Protocol registration and adherence to international standards
We registered the systematic review protocol with the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42018106284). We prepared our study protocol, performed the systematic review and wrote the report following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations.
We aimed to provide summary estimates of: the proportion of patients seeking health care at different levels of the health system who had symptoms consistent with TB; the proportion of those who were offered TB symptom screening; the proportion who were offered and received diagnostic testing for TB (including patient receipt of results); and the proportion found to have microbiologically confirmed TB who were subsequently initiated on anti-tuberculosis treatment.
We defined “TB symptom screening” as any enquiry into symptoms consistent with TB. We defined “investigation for TB” as any screening/diagnostic test for tuberculosis defined by primary studies including (but not limiting to) microbiologic (including, but not limited to smear of sputum or other body fluid, culture or Xpert), or radiological (including but not limited to chest x-ray or ultrasound), or referral to another health facility with the intent to diagnose TB. “investigation” was defined as undergoing a TB investigation. “Receipt of result” was defined as receiving outcome after undergoing a TB investigation. We defined “initiation of TB therapy” as commencement of any course of therapy with intent to treat active TB. We defined “recruitment period” as the time during which a patient with symptoms consistent with TB attended any healthcare setting. For participant follow-up time, we adopted the definitions provided by individual studies.
We included studies published in any language in or after 2000, that recruited adult participants from WHO’s Published List of 30 High TB Burden Countries, attending any healthcare setting for any reason with symptoms consistent with TB. To be eligible, a study needed to report data allowing extraction of at least one of the following proportions of the population of interest that enter into any step of the TB cascade of care: offered TB symptom screening; offered TB investigation for TB; received investigation for TB; and initiated TB therapy.
Eligible study designs were cross-sectional studies, standardised patient studies, exit interview studies, and cohort studies (prospective and retrospective). Standardised (simulated) patient were studies that involved a covert member of the research team (the standardised patient) who presented to a healthcare facility or pharmacy and, when questioned by health workers, would give a history of TB symptoms that should prompt further clinical questions, examinations and tests for TB. Exit interview studies are typically done at the point of clinic exit shown in Fig. 1, where a sample of patients leaving the health facility are asked about the screening and diagnostic tests received during their clinic visit. We excluded studies that reported on clinical trials, register linkage studies, autopsy studies, prevalence surveys, and community-based studies because participants in these studies would not be representative of patients in routine care. Studies starting with diagnosed TB patients were excluded as being unable to provide unbiased numbers for stages earlier in the TB care cascade.
Information Sources And Data Extraction
We systematically searched for studies meeting our eligibility criteria in Medline (Pubmed), Embase (OVID), and CINAHL (EBSCOHost) using the search strategies shown in Appendix 1. We included studies published between 01 Jan 2000 and 22 January 2019, when we ran the search.
Two reviewers (THD and JL) independently screened titles and abstracts of the articles identified through the electronic searches against the eligibility criteria. THD and JL independently assessed full texts of the included papers, extracted data from eligible studies using a standardised electronic form (Google Forms, Google, United States), and documented reasons for non-inclusion. A third reviewer, PM, resolved disagreements in eligibility.
We extracted the following data from the eligible articles: first author; year of publication; facility and country of data collection; dates of study; level of healthcare facility (primary care, hospital); study definitions of review outcomes (TB symptoms, TB symptom screening, TB investigation); management options available on site (e.g. smear, chest X-ray, Xpert, TB treatment); study design; study eligibility criteria; study population characteristics (HIV status, sex, age); number of patients recruited; number of patients with TB symptoms; number of patients symptom-screened; number of patients with symptoms tested for TB; number of patients with microbiologically confirmed TB; number of patients started on TB treatment; and factors associated with an individual being screened based on quantitative analysis. We excluded studies that did not report information on any of the study outcomes.
Assessment Of Methodological Quality
For a meta-analysis of exit-interview and standardised patient studies, no accepted risk of bias tool exists. We therefore adapted the QUADAS-2 tool to our specific question (see Appendix 2) to assess risk of bias, at the level of the study, across three domains: patient selection, classifying TB symptoms, and diagnosing TB. For each domain, we reported the level of risk or concern as being either high, low or unclear.
For each included study, we reported on the following proportions (and corresponding 95% exact binomial confidence intervals, either as reported in respective articles or, if not available, as calculated by us): a) patients attending a health care facility for any reason who were offered symptom screening for TB; b) patients with TB symptoms who were offered further investigation for TB; c) patients who were offered further investigation for TB who receive results of TB testing; d) patients who receive results of TB testing who were initiated on TB therapy; and e) missed TB: the proportion of patients with TB who were not initiated on TB therapy. We performed descriptive analysis producing forest plots of these proportions. We estimated the pooled weighted proportion of participants (and 95% confidence interval) who were offered a diagnostic test for TB using the double arcsine transformation. All statistical analysis was carried out in R V3.6.0 (R Foundation for Statistical Computing, Vienna).