In a large country like India with a population of more than 1.4 billion, access to quality healthcare continues to pose an enormous challenge for the masses.&nbsp;The paucity of &nbsp;hospital beds, lack of paramedical staff, &nbsp;broken supply chains, dearth of trained epidemiologists, and shortage of medical supplies during the Covid-19 crisis exposed our grossly inadequate public healthcare systems like never before. On the flip side, however, it also resulted in some breakthrough medical interventions. Under normal circumstances, vaccine development would usually take anywhere between 10-15 years, but India was swift to respond to the situation and scaled up its efforts by developing covid vaccines in less than a year, highlighting the ability of our healthcare community to achieve impossible targets through integration and collaboration.While we found ourselves in dire straits due to the rampant spread of the novel coronavirus, the pandemic has derailed us from the path to fight many other diseases that could impair our healthcare systems, if not addressed in due time.Tuberculosis, a bacterial infectious disease that directly affects the lungs, has been a subject of concern worldwide and affects millions of people across the country. India reports an alarming chunk of about 3 million TB cases every year, with a mortality number of almost half a million in 2019. In 2020, India alone accounted for 26% of the TB cases across the globe. In addition to this, there are more than a million &lsquo;missing&rsquo; cases every year that go unreported because they largely remain undiagnosed or inadequately diagnosed. The Global Tuberculosis Report published by the World Health Organization (WHO) &nbsp;in October 2021, revealed that the Covid-19 pandemic and its impact on our healthcare systems had &lsquo;reversed years of progress in providing essential TB services and reducing TB disease burden.&rsquo;&nbsp;The National Strategic Plan (NSP) 2017-2025 formulated by the Govt. of India, is a flagship public health initiative built on the success and learnings of the last NSP and serves as a comprehensive framework for all the stakeholders who are working towards eliminating TB from India. The plan proposes the adoption of bold strategies coupled with the availability of resources to realize its vision of a &lsquo;TB free India&rsquo; by 2030, in line with the UN Sustainable Development Goals (SDGs).While India has been making consistent efforts to ramp up its services by treating more than 10 million TB patients under RNTCP, we are far from meeting the 2030 SDGs and 2035 End TB targets. Inadequate diagnosis and treatment, outdated and ineffective diagnostic tools like sputum-smear microscopy, and multidrug resistant tuberculosis (MDR TB) which account for about 1% of new TB cases; continue to be some of the major challenges in controlling the spread of TB. &nbsp;In addition to this, regulating and monitoring the spread of TB is a Herculean task in a densely populated country such as ours, and the ongoing pandemic has further aggravated the situation by diverting the majority of our healthcare staff and diagnostic services towards Covid management.&nbsp;Recent research indicates that 75% of MDR TB cases globally were not treated accurately and contributed to active transmission of MDR TB in the community (Farhat et al 2019). In some sense, as the world is effectively treating drug susceptible forms of TB, the community transmission of drug resistant forms can snowball into a difficult to treat epidemic.&nbsp;This poses a crucial question before us: How can we effectively combat the spread of tuberculosis and mitigate the damage caused to our healthcare systems? Although prior techniques have had limited impact in controlling the spread, comprehensively-deployed interventions based on the four strategic pillars of the &lsquo;Detect-Treat-Prevent-Build&rsquo; (DTPB) model can allow us to design and to bring about a rapid transformation in the prevention and treatment of tuberculosis.<h3>A case for Whole Genome Sequencing&nbsp;</h3>For several years, clinical microbiology heavily relied on the use of conventional phenotypic and genotypic methods for the identification and treatment of infections. Not only are these methods extremely time consuming and expensive, the lack of technological infrastructure has also prevented us from distinguishing highly genetically related strains. The need of the hour is to build solutions that are affordable and accessible and can revolutionize TB diagnostics while facilitating personalized drug therapy by employing a decentralized approach to diagnosis and treatment.