Why is improving screening for tuberculosis of the lungs important?
Systematic screening in settings where tuberculosis is common is a recommended strategy for early detection of tuberculosis. Screening helps identify people who are more likely to have tuberculosis so they can have confirmatory testing. These are additional tests to confirm the presence of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Asking about tuberculosis symptoms (for example, cough, coughing up blood, fever, and fatigue) and doing a chest X-ray (CXR), which shows lung abnormalities, are commonly used screening methods. Tuberculosis is treatable with antibiotics, which means that early detection may result in lower mortality and morbidity, less transmission of tuberculosis, and more equitable access to care.
Not recognizing lung tuberculosis when it is present (a false-negative result) may result in delayed treatment and further transmission. Conversely, a screening result that is thought to be positive while it is not may result in unnecessary confirmatory tests, which burdens both the individual and the public health system.
Knowing how often screening tests lead to false-positive and false-negative results – this is called accuracy - may help in choosing a screening method.
What is the aim of this review?
To find out how accurate asking about symptoms and CXR are as screening tests for lung tuberculosis in adults with unknown or negative HIV status.
What was studied in the review?
We studied the accuracy of three types of symptom questions: (i) cough for two or more weeks, (ii) cough of any duration, and (iii) any tuberculosis symptom. For CXR, we studied two definitions for a positive result: (i) any CXR lung abnormality and (ii) CXR lung abnormalities suggestive of tuberculosis. The results are interpreted by staff trained in radiology.
What are the main results in this review?
The review included 59 studies, of which 48 reported on one or more symptom screening questions and 37 reported on CXR.
The results below indicate a situation in which five individuals (0.5%) have lung tuberculosis among a group of 1000 screened individuals.
Cough for two weeks or more: if 1000 individuals were screened, 58 would screen positive, meaning they report cough for two weeks or more and, of these, 56 (97%) would not have lung tuberculosis. Of 1000 individuals, 942 would screen negative, meaning they do not report cough for two weeks or more and, of these, three (0.3%) would have lung tuberculosis.
Cough of any duration: of 1000 individuals, 127 would screen positive and, of these, 124 (98%) would not have lung tuberculosis. Of 1000 individuals, 873 would screen negative and, of these, two (0.2%) would have lung tuberculosis.
Any tuberculosis symptom: of 1000 individuals, 351 would screen positive and, of these, 348 (99%) would not have lung tuberculosis. Of 1000 individuals, 649 would screen negative and, of these, one (0.2%) would have lung tuberculosis.
Any CXR lung abnormality: of 1000 individuals, 113 would show lung abnormalities on CXR and, of these, 108 (96%) would not have lung tuberculosis. Of 1000 individuals, 887 would not show lung abnormalities and, of these, no one (0%) would have lung tuberculosis.
CXR lung abnormalities suggestive of tuberculosis: of 1000 individuals, 48 would screen positive and, of these, 44 (92%) would not have lung tuberculosis. Of 1000 individuals, 952 would screen negative and, of these, one (0.1%) would have lung tuberculosis.
How reliable are the results of the studies in this review?
In the included studies, the diagnosis of tuberculosis was made by assessing the study participants with confirmatory tests (the reference standard). This is the best available method for deciding whether participants really had lung tuberculosis.
However, there were problems with how the studies were conducted. In many studies, those without symptoms or CXR abnormalities were not tested with a confirmatory test. Therefore, the numbers of those without symptoms or CXR abnormalities, but nevertheless having tuberculosis (people who tested falsely negative), may have been underestimated in these studies. Consequently, screening for symptoms or CXR abnormalities might appear more accurate than it really is.
In addition, results from individual studies included in the review varied, for example, because of regional variation. Therefore, we cannot be sure that screening for symptoms and CXR abnormalities will always have the same accuracy.
What are the implications of this review?
The results of the review suggest that screening for tuberculosis with symptom questions or CXR might result in a high yield of persons with tuberculosis disease. However, this screening might also result in a high proportion of persons without the disease screening positive. Additional considerations for the best design of screening programmes include the local epidemiological situation, availability and accessibility of CXR, and the need for confirmatory tests.
How up to date is this review?
The review authors searched for and included studies published from 1 January 1992 to 10 December 2018. A repeat of the search to 2 July 2021 revealed no further studies that would inform the results of the analysis.
The summary estimates of the symptom and CXR index tests may inform the choice of screening and diagnostic algorithms in any given setting or country where screening for tuberculosis is being implemented. The high sensitivity of CXR index tests, with or without symptom questions in parallel, suggests a high yield of persons with tuberculosis disease. However, additional considerations will determine the design of screening and diagnostic algorithms, such as the availability and accessibility of CXR facilities or the resources to fund them, and the need for more or fewer diagnostic tests to confirm the diagnosis (depending on screening test specificity), which also has resource implications.
