C-reactive protein: another addition to our armamentarium against tuberculosis?

Tuberculosis remains one of the major infectious diseases that causes increased morbidity and mortality worldwide, and particularly affects people living with HIV and AIDS.1WHOGlobal tuberculosis report. World Health Organization, Geneva2022Google Scholar The success of a tuberculosis control programme depends on identification, diagnosis, and linkage to treatment.2Cole B Nilsen DM Will L Etkind SC Burgos M Chorba T Essential components of a public health tuberculosis prevention, control, and elimination program: recommendations of the Advisory Council for the Elimination of Tuberculosis and the National Tuberculosis Controllers Association.MMWR Recomm Rep. 2020; 69: 1-27Crossref PubMed Google Scholar Early diagnosis and treatment of tuberculosis is essential to reduce morbidity, mortality, and transmission. Active case finding in populations with a high incidence of tuberculosis is a potentially effective intervention but requires screening approaches that have adequate diagnostic performance and can be applied at scale in low-income and middle-income countries (LMICs). In The Lancet Global Health, Maria Ruperez and colleagues3Ruperez M Shanaube K Mureithi L et al.Use of point-of-care C-reactive protein testing for screening of tuberculosis in the community in high-burden settings: a prospective, cross-sectional study in Zambia and South Africa.Lancet Glob Health. 2023; 11: e704-e714Summary Full Text Full Text PDF Scopus (1) Google Scholar report on the utility of point-of-care C-reactive protein in screening for tuberculosis in a community setting in LMICs. C-reactive protein is an acute-phase reactant that is elevated in most inflammatory and infectious conditions, including tuberculosis, and can be measured in finger-prick blood using point-of-care devices. In 2021, on the basis of findings from studies among people living with HIV, WHO recommended C-reactive protein as a screening tool for tuberculosis alongside symptom screening in this target group.1WHOGlobal tuberculosis report. World Health Organization, Geneva2022Google Scholar, 4WHOWHO consolidated guidelines on tuberculosis module 2: screening—systematic screening for tuberculosis disease.https://www.who.int/publications/i/item/9789240022676Date: March 22, 2021Date accessed: May 15, 2022Google Scholar The potential of point-of-care C-reactive protein for tuberculosis screening in non-HIV target groups has not been extensively studied. Ruperez and colleagues implemented a point-of-care C-reactive protein test for tuberculosis screening embedded in a tuberculosis prevalence survey in Zambia and South Africa. Their study reports an overall sensitivity of 50·0% (95% CI 38·3–61·7) for point-of-care C-reactive protein in a mixed population of HIV-positive and HIV-negative individuals.3Ruperez M Shanaube K Mureithi L et al.Use of point-of-care C-reactive protein testing for screening of tuberculosis in the community in high-burden settings: a prospective, cross-sectional study in Zambia and South Africa.Lancet Glob Health. 2023; 11: e704-e714Summary Full Text Full Text PDF Scopus (1) Google Scholar The sensitivity was higher in people living with HIV at 60·0% (38·7–78·9), with a specificity of 62·9% (56·6–68·9). Previous studies on C-reactive protein have used diverse populations, including patients with symptomatic tuberculosis presenting to health facilities, people living with HIV before or during antiretroviral treatment, and mixed populations.5Saripalli A Ramapuram J C-reactive protein as a screening test for tuberculosis in people living with HIV in southern India: a cross-sectional, observational study.J Clin Med. 2022; 113566Crossref PubMed Scopus (2) Google Scholar, 6Meca AD Turcu-Stiolica A Bogdan M et al.Screening performance of C-reactive protein for active pulmonary tuberculosis in HIV-positive patients: a systematic review with a meta-analysis.Front Immunol. 2022; 13891201Crossref PubMed Scopus (3) Google Scholar Generally high sensitivities were observed in those with symptoms, inpatients, and people living with HIV compared with community-based studies that might represent, compared with these groups, a relatively healthy population.1WHOGlobal tuberculosis report. World Health Organization, Geneva2022Google Scholar In this community screening study, a finding of lower sensitivities compared with health facility studies is not surprising because patients diagnosed with tuberculosis in the community will be more likely to have a less extensive pathology than those diagnosed in a health facility. Nonetheless, the findings from Ruperez and colleagues’ study showed that the sensitivity of point-of-care C-reactive protein was superior to symptom screening, even though the screening algorithm used was more restrictive and therefore probably less sensitive than the four-symptom screen recommended by WHO for tuberculosis screening among people living with HIV.1WHOGlobal tuberculosis report. World Health Organization, Geneva2022Google Scholar What is important about this study? We think the findings show the potential usefulness of point-of-care C-reactive protein in a community setting in a relatively healthy population. The combination of point-of-care C-reactive protein plus symptom screening increased the sensitivity of identifying individuals with tuberculosis (combined sensitivity of 60·5% [95% CI 48·6–71·6] vs 34·2% [23·7–46·0] of symptom screening alone), although this was noted to be lower than that of chest x-ray alone, which is more difficult and costly to deploy at community and lower-level facilities. In people living with HIV, the sensitivity of point-of-care C-reactive protein plus symptom screening was 72·0% (95% CI 50·6–87·9) compared with symptom screening alone, which had a sensitivity of 36·0% (18·0–57·5). Given that symptom screening is the most commonly used screening tool in most LMICs, this finding is of clinical significance. In contrast to other studies, Ruperez and colleagues used a point-of-care platform that enabled results availability in 15 min, as opposed to laboratory-based assays that have long turnaround times and are thus of limited application in community settings, especially those with underdeveloped health-care infrastructure. Additionally, the study shows the role of point-of-care tests in improving access to health-care services and diagnostics in LMICs where there is a high infectious disease burden.7Kuupiel D Bawontuo V Mashamba-Thompson TP Improving the accessibility and efficiency of point-of-care diagnostics services in low- and middle-income countries: lean and agile supply chain management.Diagnostics (Basel). 2017; 7: 58Crossref PubMed Scopus (41) Google Scholar, 8Yadav H Shah D Sayed S Horton S Schroeder LF Availability of essential diagnostics in ten low-income and middle-income countries: results from national health facility surveys.Lancet Glob Health. 2021; 9: e1553-e1560Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar Ruperez and colleagues’ study therefore adds to the existing tuberculosis screening knowledge pool and tools for tuberculosis screening in LMICs. This study is unique in showing the role of point-of-care C-reactive protein in combination with symptom screening in patients suspected of having tuberculosis in a community setting. Point-of-care C-reactive protein plus symptom screening did not reach the minimum WHO target product profile of 90% sensitivity and 70% specificity for a tuberculosis screening test. Whether the lower sensitivity and specificity shown by Ruperez and colleagues, both overall and among people living with HIV (including those receiving and those not receiving ART) still represents a useful approach will partly depend on the cost-effectiveness, which is largely dependent on the specificity of a test. However, it seems promising enough to warrant further studies. We declare no competing interests. Use of point-of-care C-reactive protein testing for screening of tuberculosis in the community in high-burden settings: a prospective, cross-sectional study in Zambia and South AfricaPoint-of-care C-reactive protein testing alone does not meet the 90% sensitivity stipulated by WHO's target product profile for desirable characteristics for screening tests for detecting tuberculosis. However, combined with symptom screening, it might improve identification of individuals with tuberculosis in communities with high prevalence, and might be particularly useful where other recommended tools, such as chest x-ray, might not be readily available. Full-Text PDF Open Access