&nbsp;Whole genome sequencing (WGS) is a technique that allows us to determine the entirety of an organism&rsquo;s DNA in a cost-effective way through a single comprehensive test. The use of WGS technology for the diagnosis of tuberculosis has been gaining traction across the world as it enables an &lsquo;all-in-one&rsquo; approach by providing epidemiological data and comprehensive information on genetic background and expected sensitivity of the strains.While the use of Whole Genome Sequencing (WGS) for the treatment of tuberculosis has been deployed in countries such as the UK, Spain, &amp; Italy, there have been little efforts to expand the scope for this approach in India where we have merely laid the groundwork for its use.Given the tremendous success of WGS based prediction of drug resistance in a single step, national programs must consider a change in strategy, moving away from sequential in vitro diagnostics, to large scale comprehensive screening using WGS.&nbsp;These platforms are &nbsp;cost effective and can provide unprecedented asset utilization, wherein each installation can perform &gt;600,000 tests per year. Tentatively, 10 such installations can effectively cover the entire estimated TB caseload of India, at a cost comparable to current CBNAAT tests. Consequently, only a very small select number of cases will need culture DST to resolve outcome based discrepancies.&nbsp;The expansion of genome sequencing based tests in India, which are extremely cost effective and provide comprehensive information in a quick turnaround time of less than 12 days, will enable us to combat diagnostic inaccuracies and delays that impede appropriate drug administration. By investing in sequencing technologies and ramping up the infrastructure and expertise for &nbsp;genome based tests, we can create a unique opportunity by establishing it as the gold standard in TB diagnostics and provide accessible healthcare to the masses; an attempt to truly revolutionize and re-envision the future of healthcare in our country as we strive to achieve our 2025 end TB targets. &nbsp;

Data Scientist working on Genomics and Metagenomics, with special focus on Infectious diseases, Virology and disease epidemiology

Can India eliminate Tuberculosis by 2025: A roadmap for inclusive diagnostics

&lsquo;So much done; yet, so much to achieve!,&rsquo; Tuberculosis (TB) is still looming as a major global concern, being the 2nd leading infectious killer after COVID-19 (above HIV/AIDS). Almost 1.5 million people lost their lives to TB in 2020 and an estimated 10 million fell ill worldwide; including 5.6 million men, 3.3 million women and 1.1 million children. Individuals infected with TB bacteria, have a 5-10% lifetime risk of falling ill with TB, and immunocompromised individuals (people with HIV, malnutrition, diabetes, or using tobacco) have greater risk of contracting the disease [1].More than 95% of the cases and higher mortality are witnessed in developing countries, affecting people of all age, reducing the productivity of the nation. India leads amongst the countries accounting for 2/3rd of the global TB cases, followed by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa. Growing Multidrug-resistant TB (MDR-TB) cases have only increased the disease burden worldwide [1]. These patients do not respond to isoniazid and rifampicin (the 2 most-effective first-line anti-TB drugs). Treating MDR-TB is complex and quite expensive, primarily due to its association with important adverse events in patients. The success rate of treatment lowers from 83% in patients having newly diagnosed or relapse non-DR-TB receiving first-line therapy to 54% in MDR-TB patients, to 30% in extensively DR-TB (XDR-TB- showing resistance to at least one fluoroquinolone and one second-line injectable agent) patients [2].&nbsp;Early and comprehensive detection of TB and MDR-TB is the call of the hour and over the recent decades, many techniques have been devised to tackle this issue. The gold standard for TB diagnosis is culture &ndash;drug sensitivity test (CDST); however, due to its time-consuming nature, several major alternatives were devised like line-probe assays, real-time PCRs, GenXpert (Xpert) [2]. The line-probe assays, although simple, quick and easy-to-perform, requires expensive equipment, whereas real-time PCRs despite of lesser contamination chances and rapid results, require specific equipment and skilled technicians [2]. Xpert MTB/RIF, which is a rapid molecular-based test endorsed by WHO, based on cartridge-based assay has revolutionized the TB diagnosis and can detect MTB complex and RIF resistance, using semi-quantitative nested real-time PCR for amplifying hotspot region of the rpoB gene. It has remarkable sensitivity (100%) and specificity (99%) for smear-positive samples and 67% sensitivity and 99% specificity for smear-negative samples, as compared to CDST. Xpert has been very valuable in tackling TB burden in low- and middle-income countries, with turnaround time (TAT) being &lt;2hours [2] , with Xpert Ultra, adding more value, thereby increasing the sensitivity, especially in paucibacillary TB including tuberculous pleurisy, tuberculous meningitis and paediatric TB [3] as well as in pulmonary and extra-pulmonary TB [4]. XpertUltra is a 10-channel upgradation of classic Xpert MTB/RIF, with information regarding second-line injectable drugs (SLIDs) and 98-100% specificity[5] however most of the SLIDs are not recommended in the current treatment protocols longer. Despite these advantages, mutations linked with isoniazid resistance could be missed by Xpert and thus warrants other tests CDST for confirming. The higher cost also makes it unaffordable in many high-burden countries, along with need for constant electric supply and sensitivity to heat and dust adding to the challenges [2].Some of these issues can be effectively addressed by using sequencing technology, especially next generation sequencing (NGS), which can rapidly analyze the entire genome, allow species identification, screen all mutations, detecting drug resistance and predicting evolution of organism. Whole Genome Sequencing (WGS) screens the entire genome using high-end sequencing technique, spanning entire genome, to trace the culprit gene/mutation causing TB or drug resistance. It is more advantageous, as it gives greater genome coverage (not only the target region), &nbsp;increased epidemiological information and understanding of new resistance mechanism for both existing and novel drugs [2]. WGS can assist in efficient prediction of treatment outcomes and resistance profiles of all anti-TB drugs in a single run with rapid results [6]. Poly-microbial infections (mixed and co-infections) can cause misidentification of strains and underestimation of disease transmission, resulting in poor treatment outcomes [7]. Susceptibility profile of drugs like pyrazinamide can be achieved with WGS, which can help in shortening the treatment regimen. WGS can provide high resolution in investigating disease transmission outbreaks, influence early decision of optimum drug therapy and improve patient outcomes [8]. WGS was found to be 7% more cost-effective and consistent in performance as compared to DST [9, 10]. &nbsp;With the advent of WGS, there has been a revolutionary change in TB diagnosis, which can facilitate rapid and timely diagnosis and thereby appropriate treatment for the patients. Disruption in the transmission outbreaks can speed-up the path towards TB elimination, a goal definitely nurtured by all!Reference:<ol><li>W.H.O. Tuberculosis. 2021.[Internet]. https://www.who.int/news-room/fact-sheets/detail/tuberculosis.&nbsp;</li><li>Nyugen TNA, Anton-Le Berre V, Ba&ntilde;uls AL, Nguyen TVA. Molecular Diagnosis of Drug-Resistant Tuberculosis; A Literature Review. Front Microbiol. 2019 Apr; 10: 794. &nbsp;201. doi: 10.3389/fmicb.2019.00794.</li><li>Jiang J, Yang J, Shi Y, Jin Y, Tang S, Zhang N, et al. Head-to-head comparison of the diagnostic accuracy of Xpert MTB/RIF and Xpert MTB/RIF Ultra for tuberculosis: a meta-analysis. Infectious Diseases. 2020;52(11): 763-775. http://doi.org/10.1080/23744235.2020.1788222.&nbsp;</li><li>Zhang M, Xue M, He J. Diagnostic accuracy of the new Xpert MTB/RIF Ultra for tuberculosis disease: A preliminary systematic review and meta-analysis. Int J Infect Dis. 2020; 90:35-45. doi: 10.1016/j.ijid.2019.09.016.</li><li>Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, et al. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infect Dis. 2021; S1473-3099(21)00452-7. doi: 10.1016/S1473-3099(21)00452-7.</li><li>He G, Chen X, Chen J, Zhang W. Prediction of treatment outcomes for multidrug-resistant tuberculosis by whole-genome sequencing. Int J Infect Dis. 2020 Jul; 96:68-72. doi: 10.1016/j.ijid.2020.04.043.</li><li>Advani J, Verma R, Chatterjee O, et al. Whole Genome Sequencing of Mycobacterium tuberculosis Clinical Isolates From India Reveals Genetic Heterogeneity and Region-Specific Variations That Might Affect Drug Susceptibility. Front Microbiol. 2019 Feb 26; 10:309. doi: 10.3389/fmicb.2019.00309. &nbsp;</li><li>Katale BZ, Mbelele PM, Lema NA, Campino S, Mshana SE, Rweyemamu MM, et al. Whole genome sequencing of Mycobacterium tuberculosis isolates and clinical outcomes of patients treated for multidrug-resistant tuberculosis in Tanzania. BMC Genomics (2020) 21:174 https://doi.org/10.1186/s12864-020-6577-1.&nbsp;</li><li>World Health Organization. Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis. 2020.</li><li>CRyPTIC Consortium and the 100,000 Genomes Project, et al. Prediction of susceptibility to first-line tuberculosis drugs by DNA sequencing. N Engl J Med. 2018 Oct 11;379(15):1403-1415. doi: 10.1056/NEJMoa1800474.</li></ol>

Tuberculosis (TB) is still looming as a major global concern, being the 2nd leading infectious killer after COVID-19 (above HIV/AIDS).

