Tuberculosis (TB) has taken a backseat over the last few decades as it has not received the funding appropriate to such a major health threat to the developing world. The World Health Organization (WHO) published statistics last month showing that worldwide TB rates are stabilising. Interestingly, however, there are a few countries where TB rates are increasing. The Health Protection Agency (HPA) has released statistics showing that the UK has seen a 2% increase (the only European country where TB is actually on the rise) and in African countries where HIV/TB co-infection is rife, TB deaths have quadrupled over the last 15 years. Clearly, tuberculosis is making a comeback – the disease is stronger now than ever before, and is rapidly becoming more drug-resistant with a number of mutant forms. In fact, TB is second only to HIV as the world’s deadliest infectious disease, claiming a life every 20 seconds. One of the key obstacles in controlling TB infection is the extremely poor diagnostic methods that currently exist. This article will examine those current diagnostics and reveal details of a new test that is set to change the way that TB is diagnosed and ultimately controlled throughout the world.
Global TB targets
Over the last year, the World Health Organization has expressed concern that they may not be able to reach the targets for TB as defined in the UN’s Millennium Development Goals (MDGs). These targets for 2015 included minimum requirements for cases detected and treated and require falling rates of TB incidence. Additionally, as defined by the “Stop TB Partnership” in 2006, prevalence and mortality rates should be halved from 1990 rates. This would essentially mean 50 million people would receive treatment and 14 million lives would be saved. As we know, early detection and proper treatment are essential to combat TB. UN Secretary-General, Ban Ki- Moon, said that the global rate of decline was “far too slow,” and argued that although “the epidemic is continuing its decline, the rate of decline is far too slow. Unless we accelerate action, the numbers of those falling ill will continue to grow.” A 2008 report said: “The detection rate increased only marginally to 61%, short of the 65% benchmark for 2006 contained in the ‘Stop TB Partnership’ Global Plan and the ultimate target of 70%.”
TB and co-existent factors
One-third of TB cases come from Sub- Saharan Africa and Southeast Asia, where widespread poverty and a lack of public healthcare are the main factors attributable to this. People who have TB, or live in poverty, can often become stuck in a vicious circle of continuous proliferation of both. TB most commonly attacks people in their working years making them unable to earn. Additionally, the costs associated with healthcare for TB can put families of sufferers under tremendous financial strain. This has a significant impact on children as they often become malnourished and have to leave school to take care of their family or even become orphans. In turn, people living in poverty often share living space with many people and cannot afford or access healthcare and are therefore much more likely to contract TB. There is a strong connection between HIV and TB. A third of all HIV/AIDS sufferers are co-infected with TB and the WHO Global TB Report showed that approximately 1.37 million HIV/AIDS sufferers were diagnosed with TB in 2008. TB is the leading cause of death among HIV sufferers. Shockingly, new data shows that 25% of all TB deaths are HIV-related – double the amount previously thought.
Current diagnostic technology
Optimum TB management requires rapid detection, prevention and treatment – but current technology is outdated and impractical. According to WHO, “only 2% of MDR-TB cases worldwide are being diagnosed and treated appropriately.” The current testing method, where the patient’s sputum is treated with a stain and then studied under a microscope to detect acid fast bacteria (AFB), is 125 years old and fails to detect half of all active cases; a failure rate that is even higher in those co-infected with HIV. Tests that are more accurate exact a price, both monetarily and in the prolonged length of time it takes to accurately diagnose someone with TB. Due to the slow growth nature of the TB organism, (the organism has a doubling time of 24 hours) culture testing can take weeks to provide any results. It then takes even longer to determine if there is drug resistance, as the culture requires inoculation and monitoring to see if it grows in the presence of the antibiotics, in order to determine its susceptibility pattern. Adding up all these procedures currently required to diagnose drug resistant TB, it can take months to obtain a result. Unfortunately, for many patients in the developing world, this amounts to a post-mortem diagnosis, particularly as they are often co-infected with HIV – a rapidly fatal combination. Additionally, because diagnosis takes so long, these patients are sent back into the community, rather than isolated and treated appropriately, allowing for further propagation of the organism in the local area. In most of the developed world, patient isolation is implemented to prevent transmission to surrounding family and communities. However, in the UK there are currently no guidelines advocating isolation while a result is obtained, making a rapid diagnosis even more necessary. Until now, if a clinician were to opt for a quicker TB diagnostic method than culture, accuracy would suffer. Sputum smear testing can theoretically produce results within a day. However, 30% or more of smear-negative results are culture-positive in follow-up verification, proving this diagnostic method to be highly insensitive and dangerously inaccurate. Missed diagnosis via smear testing is estimated to contribute to an estimated 20% of transmitted TB infections. Additionally, in an unexpected twist of fate, patients with HIV/TB coinfection are actually more likely to be smear negative but progress rapidly to a fatal outcome. Coinciding with World TB Day, UN Secretary-General Ban Ki-Moon called for faster action to combat TB on a global scale. He highlighted the need for infection prevention, early detection, and worldwide availability of treatment, while calling for more effort to combat multidrug-resistant (MDR) TB, extensively drug-resistant (XDR) TB and the TB/HIV co-epidemic. With this in mind, he called for organisations to come together and develop diagnostic solutions that will prevent the spread of the disease. Specifically, WHO has called for faster and more accurate diagnostics based on the detection of the rpoB gene as a surrogate marker for MDR.
