Pre-treatment loss to follow-up in tuberculosis patients in low- and lower-middle-income countries and high-burden countries: a systematic review and meta-analysis
Peter MacPherson a, Rein MGJ Houben b, Judith R Glynn b, Elizabeth L Corbett c & Katharina Kranzer c
a. Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, England.
b. Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, England.
c. Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, England.
Correspondence to Peter MacPherson (e-mail: firstname.lastname@example.org).
(Submitted: 20 May 2013 – Revised version received: 02 October 2013 – Accepted: 03 October 2013 – Published online: 22 November 2013.)
Bulletin of the World Health Organization 2014;92:126-138. doi: http://dx.doi.org/10.2471/BLT.13.124800
Since tuberculosis was declared a global emergency in 1993 by the World Health Organization (WHO), new cases of tuberculosis and deaths from the disease have dropped dramatically in several countries with a high burden of the disease.1 All six WHO regions are on track to meet the Millennium Development Goal target of reducing tuberculosis incidence and deaths from tuberculosis by half between 1990 and 20151,2 and, with the sole exception of the African Region, all are on track to halve tuberculosis mortality rates.2 Nevertheless, the situation remains precarious.3 Twenty-two predominantly low- and middle-income countries were estimated to account for 82% of the 5.7 million tuberculosis cases notified in 20101 and high rates of death from tuberculosis among people living with human immunodeficiency virus (HIV) infection prevail in much of sub-Saharan Africa.4,5
Rapid case identification of individuals with sputum smear-positive tuberculosis and rapid initiation of anti-tuberculosis chemotherapy are key to controlling tuberculosis6 and are promoted as part of the DOTS strategy model of passive case-finding that has been adopted by most national tuberculosis programmes (NTPs).7 From the patient’s perspective, the tuberculosis diagnostic and care pathway (Fig. 1) begins with a recognition of symptoms that prompt care seeking. Individuals may drop out of care during the diagnostic process (“loss to follow-up during diagnostic period”), before initiating treatment (“pre-treatment loss to follow-up”, formerly known as “initial default”) or after treatment has begun. Patients diagnosed with smear-positive tuberculosis who do not initiate treatment represent an important failing in the provision of care.8,9 High rates of mortality are reported in this group.10 Moreover, bringing these patients into care could reduce tuberculosis transmission to others.11 Patients with a diagnosis of tuberculosis who are lost to follow-up before they receive treatment are not included in routine reporting by NTPs. Thus, programme effectiveness may be overestimated.8
Fig. 1. The diagnostic and care pathway for tuberculosis
Efforts to improve tuberculosis case detection rates have centred on ensuring rapid treatment for all individuals diagnosed with smear-positive tuberculosis.12,13 With this goal in mind, WHO has recently changed its policy, which now calls for two sputum specimens instead of three and same-day collection.13,14 However, assessing the impact of these changes on linkage to treatment has been hampered by a lack of understanding of the extent of pre-treatment loss to follow-up8 and of the patient, provider and health system factors that contribute to it.15
Although nearly 50 years have passed since high rates of pre-treatment loss to follow-up were first identified as a potential major contributor to the failure of tuberculosis control programmes, researchers and policy-makers have paid little attention to the fate of patients who do not access treatment after receiving a diagnosis of tuberculosis.16,17,18 Indeed, the “Piot model” used to describe loss to care at different stages for any disease was first developed for tuberculosis.18
This study had two main objectives: (i) to systematically quantify pre-treatment loss to follow-up in low- and lower-middle income countries and in countries with a high burden of tuberculosis; and (ii) to describe the reasons for drop-out and the outcomes seen in individuals with a tuberculosis diagnosis who do not initiate treatment. A secondary objective was to assess the quality of the studies reporting on pre-treatment loss to follow-up.
We followed PRISMA reporting guidelines for systematic reviews.19 To define the points at which tuberculosis patients drop out of care, we developed the tuberculosis diagnostic and care pathway described in Fig. 1 using terms recommended recently that replace previously used terms such as “initial default”.9
For this study, patients in a national tuberculosis care programme who received a diagnosis of tuberculosis on the basis of at least one positive sputum smear or culture but did not start tuberculosis treatment were defined as having pre-treatment loss to follow-up. This included individuals who died before initiating treatment.
