**3. MDR TB diagnosis: Clinical versus laboratory methods**

Bacteriological confirmation of TB and Drug sensitivity Testing (DST) of patients presenting with clinical features of Tuberculosis is targeted as universal standard for patient care in TB [1]. When this is incorporated into routine clinical care package and results are available for periodic analysis, it forms a strong database for information about drug resistance in that area.

#### **3.1. Clinical criteria**

WHO global TB report [1] revealed that only 2.8 million (58%) of the 4.9 million incident pulmonary TB patients notified in 2013 were bacteriologically confirmed (smear- or culturepositive according to a WHO-recommended rapid diagnostic such as Xpert MTB/RIF). The remaining 42% notifications were diagnosed clinically (symptoms, signs, chest X-ray abnor‐ malities, or suggestive histology). Notifications of new cases are mainly from the high-burden countries, majority of which are low- and middle-income economies. Their capacity for confirmatory testing and DST is limited. Although almost half of notified global TB diagnosis is by clinical methods, this form of diagnosis is attended by poor specificity and false-positive diagnosis. Low laboratory rates, on the other hand, may suggest underdiagnosis of true TB cases and contribute to the gap noticed between notified and estimated incident TB cases [1]. The need for skilled health care workers who can make presumptive diagnosis to improve notification while laboratory methods are being scaled-up, especially in the high-burden countries cannot be overemphasized.

However, the drawback of clinical criteria alone to make a diagnosis in MDR TB is obvious. Detection of TB without investigating drug sensitivity potentially can lead to inadequate treatment and this could lead to spread of MDR TB.

#### **3.2. Laboratory diagnosis – Screening and confirmatory tools**

isolation and airflow regulation within wards, which made the wards conducive for trans‐ mission between patients in contact with MDR TB cases. There was also notable direct transmission from patients to health care workers, which was evident by Tuberculin Skin Test (TST) conversion as well as later linkage mappings that correlated the strains in the patients'

In the high-burden countries, there are reportedly 20-35.2% of new cases and 54-62% of relapse cases that develop MDR TB, accounting for 82% of all incidences of MDR TB [1]. Thus, high burdens of MDRTB and XDR TB are eventually perpetuated from direct transmission within communities. In cases where TB–HIV coinfections are also prevalent, this significantly favors direct transmissibility [31]. Direct transmission is therefore the most common way drugresistant TB is spread and this must be stemmed to arrest the imminent global health threat

Bacteriological confirmation of TB and Drug sensitivity Testing (DST) of patients presenting with clinical features of Tuberculosis is targeted as universal standard for patient care in TB [1]. When this is incorporated into routine clinical care package and results are available for periodic analysis, it forms a strong database for information about drug resistance in that area.

WHO global TB report [1] revealed that only 2.8 million (58%) of the 4.9 million incident pulmonary TB patients notified in 2013 were bacteriologically confirmed (smear- or culturepositive according to a WHO-recommended rapid diagnostic such as Xpert MTB/RIF). The remaining 42% notifications were diagnosed clinically (symptoms, signs, chest X-ray abnor‐ malities, or suggestive histology). Notifications of new cases are mainly from the high-burden countries, majority of which are low- and middle-income economies. Their capacity for confirmatory testing and DST is limited. Although almost half of notified global TB diagnosis is by clinical methods, this form of diagnosis is attended by poor specificity and false-positive diagnosis. Low laboratory rates, on the other hand, may suggest underdiagnosis of true TB cases and contribute to the gap noticed between notified and estimated incident TB cases [1]. The need for skilled health care workers who can make presumptive diagnosis to improve notification while laboratory methods are being scaled-up, especially in the high-burden

However, the drawback of clinical criteria alone to make a diagnosis in MDR TB is obvious. Detection of TB without investigating drug sensitivity potentially can lead to inadequate

samples with those of the health workers [29].

6 An Overview of Tropical Diseases

from TB.

**3.1. Clinical criteria**

countries cannot be overemphasized.

treatment and this could lead to spread of MDR TB.

