Tuberculosis remains one of the world’s deadliest communicable diseases. It was estimated that 10 million people fell ill with tuberculosis (TB) and 1.5 million died of the disease globally in 2018 [1]. Prompt case detection and subsequent start of effective treatment especially in TB high burden countries are a major strategy for its control [2] [3] [4] [5]. Systematic screening of individuals presenting to health facilities seeking health care and certain risk groups with high TB prevalence is an important approach to improve early detection of TB.

Symptoms and chest radiography are the available methods to screen for active TB in most resources limited settings while sputum smear microscopy, mycobacterial culture and currently endorsed molecular Xpert MTB/RIF assay (Cepheid, Sunnyvale, Califormia) are confirmation tests [6] [7] [8]. However, current screening algorithm relies mostly on TB symptoms questionnaire followed by chest radiography—a strategy that is inadequate in TB case detection [9]. Furthermore, the rapid and widely used smear microscopy has varied and limited sensitivity while culture is often not available in resource limited setting for routine use [10] [11] [12]. Therefore, majority of TB patients remain undetected and there is a need for alternative TB diagnostic algorithm especially in TB high burden countries with limited resources.

Inflammatory markers are emerging as tools of choice for TB screening with potentials of being rapid and point of care utility [13]. C-reactive protein (CRP) is an acute phase molecule found in plasma whose levels rise significantly in response to tissue damage and infections such as active TB independently of HIV status [14] [15] [16] [17]. Several observational studies have shown that CRP has association and high sensitivity for the presence of TB [16] [18] [19] [20]. However, despite the evidence shown in the previous observations on the role of CRP as a biomarker for TB, performance of screening using CRP has varied across different settings. It is therefore important to determine performance of CRP for screening pulmonary TB in our setting.

We aimed to establish the role of CRP as a screening tool for active pulmonary TB in an observational study of patients with PTB and controls without PTB in urban Tanzania. To address this need, we specifically 1) compared baseline characteristic and distribution of CRP in pulmonary TB cases and controls 2) determined the discriminatory accuracy of CRP and TB symptoms for pulmonary TB among adults.

In this observational study of adult pulmonary TB cases and controls in urban Tanzania, we determined screening performance of CRP for pulmonary TB. We found that CRP at concentration cut-off ≥10 mg/L was associated with best combination of sensitivity, specificity and AUC for discriminating pulmonary TB cases. We also demonstrated that classical TB symptoms and CRP concentration cut-off ≥10 mg/L can accurately predict pulmonary TB cases. These findings are of clinical relevant because CRP can be easily measured and utilized at point of care [25]. Furthermore, night sweats, fever and nutritional status are routinely sought by clinicians when evaluating patients.

The findings on performance of CRP on identifying pulmonary TB cases are in agreements with other findings elsewhere. Lawn and his colleagues in South Africa demonstrated a CRP of 10 mg/L and above have a relatively high sensitivity of 85.2% and reliably rule out active PTB [26]. However, their finding applies only to half of their study population. Another study in the same country revealed any elevated CRP with confirmed TB can be useful for ruling out TB at NPV of 0.72 - 0.96 [27]. However, raised CRP might have been caused by other diseases processes, notably intestinal parasites and respiratory infection [28] [29]. Thus, other diseases should be considered and looked for in a patient with significantly raised CRP levels. In the present study we addressed the impact of helminthiasis and respiratory infections on serum levels of CRP. We found no statistically significant differences in frequencies of their distribution in the two groups. These findings were in contrary to observations from other studies. Studies in Tanzania and Ethiopia demonstrated high co-existence of pulmonary TB and helminthiasis [30] [31]. It was known that both diseases have impact on cellular mediated immunity and influence the natural course of one another [31] [32] [33]. However, similar prevalence in present study could be partially explained by several factors. First, our study setting is urban which is characterized by low exposure to worms and high literacy associated with frequent practice of de-worming. Second, our study participants were recruited from same environment. Last, our two groups have equal distribution of socio-demographic characteristics, which are important determinants of helminthiasis [34] [35]. A major difference in our study was a similar proportion of HIV infection in cases and controls, i.e., 13.13% vs 11.7%. This is in disagreement with the fact that the two diseases are closely related. Previous studies in pulmonary TB have reported higher rates of HIV infection and patterns of co-existence were described in many places. Studies in Tanzania observed high prevalence of TB-HIV co-infection [36] [37]. Similar observations of high prevalence were demonstrated in India [38] [39]. Meta-analysis of studies done in Sub-Saharan Africa demonstrated a very high prevalence (34.4%) of HIV infection among pulmonary TB patients [40]. However, overall prevalence of HIV in our study population is higher than Tanzanian general population [41]. The similar distribution in HIV prevalence between pulmonary TB cases and controls can be partly explained by overly selection of study participants of a case-control study design.

