Point-of-Care C-Reactive Protein Testing to Facilitate Implementation of Isoniazid Preventive Therapy for People Living With HIV

Abstract

Background Symptom-based tuberculosis screening identifies less than one-third of eligible HIV-infected patients as candidates for isoniazid preventive therapy (IPT). We evaluated whether testing for C-reactive protein (CRP) improves patient selection for IPT. Methods We measured CRP levels (normal < 10mg/L) using a point-of-care (POC) assay on stored serum samples from HIV-infected Ugandan adults initiating antiretroviral therapy. We assessed diagnostic accuracy in reference to baseline tuberculosis status adjudicated by an expert committee and calculated net reclassification improvement (NRI) to quantify the incremental discriminatory benefit of POC-CRP in determining IPT-eligibility compared to the WHO symptom screen. Results Of 201 patients (median CD4 cell-count 137 cells/μL, IQR 83-206), five (2.5%) had tuberculosis. Compared to the WHO symptom screen, POC-CRP had similar sensitivity (100% vs. 80%, p=0.30) but greater specificity (21% vs. 87%, p<0.0001) for tuberculosis. If based on the WHO symptom screen, no patients with tuberculosis but only 42/196 patients without tuberculosis would have been considered IPT-eligible. If POC-CRP were used instead, one patient with tuberculosis (reclassification of cases -20%, p=0.32) and 129 patients without tuberculosis (reclassification of non-cases +66%, p<0.001) would have been reclassified as IPT-eligible, an NRI of 46% (p=0.03). In addition, POC-CRP testing would have reduced the proportion of patients without active tuberculosis requiring confirmatory tuberculosis testing (87% vs. 21%, p<0.0001). Conclusions POC-CRP testing increased more than four-fold the proportion of HIV-infected adults immediately identified as IPT-eligible and decreased the proportion of patients requiring referral for further tuberculosis diagnostic testing. POC-CRP testing could substantially improve implementation of tuberculosis screening guidelines.

Diagnostic accuracy of C-reactive protein for active pulmonary tuberculosis: a meta-analysis

“…Most studies were designed to evaluate the diagnostic accuracy of CRP for pulmonary TB. 8,9,22,28 All studies selected patients either consecutively or by random sample. 8,9,17,22,28 Two studies enrolled a representative spectrum of patients 8,9 while three studies restricted enrollment to patients with a high probability of pulmonary TB ( e.g.…”

“…17,22,28 All studies reported the time elapsed between blood collection for CRP testing and specimen collection for pulmonary TB evaluation. 8,9,17,22,28 Most studies reported that pulmonary TB status was assessed without knowledge of CRP results. 8,9,22,28 All but one study used culture as the reference standard for pulmonary TB.…”

“…8,9,17,22,28 Most studies reported that pulmonary TB status was assessed without knowledge of CRP results. 8,9,22,28 All but one study used culture as the reference standard for pulmonary TB. 9 All studies acknowledged industry involvement 8,9,17,22,28 including two studies that reported receiving donated POC CRP assays from the manufacturer.…”

“…9 All studies acknowledged industry involvement 8,9,17,22,28 including two studies that reported receiving donated POC CRP assays from the manufacturer. 9,28 …”

“…All studies were conducted in countries with high TB/HIV burden and included patients infected with HIV (936 HIV-infected patients), 8,9,17,22,28 including four studies that restricted enrollment to HIV-infected individuals. 8,9,17,28 Two studies (N=697) evaluated CRP as a screening test for pulmonary TB, 8,9 enrolling a high-risk population for whom TB screening is recommended: patients with advanced HIV/AIDS (CD4 cell count ≤ 200 cells/μL) initiating antiretroviral therapy (ART). The remaining three studies evaluated CRP as a diagnostic test for pulmonary TB among patients self-reporting symptoms suggestive of pulmonary TB.…”