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 Table of Contents  
Year : 2016  |  Volume : 4  |  Issue : 4  |  Page : 230-237

Tuberculosis diagnosis: Challenges and solutions

1 Department of Epidemiology and Biostatistics; McGill International TB Center, McGill University, Montreal, Canada
2 McGill International TB Center; Department of Microbiology and Immunology, McGill University, Montreal, Canada

Date of Web Publication12-Oct-2016

Correspondence Address:
Madhukar Pai
Department of Epidemiology and Biostatistics, McGill International TB Center, McGill University, 1020 Pine Ave West, Montreal, QC H3A 1A2
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DOI: 10.4103/2468-6360.191903

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More than 9 million people develop tuberculosis (TB) every year, but nearly a third are not diagnosed or not reported. The current diagnostic tools available range from a 100-year-old microscopy technique to the newest generation automated nucleic acid amplification tests, but they alone are not sufficient to ensure that we meet the goals of the end TB strategy. Several new TB tests are under development. As new diagnostics are developed, it is critical that we understand the particular challenges that arise in TB diagnosis, and ensure that existing tools are implemented correctly. We must encourage the development of diagnostics that meet the specific needs of the TB community as well as ensuring that new technologies are accessible to low- and middle-income countries. Finally, strong policy guidance is required to ensure that new and existing diagnostics are used as efficiently as possible. With this co-ordinated approach, new diagnostic tools can be the cornerstone of the effort to end TB.

Keywords: Diagnostic accuracy, diagnostics, drug-susceptibility testing, latent tuberculosis infection, tuberculosis

How to cite this article:
Huddart S, Nash M, Pai M. Tuberculosis diagnosis: Challenges and solutions. J Health Spec 2016;4:230-7

How to cite this URL:
Huddart S, Nash M, Pai M. Tuberculosis diagnosis: Challenges and solutions. J Health Spec [serial online] 2016 [cited 2020 Jul 14];4:230-7. Available from: http://www.thejhs.org/text.asp?2016/4/4/230/191903

  Introduction Top

More than 9 million people developed tuberculosis (TB) in 2014. Despite decades of medical advances, the rate of TB incidence has decreased by <2% year to year. [1] A cornerstone of the effort to reduce the global TB burden is accurate and efficient diagnosis, which can avert deaths and prevent further transmission. However, of the 9.5 million new cases occurring each year, a full third are not diagnosed or not reported. [2] These patients are referred to as the 'missing three million' and to find and diagnose them, will require improved diagnostics and other interventions to reduce gaps in the diagnostic care cascade.

  Current tuberculosis diagnostics landscape Top

The current landscape of the World Health Organization (WHO) endorsed TB diagnostics includes a variety of tests targeted for specific uses in multiple settings [Table 1].
Table 1: Currently available tuberculosis diagnostics tools

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Active tuberculosis

Currently, most TB patients are diagnosed using sputum smear microscopy (SSM). The simplistic nature of this test makes it amenable for use in low-resource settings. [3],[4] However, the test lacks adequate sensitivity, it cannot offer information on drug sensitivity and it performs poorly in many TB patient subgroups, such as those who are unable to produce sputum or have low bacterial loads (i.e., children and those with extrapulmonary disease). [12],[13],[14],[15],[16] Fluorescent staining and light-emitting diode microscopy is the best technology available today [Figure 1], and at least 2 smears are needed to be read by a trained technician in a laboratory with adequate quality assurance.
Figure 1: Light-emitting diode fluorescence microscopy for tuberculosis detection

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Cultures are another commonly used method for the diagnosis of active TB which, in contrast to SSM, can perform drug-susceptibility testing (DST). Although liquid cultures [Figure 2] are the most sensitive among TB tests, they are not widely available in high-burden countries. Further, due to the slow growth of Mycobacterium tuberculosis (MTB), cultures are not conducive to the rapid test-and-treat diagnostic strategy desired for effective TB patient care. [5] However, liquid cultures are critical for DST and for paucibacillary TB cases.
Figure 2: Automated liquid culture technology