The recruitment period was defined as the time during which patients with a diagnosis of tuberculosis were recruited to studies or during which data from such patients were extracted from national programme registers. For studies with individual follow-up, the follow-up period was defined as the time between diagnosis and the most recent date of active follow-up. For studies in which tuberculosis treatment registers were checked retrospectively, we present the minimum and maximum follow-up periods available. Because studies had different follow-up periods and varying temporal definitions for pre-treatment loss to follow-up, we used the definition given in each study rather than a time-delineated definition. However, we did require a follow-up period of at least 4 weeks to allow enough time for patients to link to care and treatment.
Inclusion and exclusion criteria
Studies were included in the review if they reported on the proportion of patients having smear- or culture-positive tuberculosis who experienced pre-treatment loss to follow-up in NTPs in low- or lower-middle-income countries as defined by the World Bank on 1 July 2011,20 or in any of the 22 countries with a high burden of tuberculosis as defined by the Stop TB department of WHO.1 Studies that reported on clinical trials, including randomized and non-randomized active case-finding studies, were excluded because participants in these studies would be more likely to receive intensive follow-up and tracing and would not be representative of patients with tuberculosis diagnosed routinely. Studies that reported only on paediatric patients – i.e. children 15 years of age or younger – were excluded. Studies that recruited both adults and children were included even if the data were not disaggregated by age group.
We systematically searched the Ovid, Medline and Global Health databases for studies published between 1 January 1994 and 31 January 2013. Our search strategy is outlined in Table 1. We also hand searched the abstracts of the Union World Conference on Lung Health from 2009 to 2012. We identified additional studies through reference lists and annotated bibliographies and by corresponding with researchers in the field. If the manuscript did not give the absolute number of individuals with pre-treatment loss to follow-up, we contacted the authors to obtain the data.
Table 1. Systematic strategy used to search for studies on pre-treatment loss to follow-up in tuberculosis patients
Three authors (KK, PM, RH) reviewed titles and abstracts to obtain the full texts of relevant articles. All three assessed the full texts to determine their suitability and based their final inclusion in the review on consensus as a team. PM and KK extracted data from included studies using a pre-designed table.
Quality of selected studies
One researcher (PM) used a modified version of the Newcastle-Ottawa scale to assess studies in terms of quality and of the risk of bias in the selection of participants and in the ascertainment of outcomes. Each study could score up to six points in each of these two categories, each having six items. The section for the selection of comparison groups was removed from the Newcastle-Ottawa scale because no study had a comparison group. The factors considered included: the representativeness of the patients recruited with respect to the underlying population of tuberculosis patients diagnosed in the routine health-care system; the test used to ascertain the diagnosis of tuberculosis; the method of identification of pre-treatment loss to follow-up; and the adequacy of follow-up (judged in terms of the proportion of participants whose outcomes were ascertained, with > 85% being adequate). In studies in which laboratory and treatment registers were linked, we evaluated the process and variables used for linkage (including personal identifiers and dates).
Data analysis and statistical methods
For each included study, we report on the number of patients who received a diagnosis of smear- or culture-positive tuberculosis and the proportion who initiated antituberculosis treatment. For patients identified as having experienced pre-treatment loss to follow-up, we report the duration of follow-up and, if available, the proportion who were successfully traced and their outcomes (alive but not on treatment; alive after starting treatment; deceased; or transferred to another facility but treatment and vital status unknown). To calculate summary estimates of pre-treatment loss to follow-up, we classified as treatment initiators those tuberculosis patients who were classified as having experienced pre-treatment loss to follow-up but who, on tracing, were found to have initiated treatment at an alternative site. We assessed heterogeneity using the I2 statistic. On initial analysis, we found substantial heterogeneity between studies. Therefore, we estimated the pooled proportion of patients with a diagnosis of tuberculosis and pre-treatment loss to follow-up (and the corresponding 95% confidence intervals) using a random-effects model, weighting for the inverse of the variance and stratification by study region. Stata 12.1 (Statacorp, College Station, Texas, USA) was used to analyse the data.
Ethical approval was not required for this study.
We identified 5096 potentially relevant studies, of which 23 were eligible for inclusion in the analysis (Fig. 2).10,21–42 These reported on a total of 34 706 patients with smear- or culture-positive tuberculosis, 3474 of whom had experienced pre-treatment loss to follow-up. The characteristics of the included studies are summarized in Table 2. There were 13 studies from sub-Saharan Africa (8 countries), 9 from Asia (5 countries) and 1 from the western Pacific (1 country).