**2.3. Implications of transmission versus acquired cases**

**3. MDR TB diagnosis: Clinical versus laboratory methods**

The field of TB diagnosis has been dynamic, changing constantly with the new challenges posed by the bacilli: from being fully susceptible to multidrug therapy to the appearance of MDR TB and now XDR TB. Whereas the need to have accurate bacteriological diagnosis and appropriate drug sensitivity has not changed, the tools to achieve these have continued to evolve as newer and hopefully equally or more effective diagnostic technologies are devel‐ oped. Diagnosis of MDR TB requires culture to confirm TB and drug susceptibility testing or molecular testing. The challenges faced in achieving these include:


Increasingly, molecular technologies are being incorporated into drug resistance surveys to simplify logistics. By 2009, the EXPAND –TB (Expanding Access to New Diagnostics for TB) was launched to accelerate access of MDR TB high-risk populations in high TB burden countries to sophisticated but rapid diagnostic molecular techniques and provide laboratory services. The 27 high MDR TB burden countries were equipped with 97 new or refurbished laboratories and line probe assays (DNA strip test that allows simultaneous molecular identification of TB and the most common genetic mutations causing resistance to Rifampicin and Isoniazid) in reference laboratories which can diagnose MDR TB in two days. By December 2010, the WHO issued a policy on the use of another molecular diagnostic test Xpert MTB/RIF as an initial diagnostic test for cases at risk of MDR TB with negative sputum. The Xpert test, a cartridge-based automated diagnostic test that can identify Mycobacterium tuberculosis DNA and resistance to Rifampicin by nucleic acid amplification technique was a sputum only test for pulmonary TB [32].

A review of WHO policy followed in 2013 that Xpert MTB/RIF should be used rather than conventional microscopy, culture, and DST as the initial diagnostic test in adults and children suspected of having MDR TB or HIV associated TB. It may be used for diagnosis of drugsusceptible TB, smear-negative individuals and cases of extra-pulmonary TB testing using non-respiratory specimens such as lymph nodes. By the end of June 2014, 108 countries had benefitted from procurement of Gene Xpert machines. GenoType® MTBDRplus (Hain Lifescience, Germany) was used in the national survey completed in 2012 in Nigeria and is currently being used in the national survey in Sudan. In Pakistan, Xpert® MTB/RIF (Cepheid USA) identified additional cases missed by culture in the national survey completed in 2014. In ongoing surveys in Papua New Guinea and Senegal, Xpert MTB/RIF is being used to screen specimens for rifampicin resistance and identify those requiring further testing at national or supranational TB reference laboratories. Surveys planned in 2014−2015 in Côte d'Ivoire, the Democratic Republic of the Congo, Indonesia, and Zimbabwe will adopt the same testing algorithm [1].

This approach greatly reduces the workload for laboratories and decreases the cost of national surveys. It may also result in the detection of cases that would otherwise have been missed by culture and conventional DST, particularly in settings with delays in transporting sputum samples to laboratories for testing. Although not a complete surrogate for MDR-TB, particu‐ larly in settings where levels of drug resistance are low, rifampicin resistance is the most important indicator of MDR-TB and has serious clinical implications for affected patients.

It is noteworthy that the supply of these technologically advanced diagnostics though now in more countries cannot serve the total at-risk populations, because these machines are kept strategically in reference laboratories. There is a critical need to develop within each country a framework that would address the accessibility to reference centers. In the Western Pacific and Eastern Mediterranean regions, it is reported that there was less than one reference center per 100,000 population. In Nigeria, a high TB burden country and the fourth highest African country with MDR TB, there are only 9 reference centers which are inadequate for the whole at-risk population of 170 million.

There is therefore need in the high TB burden areas to still supplement the recent high-tech diagnostic tools with sputum smear microscopy as an initial screening tool and as such be placed in such a way that these can be accessible to all. Improvements in microscopy using fluorescent light emitting diode microscopy, which is more sensitive than light microscopy, has been proposed and adopted in South Africa, and less so in Mozambique, Bangladesh, and Nigeria [1].

The other aspect that needs careful attention in laboratory diagnosis is the need for regular quality assurance of the machines. Likewise, regular capacity training for laboratory personnel to ensure optimal standards of diagnosis and DST Xpert MT/RIF Newer areas of research for improved diagnostics is the research for correlates of protective immunity and host biomarkers of TB that could help determine the potential for susceptibility or protection [33].