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Addressing HIV-associated TB presents another significant diagnostic challenge. [17] The diagnostic accuracy of SSM is substantially reduced in patients with HIV co-infection. The lateral flow urine lipoarabinomannan (LAM) assay (Alere Determine TB LAM Ag, Alere Inc., USA), has demonstrated some utility in diagnosing TB infection in HIV+ patients with low CD4 + T-cell counts. [8] The WHO currently recommends that this test should be used only to diagnose HIV+ patients presenting with TB symptoms and fewer than 100 CD4 cells per microliter. [18] Given that TB is the most common cause of AIDS-associated deaths, developing improved point-of-care (POC) diagnostics for HIV+ TB patients is an urgent need. [17]

Two nucleic acid amplification tests (NAATs) have also been released in the market with WHO endorsement for active TB diagnosis. The first, endorsed by the WHO in 2010, is Xpert TM MTB/rifampicin (RIF) (Cepheid Inc., California, USA). This test runs on Cepheid's GeneXpert TM automated polymerase chain reaction (PCR) platform [Figure 3]. Xpert is capable of diagnosing TB and testing for RIF resistance with high accuracy, returning results in 2 h. [9] It has significant infrastructure requirements, but demands minimal technical training with patient samples being loaded directly into the Xpert cartridge. [9]
Figure 3: Xpert Mycobacterium tuberculosis/rifampicin assay for tuberculosis on the GeneXpert® automated platform

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Loopamp™ MTB kit (Eiken, Japan) is another NAAT that has recently been reviewed by the WHO for TB diagnosis. This assay is a loop-mediated isothermal amplification (LAMP). The LAMP reaction is less complicated than the PCR reaction in Xpert, thus requiring cheaper machinery to run and it is designed for microscopy centres. However, LAMP is significantly less automated than Xpert, requiring more sample manipulation and a visual assessment of the results. Sensitivity is 97% in smear-positive patients and 53% in smear-negative patients. [11]

Drug-resistant tuberculosis

For DST, there are three technological options: Cultures, NAATs (Xpert MTB/RIF, as well as line probe assays [LPAs]) and sequencing. Cultures are the gold standard as they can be used to detect phenotypic resistance to any antibiotic, but its utility is limited by its slow turnaround time and inadequate access. As previously described, Xpert is capable of detecting resistance to RIF, a good marker of multi-drug resistant (MDR) TB.

Other NAATs exist for DST, chief among them is LPAs [Figure 4]. In these assays, PCR-amplified MTB DNA is applied to a strip with probes for drug-sensitive and drug-resistant genes; binding results in a coloured line that are assessed visually. Commercial LPAs include the Hain Genotype MTBDRplus and Nipro kits. LPAs are rapid and highly sensitive for RIF and isoniazid, but the test protocol is complex and requires skilled lab technicians in reference lab settings. In addition, it is only recommended for smear-positive samples and culture isolates. [10] Whole genome sequencing is gaining traction for MTB, but its expense and low-throughput are prohibitive for most high-burden countries. However, next-generation sequencing might become important in the next decade, especially with the emergence of new TB drugs and regimens.
Figure 4: Line probe assay for rapid detection of drug-resistance

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Latent tuberculosis infection

In addition to the diagnosis of active TB, tools exist to diagnose latent TB infection (LTBI). The goal of screening for LTBI is to identify patients who would benefit from preventative therapy and avoid the development of active TB. [6] Population groups to target for LTBI testing include people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor alpha treatment, patients with end-stage renal failure on dialysis, patients preparing for organ or haematologic transplantation and patients with silicosis. The rationale for giving priority to these subgroups is that they are at very high risk of progressing from latent infection to active disease, and this could be prevented by treating LTBI.