Current scenario of TB diagnosis and what the future holds?

Medical Tourism or Health Tourism has been gaining precedence across the world, and an increasing &nbsp;emphasis on individual wellbeing, high-quality affordable medical services, and &nbsp;easier cross-border travel, has led India to become a popular hub for overseas patients.&nbsp;It is no revelation that over the past few decades, India&rsquo;s medical sector has grown by leaps and bounds due to its highly skilled medical specialists and staff, advanced medical infrastructure and facilities powered by emerging technology, and low-cost treatment options.&nbsp;Both public and private healthcare players, supported by the government and favourable National Health policies, have led the country to realize its potential to grow as the hub of medical tourism. India&#39;s efforts to &nbsp;supply vaccines to many countries across the world in the aftermath of the Covid-19 pandemic, has &nbsp;also furthered our vision of &nbsp;becoming &lsquo;One Nation, One Health System&rsquo;.While global medical tourism, valued at USD 4.0 billion in 2021, &nbsp;is expected to grow at a compound annual growth rate (CAGR) of 32.51% by 2030, India is making relentless efforts to ramp up its healthcare infrastructure and medical &nbsp;services to meet the growing demands of the changing world.<h3>What makes India a preferred destination for Medical Tourists&nbsp;</h3>With relaxed visa norms and a huge influx of patients from countries like Bangladesh, Kenya, Iraq, Oman, Tanzania, Nigeria, Afghanistan, Maldives etc, &nbsp;the country has witnessed &nbsp;over 40% growth in Foreign Tourist Arrivals (FTAs). The number of tourists visiting on medical visas has increased from 495,056 in 2017 to almost 697,000 in 2019. The reasons for the growing popularity of India as a medical hub are manifold. Unlike most developed countries like the U.S which have extremely high treatment costs, quality healthcare services in India can be obtained at a cheaper rate. Since many patients cannot afford to pay for medical insurance in their own countries, &nbsp;travelling to India to obtain medical services allows them to avail world class medical services at almost 50% less rates. This helps patients with chronic medical conditions who have to wait for longer durations to avail medical services in their native countries, gain access to prompt treatment at reasonable costs.&nbsp;The availability of world-class amenities and renowned doctors who are pioneers in their fields has also been a major enabling factor in India&rsquo;s growing popularity as a preferred destination for overseas patients. Lakhs of patients visit India every year to avail medical treatment, especially in the departments of cardiology, neurology, and orthopaedics. Treatments for cardiovascular diseases, eye surgery, hip replacement, kidney ailments etc are among the &nbsp;most commonly sought after treatments by foreign patients.&nbsp;Given that almost 70% of today&#39;s medical decisions are based on laboratory results, the availability of CAP and NABL accredited diagnostic labs equipped with state-of-the-art technology &nbsp;to generate rapid results, has also enabled these patients to opt for specialised surgical treatments &nbsp;and other forms of medical care in the country. These factors also play a crucial role in minimising unnecessary expenditures for medical tourists, by reducing the overall duration of their stay.<h3>How Genomics can be the game changer in India&rsquo;s Medical Tourism expansion strategy</h3>As India strives &nbsp;to become the leader in global healthcare delivery, it can only be made possible when we expand the use of technological advancements and next generation sequencing techniques like Whole Genome Sequencing (WGS) to provide correct treatment options for patients. &nbsp;The success of the Human Genome Project, a 13 year long project aimed at determining the DNA sequence of the entire human genome, has enabled scientists and researchers to identify advanced techniques and tools to deliver new age precision diagnostics.&nbsp;It is integral to remember that while the country gains popularity as the preferred destination for medical tourists, our priorities should first be targeted at meeting the &nbsp;clinical needs and demands of our &nbsp;own population of &nbsp;over 1.38 billion. The use of &nbsp;Whole Genome Sequencing &nbsp;(WGS) &nbsp;can help improve not just curative healthcare delivery for overseas patients, but also help adopt &nbsp;preventive health care practices &nbsp;for the masses. &nbsp;The use of Whole Genome Sequencing can be especially effective for treatments in oncology, pharmacology, &nbsp;genetic disorders, infectious and rare diseases. Given that the multiple test paradigm is experimental and ineffective with almost 68% patients going undiagnosed, patients no longer need to depend on &nbsp;time consuming tests to access accurate results for a range of medical conditions. &nbsp;With the availability of the Universal Infectious Diseases test in India that deploys Next Generation Sequencing technology, anyone suffering from a fever or infection of unknown origin can gain access to a single test that gathers genomic data to identify existing and emerging infections. &nbsp;By estimating health parameters such as lifetime risk of a disease, responses to drug and adverse reactions, genomic tests can prove to be effective screening tools for such patients and help the medical staff identify and manage existing conditions and symptoms by &nbsp;designing strategies that can reduce disease risk and delays.