Fig. 2. Flowchart for the selection of studies on pre-treatment loss to follow-up in patients with a diagnosis of tuberculosis
Table 2. Characteristics of studies included in the review and proportion of smear-positive tuberculosis patients who initiated treatment
Most studies reported on pre-treatment loss to follow-up among smear-positive patients only. Two studies included patients who were either smear- or culture-positive.29,30 In some studies smear positivity was defined as at least 125,27,28,30,35,41,42 or at least 222–24,34 positive smears, whereas others did not provide any definition.10,21,26,31–33,36–40 A study from South Africa stratified rates of reported pre-treatment loss to follow-up by smear status (smear-positive or smear-negative but culture-positive),23 whereas another study, also from South Africa, reported on pre-treatment loss to follow-up in tuberculosis patients whose diagnosis was established clinically and/or bacteriologically.29
Quality of included studies
The quality of the included studies varied (Table 3). Only a few studies (n = 4) showed a low risk of bias or scored full marks across all items assessing patient selection and ascertainment of outcomes. The methods for ascertaining pre-treatment loss to follow-up were suboptimal or poorly described in most studies; only seven studies adequately described the follow-up period allotted to each participant. The majority of studies (n = 19) identified patients diagnosed with tuberculosis by extracting data from laboratory or sputum collection registers (Table 2). Such extraction was performed retrospectively in 17 studies and prospectively in two. In the remaining 4 studies, patients with a diagnosis of tuberculosis were identified as part of ongoing epidemiological surveillance30 or were prospectively recruited for follow-up from a chest clinic33,40 or from primary-health-care centres.41 The recruitment periods ranged from 3 months24,34,36 to 90 months.30 Only 9 studies22–25,27,29,31,36,37 applied a cut-off for time since diagnosis – ranging from 1 month to 3 months – to define pre-treatment loss to follow-up.
Table 3. Modified Newcastle-Ottawa Scale for assessment of the quality of the studies included in the review of pre-treatment loss to follow-up in tuberculosis patientsa
Although most studies (n = 16) used retrospective linkage of laboratory and treatment registers to identify patients who initiated treatment for tuberculosis10,21–29,32,37–39,41,42 – and so scored full marks for this item – the quality of the procedures used to ensure accurate linkage varied considerably. Only one study27 described the variables used to link records and gave the proportion of records that were reliably matched.
Pre-treatment loss to follow-up
The proportion of patients with a diagnosis of tuberculosis who experienced pre-treatment loss to follow-up ranged from 4 to 38%.21,34 In studies from Africa pre-treatment loss to follow-up ranged from 6 to 38%, whereas in studies from Asia it ranged from 4 to 28%. Studies that reported on data from a single clinical site21,22,26,29,31,33,35,40 had higher rates of pre-treatment loss to follow-up (range: 14–38%) than studies reporting on national or regional data (range: 4–25%).10,23–25,27,28,30,32,34,36–39,41,42
In total, 10 studies10,24,25,30–34,38,40 attempted to trace tuberculosis patients with pre-treatment loss to follow-up (Table 4). One of them did not detail the tracing method used.38 Tracing rates were rather poor on average. The proportion of patients who could not be traced ranged from 0%30 to 77%.32 This limited our ability to draw inferences about the fate of tuberculosis patients with pre-treatment loss to follow-up.
Six studies – five of them from Asia – reported that patients who had initially been classified as being lost to follow-up before being treated had in fact initiated treatment for tuberculosis at another clinical facility.25,31,32,33,34,40 In the Asian studies, transfer to a private clinic for tuberculosis treatment was the commonest reason for pre-treatment loss to follow-up; from 0 to 62% of patients were found to have been treated at private clinics, although only one such study successfully traced more than 80% of the patients.33 In the only study from Africa that traced individuals and recorded if they initiated treatment elsewhere, 23% of tuberculosis patients who were initially classified as lost to follow-up before treatment in Malawi had started treatment for tuberculosis in another district.32
When we counted traced individuals who had initiated treatment at an alternative site as tuberculosis treatment initiators, we noted substantial heterogeneity between studies in rates of pre-treatment loss to follow-up (I2 = 98.4%; P < 0.001). This remained after stratifying by study region (Africa: I2 = 96.1%; P < 0.001; Asia: I2 = 98.0%; P < 0.001; western Pacific: one study only). The funnel plot showed asymmetry, suggestive of publication bias (Egger’s statistic: P < 0.001). Fig. 3 shows a forest plot for the included studies, stratified by region. In random-effects meta-analysis, the overall inverse-weighted proportion of patients with a diagnosis of tuberculosis who experienced pre-treatment loss to follow-up was 16% (95% confidence interval, CI: 13–18). Although this proportion was 18% in studies from Africa (95% CI: 13–22) and hence higher than in Asian studies, where it was 13% (95% CI: 10–15%), the CIs overlapped.
