This systematic review is, to the best of our knowledge, the first systematic review analyzing the performance of programs testing for LTBI, rather than TB disease, in homeless persons in the United States. We generally found promising yields of persons tested and LTBI detected. Compliance with testing was generally high, and even though some persons tested with TST did not return to have their tests read, we estimate that nearly four out of five persons reached by these targeted testing programs will obtain valid test results. More than 99% of persons who tested positive for infection were successfully referred to and attended at least one session of follow-up care. The proportion of persons testing TST positive of those with valid results (25%) is higher than would be expected among the general public [
35]. In studies using TST, nearly 15% of persons who had tests placed did not return at the appropriate time to have them read. Because IGRA does not require a return visit to obtain test results, it may be possible to communicate test results when the patient makes contact with the testing organization at a later date, or over the phone or through mail for persons who have means to receive these types of communications, thus it is possible that use of IGRA will reduce the number of persons who remain unaware of their infection. Although the primary goal of these testing programs was to detect cases of LTBI, we found that an average of 1.2% of persons who tested positive were found to have TB disease on follow-up evaluation. Thus, LTBI targeted testing programs in homeless populations may also aid in the detection of cases of TB disease, which may lead to earlier diagnosis and less time spent with a transmissible infection.
We elected not to include data on treatment initiation and adherence as outcomes in this review, as we anticipated that most studies that included treatment outcomes would start with persons diagnosed with LTBI, rather than following a cohort through testing and diagnosis. Current recommended LTBI treatment options for most adults include shorter course regimens such as 4 months of daily rifampin, or 12 weekly doses (3 months) of isoniazid with rifapentine by directly observed therapy (DOT), in addition to the standard treatment of 9 months of daily or intermittent (by DOT) isoniazid [
36]. Randomized controlled trials [
37,
38], a meta-analysis [
39], and an observational study [
40] suggest that shorter course LTBI treatment regimens are associated with significantly higher treatment completion rates, even among persons experiencing homelessness and other marginalized groups. A systematic review of adherence to newer short-course regimens in persons experiencing homelessness would be a valuable companion piece to this review, and allow assessment of the entire LTBI continuum of care in this high risk population.
Limitations
Meta-analyses often include a formal assessment of study bias. The Cochrane recommended tool for bias assessment was developed for the purpose of evaluating studies that compare an intervention with a control condition. This tool was considered inappropriate for the evaluation of this study because this analysis does not seek to compare one condition to another. We are unaware of any widely used and well accepted instrument for the evaluation of biases in studies that seek to estimate the yield of disease screening programs, therefore we did not conduct a formal bias assessment of individual studies. However, we can speculate on the types of biases that may have affected our results. A likely major source of bias is publication bias. The results of TTT programs for homeless persons are rarely published because assessments done by busy public health workers are intended only to inform the program. It is possible programs that publish or otherwise disseminate their results differ from programs that do not. For example, programs may publish about exceptionally successful programs, or conversely, publish about programs that faced exceptional challenges. Funnel plots of proportion with tests read of those with tests placed and proportions with positive tests of those with valid results for TST studies (Additional file
5) did not reveal any obvious asymmetry, but funnel plot asymmetry is largely due to the use of null-hypothesis significance testing. Because the included studies were not comparative in nature, there was no significance testing for the individual study proportions and publication bias may shift the entire distribution rather than causing asymmetry. Another consequence of incomplete reporting of targeted testing programs is that it is not possible to know what proportion of the homeless population is currently reached by these programs, which in turn makes it difficult to estimate the possible effects of scaling up testing in this population.
Misclassification is another potential source of bias; numbers of persons who were retained at each step of the cascade may not have been recorded correctly, and mistakes may have been made in interpreting test results. Studies did not generally provide sufficient evidence to evaluate the risk of bias due to misclassification.
In 2015, 66.4% of reported cases of TB disease in the United States were in persons who were born in another country, and TB incidence was nearly 13 times higher in persons born outside the US than those born in the US. Per data from the Online Tuberculosis Information System, 30.5% of recently homeless persons with TB diseases between 2011 and 2015 were also born outside the US [
41]. However, we found very little information in our included studies regarding the intersection of these two critical risk populations in our included studies. Only one study stated the proportion of the study population that was born abroad; this study found that 17.3% of 260 homeless persons tested for TB in Los Angeles in the early 1990’s were non-US born [
16].
There are also issues that limit the generalizability of our results. We included 17 studies conducted wholly or in part prior to 2000. The preponderance of older studies limits generalizability due to possible changes in LTBI prevalence. While the proportion of reported cases of TB disease in persons experiencing recent homelessness has remained at about 6% since the mid-1990s, the number of incident cases of TB disease in the United States have decreased in both the general public and homeless populations, with only 495 cases reported in 2015 in persons experiencing homelessness in the last year vs. 795 cases reported in 2005 [
2]. The decline in cases in persons experiencing homelessness may be partially due to the active case-finding activities that have been advocated for these populations since the 1990’s [
34]. We also found that studies were mainly conducted in coastal urban areas, meaning that our results may generalize poorly to testing programs for homeless persons in other settings.
Most studies in this review relied on TST, rather than IGRA for testing [
42], and the studies that did use IGRA reported a limited number of cascade steps. In addition, the two studies that used IGRA exclusively were both conducted in San Francisco, and both recruited from healthcare facilities, limiting generalizability of results. Given these limitations, we do not think it is appropriate to use the results of this review to compare relative performance of TST with IGRA. The two studies which relied exclusively on IGRAs for testing did not report the number of persons (either those testing positive or overall) who received their test results, but in a separate review [unpublished] of targeted blood-borne infection testing for homeless persons, we estimated that only 57.9% of persons testing positive for HCV infection and 50.8% of persons testing positive for HIV infection were given test results. Additional studies are needed to assess LTBI test positivity and referral for follow-up care using the newer IGRA diagnostics.
Almost all of the studies included in this review recruited participants from health care facilities, shelters, or other types of service agencies. Only two [
11,
16] included persons recruited through outreach or street venue based sampling. Because some homeless persons cannot or do not access services, most of the programs we reviewed likely left a large subpopulation of homeless persons without access to testing. We have conducted some stratified analyses by the type of service agency where recruitment was done, but failure to find a significant difference between proportions should be interpreted with caution because tests for heterogeneity are low-powered and frequently fail to reject false hypotheses.
We found high heterogeneity in most of our pooled proportions, indicating a high probability that study results differed from one another due to underlying program factors, rather than random variability. The random effects model that we used to calculate pooled proportions explicitly allows pooling of results sampled from differing underlying probability distributions. However, since our results indicate that real-world performance is likely to differ substantially between programs, program planners, modelers, and others who wish to incorporate our results into their work should consider our confidence intervals, in addition to our point estimates.