Two tests are available for diagnosing LTBI, the Mantoux tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). However, both cannot distinguish between people with an on-going TB infection and those who have been previously cleared from a TB infection. [19] Given that IGRAs are more expensive and technically complex, yet, they have comparable performance to TST; consequently, the WHO recommends the continued use of TST to diagnose LTBI in low- and middle-income countries. [20] However, both TST and IGRAs have poor ability to identify those who are at the highest risk of progressing to active TB, and there is a pressing need to identify more predictive biomarkers. [21]

The post-2015 end TB strategy has called for 'Integrated, patient-centred care and prevention' which entails the timely diagnoses of all TB patients with universal and rapid DST. [22] To achieve this goal, the TB community will require new and improved diagnostic tools that are accessible to the people who need them most, with strong guidance as to how they should be used.

  Challenges and solutions Top

Need for new tools

The development and rollout of Xpert has reinvigorated a once-dormant diagnostic pipeline. Xpert's sensitivity and DST capability have the ability to increase the number of bacteriologically confirmed cases and reduce treatment delays in high-burden settings. [23] It also performs better in paucibacillary patients such as children. [24] Despite its potential value added to current diagnostic algorithms, pragmatic concerns have slowed Xpert's uptake. A single Xpert test costs ten times as much as smear microscopy and there is considerable upfront investment required to purchase the machine. [4] Currently, most Xpert's use in high-burden countries is subsidised by donor contributions. Even with subsidised pricing, Xpert is rarely used as an upfront diagnostic among patients with presumed TB; most countries are using Xpert primarily as a DST. Xpert was not designed to serve as a POC test at the primary care level (i.e., at the level of microscopy centres) and is primarily implemented in district and reference laboratories. [25]

Xpert is not a silver bullet in the effort to control the TB epidemic, and more diagnostic tests are required. Thankfully, other TB tests are under development, as shown by the pipeline in [Figure 5]. However, TB research and development is chronically underfunded and this has negatively impacted the development of novel diagnostic tests. [26]
Figure 5: Pipeline of new tuberculosis diagnostics under development (Source: FIND, Geneva, with permission)

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To encourage private investment in TB diagnostics, target product profiles (TPPs) have been developed to summarise the needs of the TB community to the private sector as well as market valuations that note the sizeable need of TB patients. [3],[27],[28],[29] The most pressing needs identified are for '(1) a sputum-based replacement test for smear microscopy; (2) a non-sputum-based biomarker test for all forms of TB, ideally suitable for use at levels below microscopy centres; (3) a simple, low-cost triage test for use by first-contact care providers as a rule-out test, ideally suitable for use by community health workers and (4) a rapid DST for use at the microscopy centre level'. [27] It is hoped that these TPPs will guide the current pipeline of novel assays towards the most urgent diagnostic needs.

The pipeline currently holds a bevy of new NAATs [Figure 5], but there are also efforts to improve the existing diagnostics such as sputum smears and chest X-rays. Of particular note in the NAAT pipeline is the development of GeneXpert Omni [Figure 6], a more robust, battery-operated POC platform for Xpert MDR/RIF assays geared towards more peripheral health centres. Multiple other NAAT tests are in the final stages of development, but have not been extensively evaluated in field conditions.
Figure 6: The Gene Xpert Omni technology that will be introduced in 2017, with the Xpert Mycobacterium tuberculosis/rifampicin ultra-cartridge

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Given that SSM currently dominates TB diagnostic algorithms, several products seek to improve the accuracy and ease of this assay. The Lung Flute (Medical Acoustics, USA) and a bag collection system in development by Deton Corp., (USA) aim to facilitate the collection of sputum. OMNIgene; SPUTUM (DNA Genotek Inc., Canada) is a new reagent that can be added to sputum to decontaminate the sample and allow for safe storage outside the cold chain for up to 8 days. There are several automated microscopy systems under development that could increase the throughput of SSM, even if they cannot overcome the inherent low sensitivity of microscopy.