Importantly, data from our study demonstrated that using CRP at cut-off ≥10 mg/L were associated with excellent combination of sensitivity, specificity and AUC for discriminating pulmonary TB cases, while higher cut-off values are associated with increasing specificity and AUC in expenses of sensitivity thus, compromising ability to discriminate pulmonary TB cases. Thus, CRP cut-off value ≥10 mg/L will reliably discriminate pulmonary TB from a vast majority of TB suspects in high TB burden settings. The demonstrated relatively high sensitivity and specificity of 89.9% and 80.9%respectively at CRP concentration of ≥10 mg/L is superior to varied low sensitivity of sputum smear microscopy ranging 20% - 80% [42]. Again, data from our study demonstrated that classical pulmonary TB symptoms and CRP at cut-off ≥10 mg/L were significantly more associated with pulmonary TB cases than controls. The observed association between pulmonary TB and classical TB symptoms has been described by other groups. In Kenya, 75%, 100% and 83% of pulmonary TB cases reported fever, night sweats and weight loss respectively, while in South Africa 78%, 78% and 100% reported the symptoms respectively [43]. One group in TB high burden country, China reported that TB symptoms were found in 75.8% of cases [44]. However, symptoms alone have been shown to be less reliable for pulmonary TB especially in areas with high prevalence of TB-HIV co-infection. The relationship between pulmonary TB and nutritional status is known for years. Underweight is a well-recognized risk factor for pulmonary TB and pulmonary TB can lead to underweight. Night sweats and fever are non-specific symptom of TB and are constitutional symptoms of many disease processes. Therefore, data from our study are informing CRP at cut-off ≥10 mg /L, underweight, night sweats and fever scan be used for screening pulmonary TB in high burden settings.

In spite of the findings of this study, there are limitations which need to be addressed. First, we could not exclude all possible disease processes that might be responsible for rise in CRP. Second, we are not able to perform stratified analysis base on disease severity. Third, the study was done in urban setting where the patient population might differ from other rural primary care settings. Finally, the case-control study design associated with overly selection of participants can explain the limitations observed on role of CRP and classical TB symptoms to screen pulmonary TB case.

In conclusion, this study has demonstrated that CRP is a potential tool for discriminating pulmonary TB in adults. Furthermore, CRP at cut-off ≥10 mg/l and classical pulmonary TB symptoms can be used systematically to screen pulmonary TB among suspects. The findings can therefore be used to improve TB screening algorithm by incorporating CRP concentration of ≥10 mg/L in combination with classical TB symptoms to identify patients who need further TB work out or empirical treatment. This approach can significantly contribute in reduction of TB burden. However, additional well-designed large-scale studies are required in setting of intended use to estimates the role of CRP and TB symptoms for pulmonary TB screening to support policy recommendations. Furthermore, studies are required to determine appropriate strategy of screening algorithm for pulmonary TB using CRP and TB symptoms.

We thank all study participants for participating in this study. We are grateful to the Temeke Regional Referral Hospital, as well as the District and Regional tuberculosis coordinators from the National Tuberculosis and Leprosy Programme.

The study was approved by the institutional review board of the Ifakara Health Institute (IHI; reference no. IHI/IRB/04-2015) and the Medical Research Coordinating Committee of the National Institute of Medical Research in Tanzania (NIMR; reference no. NIMR/HQ/R.8c/Vol. I/357). All study participants gave written informed consent before enrolment into the study.

The datasets that were used for analysis and preparation of this manuscript are not publicly available due the national policy on data sharing. The datasets will be available from the corresponding author upon reasonable request where concerned parties will sign a data transfer agreement approved by the Medical Research Coordinating Committee.

This work was supported by funding from the Rudolf Geigy Foundation (Basel, Switzerland).

Conceived and designed the study: EC, LK, MS, TM, HT, FM and JH. EC, MS, FM, and JH analyzed the data. TM, HT, JP, SA, RN and MT contributed clinical data. MS, LK, RJ, JP and MT contributed laboratory data. EC, FM and JH prepared the first draft of the manuscript. All authors contributed in final manuscript revisions and approved the final version.

The authors declare no conflicts of interest regarding the publication of this paper.

Chiweka, E., Maroa, T., Temba, H., Ponera, J., Athumani, S., Kamwela, L., Sasamalo, M., Naftari, R., Tito, M., Mhimbira, F. and Hella, J. (2022) C-Reactive Protein as a Triage Test in Guiding Who Should Get a Confirmatory Test for Pulmonary Tuberculosis Diagnosis among Adults: A Case-Control Proof-of-Concept Study from Urban Tanzania. Journal of Tuberculosis Research, 10, 28-44. https://doi.org/10.4236/jtr.2022.101003

aOR Adjusted odds ratio

AUC Area under the curve

BMI Body mass index

CI Confidence interval

CRP C-reactive protein

Hb Haemoglobin

HIV Human immune deficiency virus

IHI Ifakara Health Institute

IQR Inter quartile range

IRB Institutional Review Body

MTB Mycobacterium tuberculosis

NIMR National Institute for Medical Research

NPV Negative predictive value

OR Odds ratio

POC CCA Point of care-Circulating Cathodic Antigen

PPV Positive predictive value

RIF Rifampicin

ROC Receiver operating characteristic

TB Tuberculosis

USA United States of America