What is the answer?
In line with these announcements, a number of organisations have collaborated to develop a new diagnostic test for TB. The new test detects TB in less than two hours, is highly accurate, and is about to become available in Europe. The test is run on Cepheid’s GeneXpert System, a leading molecular testing platform, and was developed jointly by Cepheid, the Foundation for Innovative New Diagnostics (FIND), the University of Medicine and Dentistry of New Jersey (UMDNJ), and the US-run National Institute of Allergy and Infectious Diseases (NIAID). Not only is the advanced technology able to detect the TB organism directly from sputum, it can also simultaneously detect rifampicin resistant strains of the infection via the presence of the rpoB gene, which is generally used as a surrogate marker for multi-drug resistance. It boasts unprecedented levels of sensitivity for detection of smear positive and smear negative TB cases. Especially for HIV co-infected patients, the latter feature could be a life-saver. This new test is one of the most important diagnostic developments to have occurred in many years. It is simple enough to perform in all corners of the world, including resource-limited settings in which it is most needed.
How does it work?
When an individual is suspected of TB the first step is a chest X-ray. Following this, the sputum can be collected, then mixed with a solution that kills the TB organisms, and placed into a GeneXpert cartridge. The GeneXpert System carries out steps that would have, until recently, required a dedicated laboratory facility and highly trained molecular diagnostic specialists. Within the cartridge, specimen processing and reagent mixing involving dozens of micro-pipetting steps are used to carry out nested real-time polymerase chain reaction (PCR). This amplifies enzymatically a DNA signature sequence that is specific to the TB organism. DNA amplification and detection occurs within about 90 minutes, typically providing a definitive TB result within a two hour time-frame. Because the test is not required to be run in batches, it is possible to run a STAT test on demand for patients with X-ray findings suspicious for TB, thus maximising the medical value of the test. Building on an ingenious protocol developed by Dr David Alland, MD, and his colleagues at UMDNJ, the team engineered a protocol inside the GeneXpert cartridge that detects the presence of mutations to the rpoB gene, an indicator of refampicin resistance. Because resistance is almost always present when there is resistance to other drugs, this can be used as a surrogate marker for multiple drug resistance (MDR). Still more important is that the presence of rifampicin resistance predicts failure of first-line therapy, guiding the clinician to the most effective choice of treatment and potentially avoiding costly treatment failures.
Conclusion
Tuberculosis is not an infection that is going to vanish overnight and, contrary to popular belief, it is not a disease from the 19th Century that we no longer need to worry about – but it should be. It is a tragedy that we have not yet managed to eradicate this devastating infection from the world, both in developing countries and in our own supposedly developed country. Its close links with poverty and the HIV virus make it a much more widespread and serious issue in Africa and Southeast Asia, but it is also a concern in the UK and Europe. With over 8,000 new cases of TB reported every year in the UK, we are seeing the number of cases increase, bucking the global trend. It is my sincere hope that this new diagnostic test, which will soon be available throughout the world, will mark the tipping point when we finally start to win the battle against TB.