Chest X-rays are excellent screening tests for TB. Low cost digital X-ray systems are being developed that link to software (for computer-aided diagnosis) that automatically analyse X-rays for suspicious lesions. Breath-based tests seek to identify volatile organic compounds that indicate TB infection, examples include the TB Breathalyzer by Rapid Biosensor Systems Ltd., (UK). These assays involve relatively simple equipment and are designed for POC use.

There are multiple refinements to the 1 st generation IGRAs on the market. Several have country-specific approvals. A 3 rd generation IGRA called QFT-Plus developed by Qiagen (Australia) reports sensitivity and specificity above 95% for latent TB, but independent validation data are lacking. [29]

There are relatively few new DST assays currently under development. Molecular DST diagnostics are particularly difficult to develop, but are critical for ensuring successful treatment, especially as new drug regimens become available. [30] Part of the difficulty in developing molecular tests is that no central database of MTB mutations exists. Collating current knowledge about TB resistance patterns is necessary for the development of molecular assays and such a database may even allow for the prediction of future resistance patterns. [31] A similar situation exists for biomarker research where it is difficult to obtain well-characterised patient biological samples. [32]


New and improved diagnostic tests have the capacity to revolutionize TB diagnostics, but it is important not to neglect the last mile of diagnostic research: Accessibility. The most urgent need for new diagnostics is in the clinic with patients when they first seek medical attention for TB. For example, despite its numerous strengths, Xpert was not designed as a POC test. It requires controlled environmental temperatures and consistent electricity which are not always available in peripheral health centres of low-income nations. [25] Modelling indicates that the full benefit of improved diagnostic tests can only be felt if they are implemented as POC assays. [33] To do this, new diagnostic tests must be designed with the realities of low-resource settings in mind. [34] A recent survey of peripheral microscopy centres in 22 high-burden countries found that skills, equipment and environmental controls in peripheral lab are often limited. [35]

Another component of access is cost. To sustainably implement new diagnostics, these tests must be affordable to low- and middle-income countries. Current modelling suggests that a POC triage test and non-sputum based biomarker test would likely be affordable and cost-effective for most of the high-burden countries, but that other types of diagnostics would require external subsidisation. [36] In addition, current donor funding is largely limited to the public sector of high-burden countries. In many of these countries, however, private sector utilisation is common even among poor populations. [37]

A potential solution to this issue has recently been enacted in India. The Initiative for Promoting Affordable and Quality TB tests (IPAQT, www.ipaqt.org) is a consortium between diagnostic test manufacturers and private laboratories in India. Manufacturers provide public sector pricing to member labs that agree to ceiling prices and quality assessments. [38] This agreement has increased the volume of tests utilised and led to the lowest available private pricing of Xpert tests in the world. [37]

Strong policy guidance

A key component of implementing new diagnostics is policy guidance. Many diagnostics are in the final stages of development and need to be evaluated in real world conditions to assess their technical efficiency. Failure to do so can stall development and prevent uptake of new technologies in the field. Currently, the WHO will issue recommendations based on technical assessments alone, but governments also require feasibility and costing assessments. There have been calls for the WHO to provide programmatic recommendations based on comprehensive assessments of the technical, economic and social potentials of a new test. [39]

  Conclusion Top

Compared to many infectious diseases, TB continues to be a major killer. While new treatments and rapid assays have revolutionised the control of diseases such as HIV and malaria, TB control has only recently benefited from new technologies. Increased investments are necessary to support biomarker discovery, validation and translation into clinical diagnostics. In the meantime, countries with high TB burden will need to improve the efficiency of their healthcare systems, ensure better uptake of new diagnostics and drugs and achieve greater linkages across the TB care cascade. While we wait for next-generation tests, national TB programmes must scale-up the best diagnostics currently available, and use implementation science to achieve the maximum impact.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

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