The biomedical science behind tuberculosis treatments

In 1882, Dr Robert Koch announced his discovery of the bacterium Mycobacterium tuberculosis (TB), yet 136 years later, TB remains one of the top ten causes of death around the world.

In 2015, Public Health England and NHS England launched the Collaborative Tuberculosis Strategy for England. This five-year plan aims to decrease the number of cases each year, with the goal to eventually eliminate TB as a public health issue.

The number of reported cases in England is dropping, yet this remains an issue, with delayed treatments and drug-resistant mutations of the bacterium posing problems for medical professionals.

Delayed treatment

Due to the long delays between the onset of symptoms and the start of treatment, some patients’ infections are more serious by the time they begin treatment. In 2016, 31% of reported pulmonary TB cases experienced delays of more than four months before starting treatment.

People with compromised immune systems, such as those living with diabetes, tobacco users, those suffering from malnutrition or who are HIV positive will also have a higher risk of infection. In addition, 11.1% of people infected with TB also have at least one social risk factor (a history of drug misuse, alcohol, homelessness). Public Health England’s 2017 report on tuberculosis in England indicates that if infected, these patients are more likely to develop drug-resistant TB and have worse outcomes.

Among the treatments available is the Bacille Calmette-Guérin (BCG) vaccine, which is a programme intended for people believed to be at high risk of exposure to TB. This includes infants, children and adults below age 35. However, this vaccine is considered to have limited effectiveness for preventing TB in adults and against the most common forms of the bacterium.

Drug-resistant TB

When a person is diagnosed with TB, they can be cured by following a strict 6-month course of antibiotics. However, inappropriate or misuse of antimicrobial drugs, or the use of poor quality medicines or interruptions to the treatment can cause drug resistance and enable the patient’s infection to spread, particularly if they are in a crowded setting.

Researchers can detect drug resistance by using molecular or culture-based laboratory tests to examine the bacteria for resistance patterns and sensitivity to drug treatments. Known as multidrug-resistant TB (MDR-TB), this type does not respond to the two most powerful anti-TB drugs, Isoniazid and Rifampicin. A rare type of multi-drug resistant TB is Extensively drug-resistant TB (XDR-TB), which is resistant to most anti-TB drugs. These drug-resistant TB infections require longer and more complex treatments, which are associated with greater costs and worse side effects.

More research is ongoing to test the TB bacteria to determine potential resistance to antibiotics.

Whole Genome Sequencing: the importance of genetics in TB treatment research

Jennifer Guthrie is a PhD Candidate at the School of Population and Public Health at the University of British Columbia. She works for the British Columbia Centre for Disease Control and described her research into TB treatments.

She said, “While the highest burden of disease is seen in developing countries, TB remains a major public health issue in Canada, and after decades of decline in TB incidence, progress has stalled. TB elimination in low-incidence countries is a unique problem as infection often occurs amongst the most difficult-to-reach individuals. New research and tools are essential to reduce the burden of TB and help us reach elimination goals.

Whole genome sequencing (WGS) is an important new technology that is changing our understanding of TB and our approaches to diagnosis, phenotyping, and treatment. WGS has an advantage over the various molecular methods available as it allows us to read the entire 4.4Mbp of Mycobacterium tuberculosis ( Mtb) DNA sequence – with current sequencing technologies this can be done in under a day at a cost of $50-100/genome.

For my PhD research, I have leveraged this novel tool and have sequenced the genomes of more than 1,200 Mtb isolates from persons diagnosed with TB in the province of British Columbia, Canada over a 10-year period. Pairing the WGS results with data collected routinely for each patient I am able to fully describe the when, where, and how of person-to-person spread of TB within and between the varied regional, socioeconomic, and cultural settings of British Columbia.

The findings of this study will directly impact public health policy and practice across Canada. In addition to using WGS for TB surveillance, outbreak detection and understanding transmission, WGS data can also be leveraged to improve TB diagnostics and treatment. Current methods of antimicrobial resistance detection are largely culture-dependent and require weeks to months for a result. While there are a small number of molecular assays commercially available which will detect a handful of known resistance mutations, WGS interrogates the entire genome, allowing for the identification of resistance-associated mutations in hours to days.

This will allow clinicians to optimize the prescription of appropriate treatment and support rational drug use. The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) is working to create a comprehensive database of well-described resistance-associated mutations, and the Mtb genomes along with phenotypic data used in my research have contributed to this effort. Overall, genomics stands to accelerate TB elimination in low-incidence setting through research aimed at reducing disease spread and improving diagnostics and treatment.”

TB Symptoms

TB is a bacterial infection that spreads when the bacteria are released into the air from an infected person when they cough or sneeze. The bacteria are then inhaled by a healthy person, who becomes infected. Symptoms include a persistent, phlegmy cough, weight loss, a high temperature, fatigue, and a loss of appetite. The infection typically affects the lungs, and the important message is that it is curable once it has been diagnosed and the appropriate treatment regime is applied and followed.