB patients Types of interventions: The review will compare same day smears from one spot, two spot or more specimen on the same day to standard of diagnosis/care (spot-morning or morningspot); direct light to fluorescent microscopy; and DNA-PCR to standard of care/diagnosis (spotmorning or morning-spot). 4.0 Types of outcome measures: Page 7 of 14

8 We will compare same-day diagnosis of TB to Standard of Diagnosis/Care on the following: 4.1 Primary outcomes: Change in Tuberculosis Case Detection Rate Change in the Turn-Around-Time for the initiation of anti-tb treatment 4.2 Secondary Outcomes: Change in proportion of patients initiated on anti-tb treatment Change in drop-out rate in the TB diagnostic pathway Change in Receiver Operating Characteristics (Sensitivity, Specificity, Predictive Values) Treatment outcomes for the cohort of TB patients diagnosed and treated Cost-Effectiveness measures i.e. capital and operational costs. 5.0 Search strategy for identification of studies: The following search strategy has been piloted and has so far yielded 8 studies eligible for consideration. Endnote TM version X4 (Thomson Reuters) will be used to manage the library. a) Electronic Searches: Attempts will be made to search as widely as possible in the following data bases and resources; PubMed/MEDLINE, Google Scholar, BIOSIS Previews, MEDION, TB Evidence, Cochrane Registry of Diagnostic Studies, National Institute for Health Research/Centre for Reviews and Dissemination (CRD), The International Journal for TB & Lung Diseases and The Union s Annual World Lung Conference b) References: These will be read from primary articles and relevant ones identified and researched first electronically, then by hand and ultimately contacting the corresponding authors for additional details. c) Grey Literature Search: Abstracts of conferences in local and international scientific meetings will also be searched using various methods. Focus will be on TB and HIV meetings for example annual scientific conferences of International AIDS Society, The Union and other TB Diagnostic networks or consortia. We will search electronic data bases of the conference website, contacting conference organizers for more information e.g. a list of presentations on TB diagnostics. When feasible, hand searching will be done. d) Contacting Experts in the Field: Principal Investigators, Lead authors, implementations scientists, TB microbiologists and TB programme managers will be contacted for ongoing studies. e) Limitations: There will be no language or time limitations to this search. Abstracts of articles in languages other than English will be screened using Google Translator and wherever possible by a reviewer familiar with the language for immediate discarding or further consideration. Page 8 of 14

9 6.0 Search terms: Various combinations of the following search terms will be used for electronic searches: Disease condition: Tuberculosis, Pulmonary Tuberculosis, TB, PTB, (PLUS) Population of participants: Adults, children, HIV/AIDS (PLUS) Diagnostic tools: florescent microscopy, florescence microscopy, light microscopy, ZN microscopy, conventional microscopy, Gene-Xpert, MDR-TB/RIF, NAAT, Nucleic Acid Amplification Test (PLUS) Intervention strategy: same-day smear, same-day diagnosis, one-day diagnosis, 1-day diagnosis, frontloading, frontloaded, single specimen, one smear, two-hour-test, rapid diagnostic test (PLUS) Specimen: sputum, blood, urine, tissue aspirate 7.0 Data Collection and Analysis: 7.1 Selection of studies: This will follow the outlined criteria in section 3.1 above. Steps to control for selection bias will be as follows: a) Independent duplicate searching for studies for possible selection and data extraction will be crucial in eliminating errors and completed by two reviewers (EAO, AD or EK). b) Use of a third-reviewer (WW) as a tie-breaker where there is disagreement to achieve consensus on inclusion. c) The lead reviewer (EAO) will blind the other reviewers to the journal source of the article, authors, institution, magnitude and direction of the results (Berlin, 1997). This will be achieved through editing copies of the article, electronically or manually by photocopying. Importantly, this has time and cost implications with uncertain benefit in protecting against bias (Berlin 1997). d) Use of a non-expert (AD) in the content area of the review i.e. Tuberculosis diagnostics, as an additional reviewer in the selection process. This may be advantageous (Cochrane Handbook, 2006) since experts frequently have pre-formed opinions that may bias assessment of both the relevance and validity of articles (Cooper 1989; Oxman 1993) e) Piloting the selection criteria on a number of articles including those articles that are definitely eligible, definitely ineligible and questionable (Cochrane Handbook, 2006). Through piloting the optimal tools will be improved and subsequently consistently applied by more than one person. This effect will be tested by the kappa co-efficient. f) Listing studies that, prima-facie; readers would expect to be included in the review as excluded studies and explaining the reasons will improve transparency of the process. (Cochrane Handbook, 2006). Page 9 of 14

10 g) Use of, a priori, written protocol detailing the entire process of the review. This protocol will be updated in time. 7.2 Data abstraction and management: Data will be abstracted from published reports and where required study investigators will be contacted to provide missing information. A pre-tested tool will be used to independently abstract data by at least two reviewers. Abstracted data will include but not limited to: First author, publication year, study setting, study design, observation period, number of patients diagnosed, patient inclusion criteria, Receiver Operating Characteristics, initiation of TB treatment, turn-around times etc. Data will be processed as described by Devillé et al Assessment of methodological quality of included studies: A critical appraisal of study quality will be conducted by at least two reviewers considering the following: a) Sample size representativeness of sample; adequacy of sample size to provide the ability to estimate Receiver Operating Characteristics and the final sample size available for assessment of outcomes b) Design to control bias having a control group; control for trends; efforts to minimize knowledge of allocation; blinding of outcome assessment; avoidance of verification and inter-reader bias and Source Data Verification. c) Quality control for the diagnostic test procedure use of a Gold Standard test and use of Standard Operating Procedures to conduct the tests d) Presentation of sufficient data to validate the results and examine generalisability following the STARD guidelines (Bossuyt, 2003). This includes: patient demographics; study setting; stage or spectrum of TB disease and co-morbid conditions e.g. HIV/AIDS, Diabetes; patient case load, missing data and drop-out rates. e) QUADAS checklist (Whiting et al, 2003): Quality Assessment of Diagnostic Accuracy Studies f) The GRADE criteria (Grading Recommendations Assessment, Development and Evaluation) (Schunemann, et al. 2008) will be used to assess the composite quality of evidence available. A register of studies expected to be included but excluded from the review will be maintained and re-appraised before final discarding. 7.4 Measures of effectiveness and Unit of Analysis: Data will be coded and double-entered in Epi Info TM version 3.5.3, 2011 release (Centres for Disease Control and Prevention, Atlanta, USA); then exported to spreadsheet, Excel TM version Page 10 of 14

