New approaches to accelerating TB treatment in Africa

Summary

Tuberculosis (TB) is a deadly infectious disease. Though the global death rate from TB dropped more than 40 percent from 1990 to 2011, there remains a severe shortage of diagnostics and care options. This study considers a novel tool that can monitor and track the effectiveness of TB treatment to improve TB cure rates and improve patient management.

Background

Tuberculosis (TB) is an airborne disease spread among humans by inhaling infectious droplets produced when an infected person coughs, sneezes or spits. Although global TB incidence is falling by 1.5–2% annually, it remains one of the leading causes of death from a single infectious agent and the ninth leading cause of death worldwide.

To meet the World Health Organization’s “End TB Strategy” by 2035 and reduce TB infection rates by 90%, more needs to be done. Although TB is curable, multiple factors hinder the control of its spread:

1) A shortage of tools to identify patients at risk of poor response to treatment;

2) Insufficient early evaluation of TB treatment response, and

3) A lack of shorter TB treatment regimens to increase patient compliance. The current standard six-month regimen can lead to treatment failure, relapse and/or the development of drug resistant TB.

Novel methods to evaluate treatment response could speed up the testing of new TB treatment regimens in clinical trials. Current diagnosis takes two months and do not predict how a patient will respond to treatment. Immune responses to treatment can be used as potential alternative biomarkers to predict the effectiveness of an anti-TB treatment.

Study description

The immune system functions like an army, with different cells performing different functions. Some kill invading pathogens (organisms that cause disease), like viruses and bacteria. When these “soldiers” come into contact with the “enemy” (in the case of TB, bacteria), they issue a “battle call” by releasing chemical signals that recruit other cells of the immune system to the “battlefield” (site of infection). These cells can also release signals that let the immune system know that the bacteria have been cleared and the fight is over. Using flow cytometry (a laboratory method used to detect, identify, and count specific cells), I studied the chemical signals produced by one type of immune cell, neutrophils (a type of white blood cell), by labelling them with fluorescent colours which become more intense with more cells. Monitoring intensity changes from TB diagnosis to cure reveals that blood neutrophils are abundant, short lived and rapidly recruited to the lung during active TB and therefore may respond quickly as the progress of disease changes.

Using this method, we identified a specific signal associated with early TB treatment success. To achieve this, we recruited and followed 79 patients with TB from Durban, South Africa, collected their blood and sputum and performed chest X-rays at baseline (pre-treatment) and during treatment. The use of neutrophil counts has been evaluated as markers of TB disease severity and treatment outcomes, but this was the first full evaluation of cell surface marker changes as biomarkers of early TB treatment success.

Study outcomes

We found that the severity of TB at diagnosis is strongly associated with increased neutrophil blood counts and decreased expression (relative fluorescent intensity) of the neutrophil surface marker CD15. With treatment, both indicators rapidly return to levels found in healthy volunteers. Interestingly, both markers were able to distinguish individuals with active TB disease from those who have TB-like symptoms but are found to be without bacteria. Furthermore, it was found that for every unit increase in baseline CD15 expression, the odds of a person remaining culture positive after two months of TB treatment was reduced by 83%. These data show that these simple measures have the potential to tell healthcare providers who is likely to respond well to standard treatment and who needs more intense care. Importantly, this measure was not impacted by HIV co-infection.

Lessons

This work shows the promise of studying the relationship between the TB-causing bacteria and the host immune system and how this interaction affects treatment outcomes. It addresses the well-established difficulty of getting TB patients to adhere to treatment for six months. Interventions that improve patient compliance are urgently needed to reduce the spread of TB. Moreover, this work offers a path to development of tools that are simple, sensitive and can accurately describe the disease status of an individual at diagnosis and during treatment.

Impact

TB is difficult to diagnose and monitor in children and people living with HIV, largely due to their inability to produce sputum. This work suggests an alternative, easy tool that is not compromised by co-infection. This work has potential applications not only to TB patient treatment but also in clinical trials for new, better-tolerated drugs with fewer side effects that can shorten treatment duration.

About Lerato Noluthando Ndlovu

Lerato Noluthando Ndlovu is a South African immunologist and PhD Fellow at the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), one of the 11 Developing Excellence, Leadership, and Training in Science in Africa (DELTAS Africa) programmes. She is passionate about improving science literacy as a means to ending diseases like TB and HIV, engaging communities in Estcourt, KwaZulu-Natal, South Africa, where she grew up. Through “Science-2-Society”, she hopes to inspire high school students to actively engage with the scientific community and inspire them to pursue science.

DELTAS Africa funds collaborative consortia led by Africa-based scientists to amplify Africa-led development of world-class research and scientific leaders on the continent, while strengthening African institutions. It is implemented through Alliance for Accelerating Excellence in Science in Africa (AESA), a funding, agenda-setting, programme management initiative of the African Academy of Sciences (AAS), the African Union Development Agency (AUDA-NEPAD), founding and funding global partners, and through a resolution of the summit of African Union Heads of Governments. DELTAS Africa is supported by Wellcome and the United Kingdom Foreign, Commonwealth and Development Office (FCDO, formerly DFID).