One third of the world’s population is infected with Mycobacterium tuberculosis
Of the 2 billion people worldwide infected with Mycobacterium tuberculosis, 10% will go on to develop active tuberculosis. 80% will continue to carry the latent TB infection (LTBI), perhaps for the rest of their lives. Whilst individuals with LTBI are at greatest risk of the disease activating in the first two years, this can occur decades after infection. Risk of progression is associated with a compromised immune system.
An increasing number of individuals are infected with drug resistant strains of the disease. In 2014 there were an estimated 480,000 such cases worldwide.
Incredible gains have been made in the effort to eradicate TB; diagnosis of LTBI and drug resistant TB is crucial to lowering mortality even further.
Eradicating TB by wiping out LTBI
In low incidence countries the majority of new cases of TB are derived from a pool of patients with LTBI. Promisingly, diagnosis and treatment of LTBI in developed nations has been shown to lower tuberculosis incidence. However whilst there are diagnostic tests available for LTBI, they have their limitations.
The widely used tuberculin skin test (TST) is a low cost option which unfortunately lacks sensitivity and specificity. Interpretation by the tester opens up room for error, and the test cannot differentiate between infection, prior BCG vaccination or sensitisation with environmental mycobacteria. Crucially, this test is also ineffective in HIV patients due to their immunocompromised state.
The use of a test which is accurate for immunocompromised individuals is particularly important in regions which have a high prevalence of HIV infection, as the lifetime risk of LTBI developing into active TB in those living with HIV is 50%. Africa has the highest TB incidence rate in the world, mainly due to the HIV epidemic. In 2008, 1.4m TB patients were co-infected with HIV.
Another testing option for LTBI is the more expensive and complex interferon gamma release assays (IGRA). Unaffected by prior BCG vaccination, these tests are more specific than the TST and of similar sensitivity. They are more accurate in those with HIV however there is much room for improvement.
Crucially, there is currently no way of predicting when a healthy individual with LTBI will progress to active disease.
Eradicating TB by tackling drug resistance
Another important pool of TB which can ‘hide’ from current diagnostics and treatment, from which new cases spring, is drug resistant TB. A recent study in Cape Town found that of 138 TB patients, all had a strain which was resistant to at least two of the frontline drugs. 40% had a strain which was resistant to all frontline drugs, and 25% were also resistant to second-line therapies.
Current drug susceptibility testing technologies are struggling to meet the requirements of the current TB epidemic. Technical shortcomings such as reliance on high level infrastructure and skillsets limit the accessibility of these technologies, reducing their reach and subsequently their impact. According to the World Health Organization (WHO), in 2014 only one in four MDR-TB was diagnosed.
The work horse of TB testing is smear microscopy, a century-old procedure which must be run by a skilled technician with a good eye. Diagnostic sensitivity for this test is low, with as many as 50% of active infections missed. As such, healthworkers often rely upon empirical diagnosis, based upon two or more weeks with a persistent cough and a chest x-ray. Confirmation is made several weeks later with a culture and it is then that the patient begins treatment.
Crucially, these diagnostic methods do not detect LTBI or drug resistance. Drug resistance only becomes apparent upon treatment failure, or upon further culture which is rarely carried out.
Equipping our healthworkers to tackle TB
The WHO and FIND have stated the need for a test to predict progression from LTBI to active disease, and estimated that the need for this test would be a massive 767 million patients per year (FIND & WHO, 2006). Such a test would enable treatment of these individuals, having a massive impact on not only the outcome of the individual but also on further transmission of the disease.
An important study from the University of Cape Town has identified an RNA signature which was successfully used to predict the progression of LTBI to active TB. Whilst the researchers used sequencing during the study, they have transferred the gene signature to a qRT-PCR format to lower cost and complexity. QuantuMDx has entered an agreement with the University of Cape Town to explore running their predictive test on QuantuMDx’s handheld molecular diagnostic device Q-POC™, to support the researchers’ vision of “establishment of diagnostic methods that are scalable and inexpensive”.
The Q-POC™ device could also support the wider roll out of drug susceptibility testing by enabling this traditionally complex test to be run in microscopy centres. Battery operation will negate the need for a stable electricity source, cartridges pre-loaded with reagents will negate the need for clean running water, simple sputum processing technologies will reduce the training and skills requirement, and a closed automated system will reduce contamination risk and user error. This range of benefits has brought Q-POC™ to the attention of FIND, who are now co-developing sputum processing technologies and a drug susceptibility assay with QuantuMDx.
Working together to fight TB
Technological innovations such as Q-POC™ cannot eradicate TB alone. As a diagnostics developer, we rely on partnerships throughout the world, especially in South Africa where our company took shape. These partnerships will help ensure our technology meets the needs of healthworkers and is properly implemented for optimal impact on patient outcomes.
We will win the fight against TB, however it will require cooperation from technology developers, assay developers, health ministries, laboratory personnel, NGOs and all the supporting and training staff.