Africa-wide evaluation of host biomarkers in QuantiFERON supernatants for the diagnosis of pulmonary tuberculosis

Novel N Chegou,Claus Aagard,Habteyes Hailu,Yonas Bekele,André G Loxton ,Annemieke Geluk,Anna Ritah Namuganga ,Paul L A M Corstjens ,Jacob Sheehama ,Gebremedhin Gebremichael,Harriet Mayanja‐Kizza ,Maria M Esterhuyse,Adane Mihret,Magdalena Kriel,Stefan H E Kaufmann,Gian D Van Der Spuy,Hazel M Dockrell,Tom H M Ottenhoff,Ida Rosenkrands,Joseph Mendy,Marieta Van Der Vyver,Amelia C Crampin,Stephanus T Malherbe ,Martin Kidd,Kim Stanley,Rawleigh Howe,Jacqueline M Cliff,Desta Kassa,Josefina N Nelongo ,Belinda Kriel,Felanji Simukonda,Jayne S Sutherland,Atsbeha Gebrexabher,Gerhard Walzl

doi:10.1038/s41598-018-20855-7

Abstract

We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomarkers in stored QuantiFERON supernatants using the Luminex platform. Based on laboratory, clinical and radiological findings and a pre-established algorithm, participants were classified as TB disease or other respiratory diseases(ORD). Of the 514 individuals included in the study, 179(34.8%) had TB disease, 274(51.5%) had ORD and 61(11.5%) had an uncertain diagnosis. A biosignature comprising unstimulated IFN-γ, MIP-1β, TGF-α and antigen-specific levels of TGF-α and VEGF, identified on a training sample set (n = 311), validated by diagnosing TB disease in the test set (n = 134) with an AUC of 0.81(95% CI, 0.76–0.86), corresponding to a sensitivity of 64.2%(95% CI, 49.7–76.5%) and specificity of 82.7%(95% CI, 72.4–89.9%). Host biomarkers detected in QuantiFERON supernatants can contribute to the diagnosis of active TB disease amongst people presenting with symptoms requiring investigation for TB disease, regardless of HIV status or ethnicity in Africa.

Highlights

Tuberculosis (TB) remains a global health problem, with an estimated 10.4 million new TB patients and 1.4 million deaths due to TB, reported in 20151
We have previously shown a 3-marker host biosignature consisting of epidermal growth factor (EGF), macrophage inflammatory protein (MIP)-1β and interleukin (IL)-1α, which resulted in the correct classification of 87% of adult pulmonary TB cases and 91% of household contacts after cross validation following QuantiFERON stimulation of whole blood[12]
The proportion of individuals presenting with symptoms requiring investigation for TB and who were diagnosed with TB disease was not the same across the different study sites (Table 1, Chi-square p < 0.01), with the TB patients slightly younger than those with other respiratory diseases (ORDs) (35.7 ± 12.6 Vs. 36.8 ± 13.2; Chi-square p < 0.01, Table 1)

Summary

Introduction

Tuberculosis (TB) remains a global health problem, with an estimated 10.4 million new TB patients and 1.4 million deaths due to TB, reported in 20151. We have previously shown a 3-marker host biosignature consisting of epidermal growth factor (EGF), macrophage inflammatory protein (MIP)-1β and interleukin (IL)-1α, which resulted in the correct classification of 87% of adult pulmonary TB cases and 91% of household contacts after cross validation following QuantiFERON stimulation of whole blood[12]. This requires validation in a larger cohort of TB cases, including HIV positive and HIV negative subjects, from different geographical regions. The aim of the present study was to validate the diagnostic potential of the 3-marker biosignature together with promising markers identified in other studies for the diagnosis of TB disease amongst individuals with symptoms suggestive of TB from six African countries (Ethiopia, Gambia, Malawi, Namibia, South Africa and Uganda), irrespective of HIV co-infection

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Conclusion