Technological advances in TB diagnostic tools hold promise

Today is World TB Day. Tuberculosis has been a scourge of humankind since ancient times. There is hardly any other disease that has inflicted so much misery in terms of suffering and morbidity.

Unfortunately, India today has the largest population of TB patients in the world, with an estimated 2.2 million new cases getting registered annually. Thousands die every day in the country due to this disease.

The emergence of drug-resistant TB is compromising efforts to control the global epidemic. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) develop when the long and complex anti-TB drug therapy is improperly administered, or when patients stop taking their medicines before they are fully cured.

The WHO recommends that for the therapy to be effective, TB should be treated by a combination of four drugs. MDR-TB is defined by resistance to two of the most commonly used drugs in the four-drug (or first-line) treatment, namely, isoniazid, rifampicin, ethambutol and pyrazinamide. XDR-TB is emerging as an even more worrying threat. It is defined as a strain of disease that is resistant to any Fluoroquinolone and to at least one of the three injectble second-line drugs (capreomycin, kanamycin, and amikacin), in addition to isoniazid and rifampicin. This makes XDR-TB treatment extremely complicated, especially in resource-limited settings such as India.

The challenges in controlling tuberculosis in India span the entire spectrum, from diagnosis to detection of drug resistance to treatment. Luckily, recent years have witnessed new, more effective diagnostic tests for Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to combination medications. Both non-molecular and molecular assays have been developed. The former are mostly modifications of conventional methods, with the primary goal of providing more rapid test results.

With the ban on serological test for TB, the recent past has seen the introduction of many new WHO recommended diagnostic technologies starting with the liquid culture in 2007. The use of liquid culture has shortened the time required for detection of bacteria. The methods that employ liquid media like MGIT 960 are widely accepted.

Drug vulnerabilityOnce the probability of diagnosis of TB has been established, an early result on drug vulnerability is important for successful treatment of patients, particularly when it shows resistance to one or more drugs. The  `LJ’ medium needs about four weeks to provide results, which is quite high for a TB patient.

There are other concerns too. Since this medium is made in a laboratory, there is less standardisation and quality control. The prolonged incubation period may result in loss of potency of drugs. Further, the lack of standardisation in methodology and definitions of resistance used may cause errors in the interpretation and validity of results.

It is obsolete now. Molecular methods are also gaining popularity in the diagnosis of TB by directly detecting bacteria in the specimen. With the help of these, a large number of specimens can be processed at the same time, ensuring standardisation and quality assurance due to automation of methodology. Recently, a cartridge-based nucleic acid amplification technology called GeneXpert was introduced in India.

It is a rapid, two-hour DNA test endorsed by WHO which can diagnose TB with great accuracy. It can also detect cases with drug resistance to Rifampicin. However, the need for testing other drugs for confirmation of MDR and diagnosis of XDR still remains.

The only test that can detect resistance to all major TB drugs is the culture-based drug susceptibility test and liquid culture- based test which definitely yield faster results compared to solid culture based drug tests. Even with the introduction of molecular and other techniques, this test is going to remain in use for a long time due to its accurate detection of both MDR and XDR TB. It is known that about 40-60 per cent of culture positive specimens are smear-negative.

This means that if `AFB smear’ is used for diagnosis of TB, a large number of patients would be missed. These have less than 10,000 bacteria per ml of specimen and are considered less infectious.

The currently available technologies are not mutually exclusive. Molecular line probe assays and select non-commercial culture and Drug Susceptibility Testing (DST) methods are suitable for direct application on smear-positive specimens only. The culture capacity is still required for smear-negative specimens, while DST capacity is needed to detect XDR-TB.

The culture-based DST methods offer an interim solution, especially in resource-constrained settings. GeneXpert may be used as the initial diagnostic test for individuals, while culture and DST may be utilised at lower levels of health service for monitoring of treatment and diagnosis of resistance other than rifampicin, prevalence surveys and drug-resistance surveillance. The implementation of new technologies for TB should be decided by the health ministries of states in the context of national strategies.

Extraordinary medical advances over the last decade have had major clinical impact on improving TB diagnosis and early identification of drug-resistant TB. Early identification of TB and the institution of therapy-based on susceptibility in laboratory drug-resistance assays can lead to improved survival. This combination of rapid accurate diagnosis and correct treatment is the root of all successful TB programmes and public health strategies in the world. 
(The writer is head, division of clinical microbiology and molecular medicine at AIIMS, New Delhi)