These review findings should be interpreted with caution due to methodological limitations in the included studies and regional variation in sensitivity and specificity. The sensitivity and specificity of an index test in a specific setting cannot be predicted with great precision due to heterogeneity. This should be borne in mind when planning for and implementing tuberculosis screening programmes.
Systematic screening in high-burden settings is recommended as a strategy for early detection of pulmonary tuberculosis disease, reducing mortality, morbidity and transmission, and improving equity in access to care. Questioning for symptoms and chest radiography (CXR) have historically been the most widely available tools to screen for tuberculosis disease. Their accuracy is important for the design of tuberculosis screening programmes and determines, in combination with the accuracy of confirmatory diagnostic tests, the yield of a screening programme and the burden on individuals and the health service.
To assess the sensitivity and specificity of questioning for the presence of one or more tuberculosis symptoms or symptom combinations, CXR, and combinations of these as screening tools for detecting bacteriologically confirmed pulmonary tuberculosis disease in HIV-negative adults and adults with unknown HIV status who are considered eligible for systematic screening for tuberculosis disease. Second, to investigate sources of heterogeneity, especially in relation to regional, epidemiological, and demographic characteristics of the study populations.
We searched the MEDLINE, Embase, LILACS, and HTA (Health Technology Assessment) databases using pre-specified search terms and consulted experts for unpublished reports, for the period 1992 to 2018. The search date was 10 December 2018. This search was repeated on 2 July 2021.
Studies were eligible if participants were screened for tuberculosis disease using symptom questions, or abnormalities on CXR, or both, and were offered confirmatory testing with a reference standard. We included studies if diagnostic two-by-two tables could be generated for one or more index tests, even if not all participants were subjected to a microbacteriological reference standard. We excluded studies evaluating self-reporting of symptoms.
We categorized symptom and CXR index tests according to commonly used definitions. We assessed the methodological quality of included studies using the QUADAS-2 instrument. We examined the forest plots and receiver operating characteristic plots visually for heterogeneity. We estimated summary sensitivities and specificities (and 95% confidence intervals (CI)) for each index test using bivariate random-effects methods. We analyzed potential sources of heterogeneity in a hierarchical mixed-model.
The electronic database search identified 9473 titles and abstracts. Through expert consultation, we identified 31 reports on national tuberculosis prevalence surveys as eligible (of which eight were already captured in the search of the electronic databases), and we identified 957 potentially relevant articles through reference checking. After removal of duplicates, we assessed 10,415 titles and abstracts, of which we identified 430 (4%) for full text review, whereafter we excluded 364 articles. In total, 66 articles provided data on 59 studies. We assessed the 2 July 2021 search results; seven studies were potentially eligible but would make no material difference to the review findings or grading of the evidence, and were not added in this edition of the review.
We judged most studies at high risk of bias in one or more domains, most commonly because of incorporation bias and verification bias. We judged applicability concerns low in more than 80% of studies in all three domains.
The three most common symptom index tests, cough for two or more weeks (41 studies), any cough (21 studies), and any tuberculosis symptom (29 studies), showed a summary sensitivity of 42.1% (95% CI 36.6% to 47.7%), 51.3% (95% CI 42.8% to 59.7%), and 70.6% (95% CI 61.7% to 78.2%, all very low-certainty evidence), and a specificity of 94.4% (95% CI 92.6% to 95.8%, high-certainty evidence), 87.6% (95% CI 81.6% to 91.8%, low-certainty evidence), and 65.1% (95% CI 53.3% to 75.4%, low-certainty evidence), respectively. The data on symptom index tests were more heterogenous than those for CXR. The studies on any tuberculosis symptom were the most heterogeneous, but had the lowest number of variables explaining this variation. Symptom index tests also showed regional variation.
The summary sensitivity of any CXR abnormality (23 studies) was 94.7% (95% CI 92.2% to 96.4%, very low-certainty evidence) and 84.8% (95% CI 76.7% to 90.4%, low-certainty evidence) for CXR abnormalities suggestive of tuberculosis (19 studies), and specificity was 89.1% (95% CI 85.6% to 91.8%, low-certainty evidence) and 95.6% (95% CI 92.6% to 97.4%, high-certainty evidence), respectively. Sensitivity was more heterogenous than specificity, and could be explained by regional variation.
The addition of cough for two or more weeks, whether to any (pulmonary) CXR abnormality or to CXR abnormalities suggestive of tuberculosis, resulted in a summary sensitivity and specificity of 99.2% (95% CI 96.8% to 99.8%) and 84.9% (95% CI 81.2% to 88.1%) (15 studies; certainty of evidence not assessed).