By Ritika Sakhuja
New Delhi: Tuberculosis, a bacterium infection that affects the lungs, is a major public health problem in India, with an estimated 21.4 lakh TB cases reported in 2021, 18 per cent higher than in 2020, as per the World Health Organisation (WHO). However, pulmonary TB (PTB), a form of TB that primarily affects the lungs, is the most rampant TB among the detected population.
One of the key tools for diagnosing PTB is sputum diagnostic tests to detect the presence of TB-causing Mycobacterium Tuberculosis (MTB) in the respiratory tract. However, fuelled by increased governmental attention on eradicating TB from India by 2025, coupled with the worldwide interest in eliminating TB by 2030, technological advancements are spearheading the TB diagnostic sector. AI innovations to detect TB through chest X-rays, algorithms that predict TB through breathing sounds, and tests that can detect TB-specific volatile organic compounds in exhaled breath, are slowly taking over the industry.
In the wake of rapid innovations to detect TB, ETHealthworld spoke to diagnostic and TB experts to understand the technological advancement, significance, and the future of testing TB through sputum samples, and why it's still considered the gold standard for diagnosing TB.
Sputum microscopy replaced with the molecular diagnostic test
The most commonly used method of diagnosing TB in India is Sputum Smear Microscopy (SSM). Dr Sohini Sengupta, Medical Laboratory Director, Redcliffe Labs informed that SSM is a low-cost diagnostic test, suitable for low-resource settings. However, the industry has been witnessing a swift shift away from the SSM method as it presents low sensitivity, an inconveniently slow diagnosing process, and a lack of drug resistance detection that often leads to delayed or misdiagnosis.
Vikas Panibatla, CEO, Tuberculosis Alert India (TBAI) informed, “Initially we used to test for TB using a microscope. A lab technician had to see 100 slides to confirm TB. Additionally, it wasn’t useful for identifying multidrug resistance, which is the first major thing that has come up in catalyst-based amplification tests which are being used widely now.”
Another method is the sputum culture, considerably more sensitive than SSM. However, the TB bacteria is an extremely slow-growing bacillus and can take three to six weeks to produce results. To thwart the long time taken for standard sputum tests, the industry is now moving towards rapid diagnostic tests that use molecular technology to detect MTB DNA in sputum samples through pyrosequencing or whole genome sequencing (WGS) and can produce results in just a few hours.
“COVID-19 has increased the awareness of molecular techniques like RT-PCR and WGS in people. There is increased awareness among the doctors regarding the WGS-based test for TB and this is exponentially getting translated into the masses,” said Dr Gunisha Pasricha, Principal Scientist, Infectious Disease Expert, MedGenome Labs.
Experts informed that WGS has revolutionized TB diagnosis in India and aids active case finding. Dr Bornali Dutta, Director, Pulmonary Medicine, Respiratory and Sleep Medicine, Medanta, Gurugram, shared, “The current TB incidence in India stands at 316 per 100,000 people. Active case finding is critical to achieving TB elimination, as it identifies and treats more patients, leading to a reduction in TB incidence and eventually helping people become TB-free."
Dr Shahid Patel, Consultant pulmonologist, Medicover Hospitals, Navi Mumbai shared, “I think that within the next six months to one year, WGS will become the norm for TB testing, which will enable an accurate sputum diagnosis within five to six days, bringing it down from the current time frame of six weeks. Currently, studies are going on to examine its efficacy and safety for commercial deployment. This is something that we pulmonologists are extremely excited about.”
Listing the advances enabled by molecular diagnostic tests, Dr Namrata Jasani, senior consultant pulmonology, Global Hospitals, Parel, Mumbai, illuminated, “The molecular technology TB tests have enabled reports to be made available in as short as a two-hour time frame. The other advantage is that even if the bacillary load is very small, the high sensitivity of these tests can pick it up. The sensitivity of these tests is almost as good as 98 per cent.”
Testing for drug resistance
One major advantage of molecular technology is that it can also rule out multi-drug resistance, which is the biggest problem in India right now. According to WHO, India has the highest burden of multi-drug-resistant TB (MDR-TB) in the world, accounting for nearly a quarter of all cases. In 2020, an estimated 27,000 people developed MDR-TB in India, and an additional 17,000 people developed rifampicin-resistant TB.