Fig. 3. Proportion of patients with a diagnosis of tuberculosis who were lost to follow-up before treatmenta in 23 studies from Africa, Asia and the western Pacific
Among traced tuberculosis patients with pre-treatment loss to follow-up, the case fatality rate ranged from 0% (95% CI: 0–6)40 to 82% (95% CI: 59–94).10 The risk of death was highest in studies from Africa but varied widely and low rates of tracing rendered it unreliable. Only the study from Malawi described the time from diagnosis to death among 19 patients who were traced:10 a median of 3.5 weeks (range: 2–12) in 14 deceased patients.
Reasons for loss to follow-up
Factors associated with an increased risk of pre-treatment loss to follow-up were male sex, older age,31 living in an urban area,25 diagnosis in a hospital or stationary clinic (rather than a mobile clinic),23 geographical location of the tuberculosis laboratory (regional versus local),42 and being diagnosed with smear-negative but culture-positive tuberculosis.24 However, distance to treatment site was not associated with the risk of pre-treatment loss to follow-up in Ghana.21
Of the nine studies that traced patients with pre-treatment loss to follow-up, one undertook in-depth qualitative interviews to determine the reasons for drop-out,10 and the other eight were based on structured patient interviews, either in person24,25,30–32,34,40 or by telephone.33,40 Health-system-related obstacles for not starting treatment for tuberculosis included dissatisfaction with long waiting times in health services, the need for repeated visits, and delays in receiving the results of sputum smears.10,25,29,31 Some reasons for not starting treatment for tuberculosis were patient-related (e.g. difficulty getting time off from work or a lack of understanding of tuberculosis, its severity or the potential benefits of treatment).10,24,31,33,40 Other reasons were disease-related (e.g. weakness and fatigue).31,32
This review highlights the paucity of data on pre-treatment loss to follow-up among patients with a diagnosis of tuberculosis, despite high prevalence and mortality rates. Only 23 studies from 14 countries were identified over a period of 17 years, in sharp contrast with the 37 studies on HIV care programmes in low-resource settings that were published in a period of 5 years.43 Yet pre-treatment loss to follow-up in patients with smear-positive tuberculosis is an important problem for tuberculosis programmes because these patients are highly infectious44 and experience high morbidity and mortality.45,46
In the studies identified in this review, pre-treatment loss to follow-up was high – from 4 to 38% – and was higher in sub-Saharan Africa (18%) than in Asia (13%). Given the very high risk of death among tuberculosis patients who are not promptly treated, minimizing treatment delay and losses at all stages in the diagnostic and care pathway is critically important.12 Although tracing was suboptimal in most studies, the main reason for pre-treatment loss to follow-up was death, especially in countries in sub-Saharan Africa with generalized epidemics of HIV infection, perhaps because of the high mortality among patients having both tuberculosis and HIV infection.47,48 It is difficult to ascertain whether these deaths are caused by or result from lack of treatment. Only one study reported the time between diagnosis and death in patients who did not start tuberculosis treatment; the median of 3.5 weeks found in the study suggests that patients were severely ill at the time of diagnosis.10
The diagnostic and care pathway is often costly and long, even in settings where health care and diagnostic tests are free at the point of delivery. Reducing costs and time for the patient might improve linkage to treatment. Thus, NTPs should consider the following measures: (i) reducing the number of sputum samples for initial diagnosis from three to two;49 (ii) replacing “spot-morning-spot” sputum collection (requiring visits to the facility on two separate days) with collection of two spot sputum samples one hour apart;14 (iii) preparing two smears from the same sputum specimen;50 and (iv) introducing same-day light-emitting diode (LED) microscopy51 or automated nucleic acid molecular diagnostics,52 shown to be more sensitive and associated with reduced time to diagnosis and lower pre-treatment loss to follow-up. Further evaluation of the impact of these interventions on reducing pre-treatment loss to follow-up is required.
Health system factors, particularly relating to the recording and registration of suspected and confirmed tuberculosis cases, were found to be important contributors to pre-treatment loss to follow-up in several studies. Moreover, in many studies researchers were required to reconcile laboratory registers with treatment registers to determine the pre-treatment loss to follow-up rate, a task not easy to perform regularly under routine programmatic conditions. These issues could be addressed by using a single patient identifier for the entire diagnostic and care pathway for tuberculosis. Patients attending a facility with a positive screening for symptoms of tuberculosis would be recorded in a “cough register”53 for subsequent monthly tracing of those whose smear results had not been received and of smear-positive patients who had not returned for treatment.
