Boosting Accuracy for Tuberculosis Screening in HIV Patients

C-reactive protein can decrease the need for diagnostic rapid tests without compromising sensitivity for tuberculosis screening among patients living with HIV, according to a paper published in The Lancet Infectious Diseases. The 2021 WHO guidelines have been updated to reflect these findings.

Investigators from South Africa’s University of Cape Town conducted a systematic review and meta-analysis of individual participant data in order to update World Health Organization recommendations and guidelines for tuberculosis screening and diagnoses for people living with HIV. Today, if a four-symptom screen is known as W4SS is positive, the next step is a rapid diagnostic test. But the investigators wanted to assess the diagnostic accuracy of alternative screeners for this group.

W4SS includes any one of the following symptoms: current cough, fever, night sweats, or weight loss, the study authors added. Their alternative screeners needed to have a sensitivity of more than 90 percent and a specificity of more than 70 percent, they said. C-reactive protein assays as point-of-care assays were simple to use and cost about $2 per test, they said, and take about 3 minutes to produce results. Other factors, such as BMI, hemoglobin, and lymphadenopathy can be predictors of tuberculosis the study authors said but commented that their diagnostic accuracy is not clear.

The study authors identified 22 relevant studies from the PubMed and Embase databases, the Cochrane Library, and conference abstracts for publication that were published between 2011 and 2019 that included 15,666 participants. All but 3 of these patients were on ART. Two-thirds of the patients were female, the study authors noted, and W4SS was positive in about half of the participants. C-reactive protein was elevated in about a third of the patients, and it was measured with a point-of-care assay or laboratory assay in 5 studies.

Tuberculosis prevalence was 7.7 percent when the studies used culture as a reference standard, the study authors observed. For patients not on ART, the prevalence of tuberculosis was 9.3 percent compared to 3.3 percent of outpatients not on ART.

When studies combined W4SS with either chest x-ray or C-reactive protein, they had higher sensitivities and lower specificities than W4SS alone, the study authors observed. A similar, subsequent study showed that W4SS followed by C-reactive protein had a lower sensitivity but higher specificity than W4SS alone; and W4SS followed by chest x-ray had a sensitivity of 63 percent and specificity of 73 percent. Since that specificity was lower than W4SS, the study authors noted they did not continue their analysis of that investigation.

The study authors then tested estimates for each strategy for a hypothetical cohort of 1000 people living with HIV at different tuberculosis prevalences. For example, at a prevalence of 10 percent, the study authors found that W4SS would result in 604 rapid tests being needed. In that same scenario, C-reactive protein would result in 311 diagnostic tests needed but would miss 5 tuberculosis cases, the study authors said. Furthermore, chest x-ray would require 414 tests, but miss 10 tuberculosis tests. At 10 percent prevalence, there would be 604 diagnostic rapid tests needed after W4SS testing, or 1000 rapid tests for the entire population would detect 10 additional cases.

In a hypothetical cohort of 1000 outpatients on ART with 5 percent tuberculosis prevalence, W4SS plus chest x-ray would increase the number of diagnostic rapid tests by 378 compared to W4SS alone, and also detect an additional 18 cases.

The study authors noted that most tests—except chest x-ray and hemoglobin—had lower sensitivity and higher specificity in outpatients on ART compared to outpatients not on ART.

“C-reactive protein (≥10 mg/L) was similar to that of W4SS alone, but its specificity was higher (74 vs 42 percent),” the study authors concluded. “Chest x-ray (with any abnormality) had lower sensitivity than W4SS alone in direct comparisons, making it less suitable than a standalone screening test.”

The findings from this study have shaped the 2021 WHO tuberculosis screening guidelines for people living with HIV, the study authors noted. However, they also said that further research is needed to develop better screening tests for tuberculosis in this population because no single test or strategy met both WHO-defined sensitivity and specificity minimum thresholds.