11 2007 (Microsoft Office, Redmond, Washington, USA). The basic analysis package will be done using both Excel 2007 and Intercooled Stata TM version 11.2 (Stata, College Station, Texas, USA). The following measures of effect and units of analysis will apply: a) Difference in proportion (%) of TB patients detected b) Difference in time (days) from submission of sputum to returning of results c) Difference in proportion (%)of TB patients started on anti-tb treatment d) Difference in proportion (%) of TB patients who dropped out in the diagnostic pathway e) Sputum sample from Tuberculosis suspects. Receiver Operating Characteristics from sputum samples will be estimated sensitivity; specificity; predictive values. 7.5 Dealing with missing data: An intention-to-treat analysis will be conducted as well as sensitivity analyses using multiple imputation techniques suitable for sensitivity analyses. Assumption will be made to consider data Missing Completely At Random (MCAR). 7.6 Assessment of heterogeneity: Heterogeneity will be assessed on respective outcomes initially by the eye-ball test of the forest plots. In the event of a meta-analysis, statistical heterogeneity of drop out rates or sensitivities and specificities will be quantified by the I-squared statistic and assessed for significance using the chi-squared test as well as by plotting sensitivity against the false positive rate (one minus specificity) on a receiver operating characteristic (ROC) plot and visually considering the scatter of points. 7.7 Assessment of reporting biases: A funnel plot and imputation will be explored to assess for publication bias. 7.8 Synthesis of Data: It is likely that the studies will be less heterogeneous as most of them are from Low and Middle Income Countries. However, diagnostic studies are more often than not bound to be heterogeneous. A narrative synthesis will summarize the available evidence on same day diagnosis into two broad categories following the stated objectives 1 and 2. If the data appear to be amenable, a meta-analysis of effect measurements will be done for studies that are methodologically robust, with non-significant heterogeneity assuming a Random Effects Model. For point ROC, the Diagnostic Odds Ratio and 95% CI will be computed. The results will then be discussed in light of any methodological shortcomings. 7.9 Subgroup analyses: Subgroup analyses will include the following populations: HIV positive, HIV negative, Men, Women, children, central laboratories, and peripheral laboratories. Page 11 of 14

12 7.10 Sensitivity analyses: This will be done to check the robustness of the review process and its conclusions. For example, some studies will be included or excluded from the meta-analysis, if done; we will also impute missing data and examine the changes in summary statistics. 8.0 Results: This section will be populated after conducting the search and summarizing the data. However, the objectives will be written up separately in three series papers, one for each objective. 9.0 Administration of the Review: This review will be registered in the International Prospective Register of Systematic Reviews found at: The reviewers declare no significant conflict of interest. EAO is Research Scholar based at the Joint Clinical Research Centre, Kampala, Uganda supported by the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988) and the American Relief and Recovery Act, Fogarty International Centre, National Institutes of Health, USA. WW is a Senior Research Fellow based at the Mulago National Teaching and Referral Hospital Complex, Kampala, Uganda supported by the European and Developing Countries Clinical Trials Partnership (EDCTP) AD is PhD Research Fellow based at the University of Cape Town and Makerere University College of Health Sciences, Kampala, Uganda EK is the TB/HIV Focal Person at the Joint Clinical Research Centre, Kampala, Uganda 10.0 References: Berlin JA, Miles CG, Crigliano MD (1997), Does blinding of readers affect the results of metaanalyses? Results of a randomized trial, Online J Curr Clin Trials 1997 Page 12 of 14

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14 Squire SB, Belaye AK, Kashoti A, et al. (2005) Lost smear positive pulmonary tuberculosis cases: where are they and why did we lose them? Int J Tuberc Lung Dis 2005, 9(1): Tiwariae RP, Hattikudura NS, Bharmalb RN et al (2007). Modern approaches to a rapid diagnosis of tuberculosis: Promises and challenges ahead. May Tuberculosis 87;(3): Whiting P, Rutjes A, Reitsma J et al (2003). The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews World Health Organisation (2009) Global Tuberculosis Control: a short update to the 2009 report. Geneva, World Health Organisation, WHO/HTM/TB/ World Health Organisation (1994) Framework for Effective Tuberculosis Control Geneva, World Health Organisation Document 1994; WHO/TB/94.179:1-7 World Health Organisation, International Union Against Tuberculosis and Lung Diseases, Royal Netherlands Tuberculosis Association (2001). Revised International Definitions in Tuberculosis Control, Int J Tuberc Lung Dis 2001; 5:213-5 World Health Organization (2008) Reduction of number of smears for the diagnosis of pulmonary tuberculosis; Geneva, Switzerland: WHO, Page 14 of 14