Ending tuberculosis through better diagnostics
Author: Dr. Frederick Haraka, MD
Yes, to end tuberculosis (TB), we need better diagnostic tools!
TB is among the deadliest diseases in the world. In 2015, there were 10.4 million new TB cases worldwide. An estimated 1.4 million death were due to TB, and an additional 0.4 million deaths resulting from TB disease among people living with HIV in the same year. Tanzania is among high burden countries with TB. Tanzania has a prevalence of 295 cases per 100,000 people. For over 100 years diagnosis of tuberculosis (TB) was heavily dependent on the use of smear microscopy using a technique known as Ziehl-Neelsen stain where Mycobacterium tuberculosis, bacteria responsible for TB, is seen under the microscopy as red rod shapes. However, its sensitivity to detect TB is low, estimated between 20 and 80%. When using smear microscopy, results are obtained in a range of one to seven days depending on the healthcare infrastructure. Other ways of diagnosing TB include clinical suspicion and a chest X-ray with features suggestive of TB.
In absence of a confirmation through laboratory findings, history taking and clinical examination are often the cornerstones of TB diagnosis. Unfortunately such approaches are tricky due to the following reasons: TB symptoms are often non-specific and chest X-ray does not always show typical features of TB. Therefore, there is an urgent need for better diagnostics which ideally offer bacteriological confirmation at primary health care facilities. The gold standard for TB diagnosis is through microbiological cultures of the TB-causing bacteria, where specimen is kept in special media to allow bacteria to grow. Even after the development of liquid media such as the Mycobacterium growth indicator tube culture takes often not less than three weeks. This is too long for point of care decision. In addition, culture facilities are normally centrally located and require specialized infrastructure and skills.
At point of care, in peripheral healthcare facilities, there is still no reliable accurate diagnostic tool which is highly sensitive for TB detection. For example, in 2014, almost 40% of the notified TB cases in Tanzania were clinically diagnosed, meaning there was no bacteriological confirmation of TB. This does not necessarily mean those clinically diagnosed did not have TB, however, it could have implications with regard to under- and over-diagnosis. The latter would lead to unwanted long and demanding anti-tuberculosis therapy, which can be associated with adverse drug effects especially in HIV population and with financial burden to both the patient and the National TB program. The National TB Program encourages initiation of treatment based on bacteriological confirmation whenever possible. With newly developed improved diagnosed tools our aim should be to minimize empirical treatment to 10% or less.
In 2010, the WHO recommended the use of a novel molecular diagnostic tool known as GeneXpert. This tool was shown to be very sensitive and highly specific for TB detection and can be used in district and even sub-district levels e.g. health centres. Many countries were able to procure through concessional price and implemented GeneXpert technology in their National TB Programs. The Tanzanian National TB and Leprosy Program is currently implementing GeneXpert in some diagnostic centres. Efforts are underway to scale up the use of GeneXpert in the country. Unfortunately, the use of GeneXpert in resource limited settings encounters a number of challenges which lead to modular or instrument failures. Proper training, in particular to teach basic computer skills, was often missing when GeneXpert is rolled out. Other challenges included unreliable power supply, dust build up and uncontrolled temperatures at places where the instrument was stationed.
In terms of population level impact, recent evidence from research has indeed shown different outcomes. While GeneXpert has increased the number of bacteriological confirmation and detection of multi-drug resistance TB, it has not shown an impact on patient important outcomes such as mortality, morbidity and time to treatment compared to smear microscopy. Empirical, symptom-based treatment in patient with negative smear microscopy results appeared to undermine the expected beneficial impact of GeneXpert. On the other hand, a confirmation of TB assures that the patient is a true positive TB case, while clinical diagnosis followed by empirical treatment might include false positive. The lack of morbidity and mortality impact of GeneXpert has stimulated a debate among scientists on better strategies for the implementation of new diagnostic tools by simultaneously strengthening the TB programs and supporting the health professional who take care of people suspected of having TB.
In future, new and improved molecular diagnostic tools with high sensitivity like GeneXpert should be rolled out to the lowest level of the health care system which is actually the first point of contact for presumptive TB patients. The new molecular diagnostics should meet conditions in resource poor settings and should be easy to use for laboratory technician with minimal level of training. For this purpose, a new generation of GeneXpert has been developed. The GeneXpert Omni is portable, battery powered and more resilient to environmental changes compared to the GeneXpert. The tool is designed to be used in primary healthcare facilities with relatively low throughput. Alongside, a new cartridge known as Xpert MT/RIF Ultra which is more sensitive than the previous one, has also been developed to improve detection of TB e.g. in HIV population. It is expected that Omni combined with Ultra will improve detection and eventually control TB.
A team of scientists from the Ifakara Health Institute (IHI), the SwissTropical Tropical and Public Health Institute (SwissTPH) and the National TB and Leprosy Control Program (NTLP) are set out to implement a pragmatic clinical trial which will evaluate the incremental value of using Omni combined with Ultra compared to smear microscopy. This project is supported by the Foundation for Innovative New Diagnostics and the Stop TB Partnership’s TB REACH initiative.
The WHO through END TB strategy has set global ambitious goals to achieve zero death, disease and suffering due to TB by 2035. I’m confident that through better diagnostics such as Omni combined with Ultra, improved clinicians behavior and attitude on decision to treat enhanced training and strengthened TB program will significantly contribute in achieving the ambitious 2035 END TB goal.
About the Author. Dr. Frederick Haraka is a clinical epidemiologist and a research scientist working for Ifakara Health Institute. For the past seven years his research work has focused on evaluation of TB Diagnostics and randomized controlled trials. Email: firstname.lastname@example.org