Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults

Abstract

Background: Identification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status.

Methods: We prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations.

Results: Of 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77-0·83), with sensitivity 93% (89-95%) and specificity 54% (50-58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a 'confirmatory test for all' strategy performed better.

Conclusions: CRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status.

Funding: South African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians.

Keywords: CRP; Diagnosis; HIV; Screening; TB.

Fig. 1

Overview of study cohort.

Fig. 2

Discriminatory ability of CRP for culture-confirmed pulmonary TB among adults presenting to outpatient care with TB-related symptoms. Area under the receiver operator characteristic curve (AUROC) of CRP to distinguish pulmonary TB versus culture-negative in (a) whole study population and (b) key subgroups of interest; and the distribution of CRP presented on a logarithmic scale. There was no difference in AUROC between HIV positive and HIV negative participants (DeLong test, p = 0·1) or among people with a history of previous TB compared to those without (p = 0·5).

Fig. 3

Evaluation of potential clinical utility of CRP as a triage strategy among people presenting with TB-related symptoms Negative and positive predictive values (a) for CRP for culture-confirmed pulmonary TB using a threshold of ≥10 mg/L (red solid line), a hypothetical ‘optimal’ (sensitivity 95%, specificity 80%; green dotted line), and ‘minimal’ (sensitivity 90%, specificity 70%; yellow dotted line) TB triage test as defined by the WHO high-priority target product profile. Reported across a range of TB prevalences (true prevalence in study population indicated by dashed line [27%]). Decision curve analysis (b) comparing the strategies of an ‘optimal’ (green dotted line) or ‘minimal’ (yellow dotted line) triage test or culture for all individuals with CRP ≥10 mg/L (red solid line) to a strategy of culture for all (gray solid line) or none (black solid line) of the participants meeting study inclusion criteria (i.e. presenting with TB-related symptoms, as defined in text). Dot-dash vertical line in panel (b) represents the threshold probability above which CRP confers net benefit over a ‘culture for all’ strategy.

Fig. 4

Correlation of CRP with markers of TB severity among culture-confirmed pulmonary TB cases (body mass index ([BMI] culture days to positivity, hemoglobin and TB Score II). TB Score II was only calculated for individuals with complete data for all score components. Spearman rank correlation was calculated.