By not including individuals lost to follow-up before treatment when reporting standard programme indicators, NTPs incorrectly report case detection, cure and case fatality rates. For example, with DOTS strategy targets of 70% case detection and 85% cure rate, including individuals who experience pre-treatment loss to follow-up (using 18% in Africa and 13% in Asia, for illustration), would result in the true case detection rate rising from 70% to 85% in African countries and 70% to 80% in Asian countries, as those diagnosed but not started on treatment are included (Table 5). The cure rate however would drop from 85% to 70% in Africa and from 85% to 74% in Asia, as those detected but not started on treatment are counted as “not cured”. Moreover, in African countries, where the higher death rate in individuals with pre-treatment loss to follow-up could be attributable to HIV infection, the reported death rate would increase from 6 to 12%. In NTPs from Asia, the death rate would be unchanged at 3%. These numbers better reflect NTP’s actual performance – they are finding more cases than thought, but are not performing so well at providing treatment.
Table 5. Impact of including rates of pre-treatment loss to follow-up on national tuberculosis programme indicators in hypothetical programmes in Africa and Asia with 100 000 individuals and DOTS strategy targets (70% case detection, 85% cure) theoretically achieved, 2011
In studies from Asia, where more private practitioners offer tuberculosis treatment services alongside NTPs,54,55 a small number of patients lost to follow-up initiated treatment with private providers. Since they would not be included in NTP reports of outcomes, the success of the national programme would be underestimated. Interventions to improve links and data sharing between NTPs and private providers have proved effective in increasing case detection rates in studies from Asia56,57 and are promoted by WHO.58 Further expansion of such interventions will help to ensure that programme outcomes are accurately reported at the national level.
A limitation of this analysis is the poor quality of outcome ascertainment in several studies. The small number of traced individuals who had initiated treatment under a different provider underscores the need to tailor tuberculosis services to the individual patient and the difficulty of accurately estimating outcomes at the programme level. The varying length of follow-up of tuberculosis patients in cohort studies and the absence of time-delineated definitions for pre-treatment loss to follow-up make it difficult to draw firm conclusions. Following the framework set out in Fig. 1, NTPs should strive to adopt and routinely report retention in care throughout the diagnostic and care pathway.16,59 A focus on retention could enhance the reporting of the pre-treatment loss to follow-up rate (e.g. the proportion of smear-positive patients not initiating treatment for tuberculosis within 3 months) as part of the regular quarterly reporting system, in addition to allowing comparison within and between NTPs.
A second limitation is that negative publication bias may have resulted in an under- or overestimation of pre-treatment loss to follow-up in this review. Although we undertook a systematic literature search, we may have missed some studies reporting on pre-treatment loss to follow-up if this was not the main focus of the study.
Because the studies identified were so heterogeneous, the summary estimates should be interpreted cautiously. Our ability to draw conclusions on the risk factors or reasons for pre-treatment loss to follow-up among people with tuberculosis is limited by the poor reporting of the baseline characteristics of study participants and low numbers of traced patients in several studies. We identified studies from 8 of the world’s 22 countries with a high burden of tuberculosis. Although the data from these countries are helpful in showing the important contribution of pre-treatment loss to follow-up to suboptimal NTP performance, data from a broader range of countries and regions are urgently needed. In particular, no studies from Latin American countries or the Russian Federation were identified, perhaps because these countries have produced no studies or because we limited our search to English-language sources. To facilitate comparisons between studies and regions, all studies reporting outcomes in patients with a diagnosis of tuberculosis should specify the proportion that is lost to follow-up before getting treated.
In conclusion, there is a paucity of evidence on the magnitude and clinical consequences of pre-treatment loss to follow-up in tuberculosis patients. The limited data available suggest that pre-treatment loss to follow-up is common and that it entails a high risk of death. There is an urgent need to improve the recording and reporting of pre-treatment loss to follow-up and to evaluate and scale up interventions to reduce this problem.
Peter MacPherson and Elizabeth L Corbett are also affiliated with TB/HIV Group, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
PM (the corresponding author) was funded by the Wellcome Trust (grant number: WT089673). RMGJH was funded by the Bill & Melinda Gates Foundation. ELC was funded by a Wellcome Trust Senior Research Fellowship in Clinical Science (grant number: WT091769). The funders had no role in the design or analysis of the study, or in the writing or decision to submit for publication. PM confirms that he had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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