Concurrent evaluation of cytokines improves the accuracy of antibodies against Mycobacterium tuberculosis antigens in the diagnosis of active tuberculosis - 05/03/22

Doi : 10.1016/j.tube.2022.102169

Ruschca Jacobs ^a, Dolapo O. Awoniyi ^a, Ralf Baumann ^b,^c,^d, Kim Stanley ^a, Shirley McAnda ^a, Susanne Kaempfer ^b, Stephanus T. Malherbe ^a, Mahavir Singh ^b, Gerhard Walzl ^a, Novel N. Chegou ^a,^⁎
the AE-TBC Consortium^¹
The AE-TBC Consortium.
Gerhard Walzl ^e, Novel N. Chegou ^e, Magdalena Kriel ^e, Gian van der Spuy ^e, Andre G. Loxton ^e, Kim Stanley ^e, Stephanus T. Malherbe ^e, Belinda Kriel ^e, Jayne S. Sutherland ^f, Olumuyiwa Owolabi ^f, Abdou Sillah ^f, Joseph Mendy ^f, Awa Gindeh ^f, Simon Donkor ^f, Toyin Togun ^f, Martin Ota ^f, Amelia C. Crampin ^g, Felanji Simukonda ^g, Alemayehu Amberbir ^g, Femia Chilongo ^g, Rein Houben ^g, Desta Kassa ^h, Atsbeha Gebrezgeabher ^h, Getnet Mesfin ^h, Yohannes Belay ^h, Gebremedhin Gebremichael ^h, Yodit Alemayehu ^h, Marieta van der Vyver ⁱ, Faustina N. Amutenya ⁱ, Josefina N. Nelongo ⁱ, Lidia Monye ⁱ, Jacob A. Sheehama ⁱ, Scholastica Iipinge ⁱ, Harriet Mayanja-Kizza ^j, Anna Ritah Namuganga ^j, Grace Muzanye ^j, Mary Nsereko ^j, Pierre Peters ^j, Rawleigh Howe ^k, Adane Mihret ^k, Yonas Bekele ^k, Bamlak Tessema ^k, Lawrence Yamuah ^k, Tom H.M. Ottenhoff ^l, Annemieke Geluk ^l, Kees Franken ^l, Jolien J. van der Ploeg-van Schip ^l, Paul L.A.M. Corstjens ^m, Elisa M. Tjon Kon Fat ^m, Claudia J. de Dood ^m, Ida Rosenkrands ⁿ, Claus Aagaard ⁿ, Stefan H.E. Kaufmann ^o, Maria M. Esterhuyse ^o, Jacqueline M. Cliff ^p, Hazel M. Dockrell ^p
^e Stellenbosch University, South Africa
^f MRC Unit, The Gambia at LSHTM, South Africa
^g Karonga Prevention Study, Malawi
^h Ethiopian Health and Nutrition Research Institute (now known as the Ethiopian Public Health Institute), Ethiopia
ⁱ University of Namibia, Namibia
^j Makerere University, Uganda
^k Armauer Hansen Research Institute, Ethiopia
^l Department of Infectious Diseases, Leiden University Medical Centre, the Netherlands
^m Department of Molecular Cell Biology, Leiden University Medical Centre, the Netherlands
ⁿ Statens Serum Institute, Copenhagen, Denmark
^o Max Planck Institute for Infection Biology, Berlin, Germany
^p London School of Hygiene and Tropical Medicine, London, UK

^a DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
^b Lionex Diagnostics and Therapeutics, Braunschweig, Germany
^c Medical Faculty, Institute for Translational Medicine, Medical School Hamburg (MSH) – Medical University, Hamburg, Germany
^d Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

^∗Corresponding author. Biomedical Research Institute, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, P.O. Box 241, Cape Town, 8000, South Africa.Biomedical Research InstituteDivision of Molecular Biology and Human GeneticsFaculty of Medicine and Health SciencesStellenbosch UniversityP.O. Box 241Cape Town8000South Africa

Abstract

Background

Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of tuberculosis (TB). We assessed combinations between antibodies and cytokines for diagnosing TB.

Methods

Immuoglubulin (Ig) A and IgM antibody titres against selected mycobacterial antigens including Apa, NarL, Rv3019c, PstS1, LAM, “Kit 1” (MTP64 and Tpx)”, and “Kit 2” (MPT64, Tpx and 19 kDa) were evaluated by ELISA in plasma samples obtained from individuals under clinical suspicion for TB. Combinations between the antibody titres and previously published cytokine responses in the same participants were assessed for diagnosing active TB.

Results

Antibody responses were more promising when used in combination (AUC of 0.80), when all seven antibodies were combined. When anti-“Kit 1”-IgA levels were combined with five host cytokine biomarkers, the AUC increased to 97% (92–100%) with a sensitivity of 95% (95% CI, 73–100%), and specificity of 88.5% (95% CI, 68.7–97%) achieved after leave-one-out cross validation.

Conclusion

When used in combination, IgA titres measured with ELISA against multiple Mycobacterium tuberculosis antigens may be useful in the diagnosis of TB. However, diagnostic accuracy may be improved if the antibodies are used in combination with cytokines.

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Highlights

•	Antibody-based TB tests are known to be highly specific whereas host cytokine responses have been shown to be sensitive.
•	An approach involving the combination of anti-MTB antibodies and cytokines was assessed as a tool for TB diagnosis.
•	Antibodies alone were promising but diagnostic accuracy increased when they were used in combination with cytokines.
•	Combining antibodies with up to five host inflammatory biomarkers may be a useful approach for the diagnosis of TB.

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Keywords : Tuberculosis, Antigens, Antibodies, Cytokines, Biomarkers, Diagnosis

Plan

Classification of study participants

Antigen preparation

Enzyme -linked immunosorbent assay

Evaluation of host inflammatory biomarker responses

Statistical analysis

Results

Utility of individual anti-M.tb antibodies in the diagnosis of TB

Utility of multi-antibody models in the diagnosis of TB

Diagnostic accuracy of combinations between antibodies and cytokines

Discussion

Funding

Data availability statement

Author contributions

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Concurrent evaluation of cytokines improves the accuracy of antibodies against Mycobacterium tuberculosis antigens in the diagnosis of active tuberculosis - 05/03/22

Abstract

Background

Methods

Results

Conclusion

Highlights

Plan

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