In their 2022 study ‘25 years of surveillance of drug-resistant tuberculosis,' The Lancet elucidated that around a quarter of deaths caused by antimicrobial resistance every year across the world, are due to rifampicin and isoniazid-resistant TB. Both these drugs serve as the most widely used first-line drugs against TB, as recommended by WHO.
CDC states that MDR-TB has an extremely expensive treatment that takes a long time to complete, disrupts lives, and has potentially life-threatening side effects, and the average cost of treating a person with drug-resistant TB disease can go up to $568,000.
Experts suggest that WGS may be the answer to this serious debilitation to public health. Since 2011, rapid molecular tests have been crucial for improving access to drug susceptibility testing by enabling decentralised testing that can be done directly using sputum samples. A variety of different tests with a rapid turnaround time are now available, ensuring earlier detection and initiation of appropriate treatment.
Dr Sengupta added, “Early detection is the key to effective management of MDR-TB. The easy method of collecting a sputum sample, along with the rapid results of a sputum molecular test aids early diagnosis of drug-resistant TB.”
“WHO has recognized that WGS has great potential for rapidly diagnosing MDR TB in diverse clinical settings. However, the uptake of this technology particularly in low and middle-income countries has been hampered by the high costs of the equipment and the requirement for technical training. As recently as September 2021, WHO has released a catalogue of mutations associated with MDR TB and we think this is the first step towards endorsement of a WGS-based test for MDR-TB,” said Dr Pasricha.
Sputum culture vs Chest-X Rays
Chest radiography is another important tool for screening for PTB, and it is also useful to aid in diagnosis when PTB cannot be confirmed bacteriologically. Testing for TB through chest X-rays (CXR) with the use of Artificial Intelligence is gaining momentum as a primary tool, establishing the role of radiology when bacteriological tests cannot provide a clear answer.
Additionally, the efficacy of a sputum test really depends upon the quality of the sputum that the patient is producing. Many times, even with a proper CXR showing lots of lesions in the lungs, the patient may still not be producing any sputum. Moreover, the sample has to be taken at a specific time when it is not contaminated with food or something else. This often discourages a patient from going for a sputum test, so doctors often have to start the treatment on the basis of the CXR. This poses a problem as Sriram Natarajan, Founder, Director, and CEO, Molbio Diagnostics, pointed out that TB continues to remain a major social stigma, hence more efforts are needed to bring all TB patients into the program and create awareness.
“The prevalence and existence of TB have been the same for many years. The incidence of fresh cases is somewhere around 1 per 1,000 of the population. We see at least 10-15 patients a week (1-2 cases per day) at the hospital,” added Dr Ashok K Rajput, Consultant, Pulmonology & Sleep Medicine, CK Birla Hospital, Delhi.
“When we consider mass testing, collecting sputum samples is very difficult, as we need to get the right sample of sputum which should not include blood or saliva. Additionally, it also has less stigma compared to the other tests. So it will be easier for the patient as well as for the health worker in terms of convincing the patients to get tested before it's too late,” informed Panibatla.
However, access to high-quality radiography is limited in many settings. Experts believe that to enable an early diagnosis to potentially close the TB case-detection gap in India, CXR in combination with laboratory-based diagnostic tests when used as part of algorithms within a framework of health-system and laboratory strengthening is the way to go.
“An X-ray cannot differentiate between active tuberculosis and tuberculosis which has already been treated. Often, in spite of taking the best possible medications, some patients do not complete the entire treatment, so they can have residual scars on the lung, which will be seen as opacity on the X-ray. This can be a useful screening tool, but still, there is a need for further evaluation,” said Dr Patel.
Recommending a screening test Natrajan said, “Chest X Rays have high sensitivity but are likely to pick false positives due to lower specificity and hence recommended as a screening test. Molecular tests using sputum samples remain the most accurate way to diagnose TB.”
Experts agreed that although sputum molecular diagnostic tests are generally more expensive and require specialised equipment and trained personnel to perform, which may limit their availability in certain settings, their higher sensitivity enables more accurate detection and comprehensive information on TB infection and drug resistance, making it the gold standard in TB testing.