Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study

Abstract

Background: Symptom-based screening for tuberculosis is recommended for all people living with HIV. This recommendation results in unnecessary Xpert MTB/RIF testing in many individuals living in tuberculosis-endemic areas and thus poor implementation of intensified case finding and tuberculosis preventive therapy. Novel approaches to tuberculosis screening are needed to help achieve global targets for tuberculosis elimination. We assessed the performance of C-reactive protein (CRP) measured with a point-of-care assay as a screening tool for active pulmonary tuberculosis.

Methods: For this prospective study, we enrolled adults (aged ≥18 years) living with HIV with CD4 cell count less than or equal to 350 cells per μL who were initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda. CRP concentrations were measured at study entry with a point-of-care assay using whole blood obtained by fingerprick (concentration ≥10 mg/L defined as screen positive for tuberculosis). Sputum samples were collected for Xpert MTB/RIF testing and culture. We calculated the sensitivity and specificity of point-of-care CRP and WHO symptom-based screening in reference to culture results. We repeated the sensitivity analysis with Xpert MTB/RIF as the reference standard.

Findings: Between July 8, 2013, and Dec 15, 2015, 1237 HIV-infected adults were enrolled and underwent point-of-care CRP testing. 60 (5%) patients with incomplete or contaminated cultures were excluded from the analysis. Of the remaining 1177 patients (median CD4 count 165 cells per μL [IQR 75-271]), 163 (14%) had culture-confirmed tuberculosis. Point-of-care CRP testing had 89% sensitivity (145 of 163, 95% CI 83-93) and 72% specificity (731 of 1014, 95% CI 69-75) for culture-confirmed tuberculosis. Compared with WHO symptom-based screening, point-of-care CRP testing had lower sensitivity (difference -7%, 95% CI -12 to -2; p=0·002) but substantially higher specificity (difference 58%, 95% CI 55 to 61; p<0·0001). When Xpert MTB/RIF results were used as the reference standard, sensitivity of point-of-care CRP and WHO symptom-based screening were similar (94% [79 of 84] vs 99% [83 of 84], respectively; difference -5%, 95% CI -12 to 2; p=0·10).

Interpretation: The performance characteristics of CRP support its use as a tuberculosis screening test for people living with HIV with CD4 count less than or equal to 350 cells per μL who are initiating ART. HIV/AIDS programmes should consider point-of-care CRP-based tuberculosis screening to improve the efficiency of intensified case finding and increase uptake of tuberculosis preventive therapy.

Funding: National Institutes of Health; President's Emergency Plan for AIDS Relief; University of California, San Francisco, Nina Ireland Program for Lung Health.

Figure 1

Patient flow diagram. Abbreviation: ART (antiretroviral therapy); POC CRP (point-of-care C-reactive protein); TB (tuberculosis). *All enrolled participants underwent POC CRP testing and submitted two spot specimens for liquid culture. TB defined as ≥1 sputum culture positive for Mycobacterium tuberculosis. No TB defined as ≥2 sputum cultures negative for Mycobacterium tuberculosis.

Figure 2

A. Sensitivity of screening tests for culture-confirmed tuberculosis and Xpert-positive tuberculosis, stratified by CD4+ T-cell count. Abbreviations: POC CRP (point-of-care C reactive protein); WHO (World Health Organization). The dark blue bars represent the sensitivity of POC CRP while the light blue bars represent the sensitivity of the WHO symptom screen, in reference to culture (left) and Xpert (right). In reference to culture: Among PLHIV with CD4+ T-cell counts <200 cells/uL, sensitivity of POC CRP for culture-confirmed TB did not vary significantly by CD4 strata (p = 0·65 for trend). Compared to PLHIV with CD4+ T-cell counts ≥200 cells/uL, sensitivity of POC CRP was higher among PLHIV with CD4+ T-cell counts <200 cells/uL (73% vs. 93%; difference −20% [95% CI: −36 to −5], p-value for the difference =0·0002). In reference to Xpert: Among PLHIV with CD4+ T-cell counts ≤350 cells/uL, sensitivity of POC CRP for Xpert-positive TB did not vary significantly by CD4 strata (p=0·56 for trend). B. Specificity of screening tests for culture-positive tuberculosis, stratified by CD4+ T-cell count. Abbreviations: POC CRP (point-of-care C reactive protein); WHO (World Health Organization). The dark blue bars represent the specificity of POC CRP while the light blue bars represent the specificity of the WHO symptom screen, in reference to culture. Among PLHIV with CD4+ T-cell counts ≤350 cells/uL, specificity of the WHO symptom screen decreased significantly as CD4 strata decreased (p<0·0001 for trend). Among PLHIV with CD4+ T-cell counts <200 cells/uL, specificity of POC CRP did not vary significantly by CD4 strata (p = 073 for trend). Compared to PLHIV with CD4+ T-cell counts ≥200 cells/uL, specificity of POC CRP was lower among PLHIV with CD4+ T-cell <200 cells/uL (80% vs. 66%; difference −14% [95% CI: −20 to −10], pvalue for the difference <0·0001).

Figure 3

Receiver operating characteristic (ROC) curves for the detection of culture-confirmed pulmonary tuberculosis by POC CRP. Abbreviations: POC CRP (point-of-care C-reactive protein). Area under the receiver-operating curve for 10 mg/L (0·81, 95% CI: 0·78 to 0·83), 9 mg/L (0·81, 95% CI: 0·78 to 0·83), and 8 mg/L (0·80, 95% CI: 0·77 to 0·83) cut-points.