&nbsp;With costs that are almost 60-80% lower than their own countries, both medical tourists and native patients can benefit immensely from such cost effective and prompt medical treatment options, which were hitherto unavailable. As we expand the use of Whole Genome Sequencing in India, we can not only allow for greater detection of health problems for the masses, but also generate genomic information that can aid the translation of applications to design targeted therapeutic strategies for medical tourists.Genomics can pave the way for new age precision medicine, as India caters to the needs of overseas patients, by providing them high quality, timely and accurate treatment, while reducing their exposure to avoidable drug toxicity. &nbsp;

How India can emerge as a hub for Medical Tourism with Next Generation Sequencing

Clinicians worldwide rely heavily (almost 70%) on the laboratory results, for diagnosing the illness, recommending the appropriate treatment and follow-ups. Hence it becomes an onus on laboratorians like us, to give an early and precise diagnosis. With highly infectious diseases like Tuberculosis (TB), it is all the more important to diagnose the patient at the earliest, for initiating appropriate treatment, thereby breaking the chain of spread.&nbsp;Despite remarkable advances made over the recent decades, to control this debilitating and life-threatening disease, gaps still exist in its complete eradication. Approximately 3 million people with TB are deemed &lsquo;missing&rsquo; due to under-diagnosis and under-reporting to national TB surveillance programs. In order to achieve the goal of TB eradication by 2030, the World Health Organization (WHO), appeals to trace these missing millions. The picture is more complex, due to the emergence and rapid spread of multi-drug-resistant TB (MDR-TB) strains. &nbsp; Being a laboratorian, we always strive to give the required diagnostic information by developing and utilizing tests with high sensitivity and specificity. Sensitivity of a test is the probability (in percentage) that the sample tests positive given the patient has the disease, whereas specificity is the ability of the test to detect a true negative case. Initially the diagnosis of TB was mostly carried out by smear microscopy and imaging techniques which were not as effective as the gold-standard culture drug- susceptibility test (DST). However, DST being time-consuming, molecular assays which are based on the DNA (genetic material) isolated from the TB bacilli like line probe assay (LPA) and GenXpert, TruNAATs and sequencing were introduced in the recent decades. GenXpert, a revolutionary method, facilitated in rapid detection of presence of TB causing pathogen Mycobacterium tuberculosis (MTB) and also identified the presence of rifampicin drug resistance. However, since MTB managed to acquire resistance towards other drugs other assays such as LPA were utilized as it could detect the resistance towards first-line and second &ndash;line anti-TB drugs. The LPA&rsquo;s are based on binding of the mycobacterial DNA to probes which were specific to certain regions only and so there was always the possibility of missing some resistant strains which were harbored in the patient. Taken as a whole, these diagnostic tests though very sensitive and specific, lacked completeness and thus have limited use. Over the period, the TB pathogen still manages to evolve resistance towards most of the drugs being used against it and this poses a great dilemma to the laboratorians as well as the clinicians, not to forget the patients dealing with it first-hand! These issues led to the introduction of sequencing method into TB diagnosis.&nbsp;What do we know about sequencing?Since the discovery of DNA, way back in 1953, research and diagnostic fields have progressed immensely. The nucleotide sequence of DNA often called the alphabet of life (adenine, guanine, cytosine, thymine) carries the information regarding the gene, that can give better understanding of its functions. Any change from the normal sequence, gives rise to mutation and these occurring in the MTB genome, causing emergence of various drug-resistance. Identifying these mutations is vital for understanding how the disease progresses. &nbsp; &nbsp;The most recent development in sequencing method called as next generation sequencing (NGS), which is based on the same premise of DNA sequencing albeit in a high through-put manner (that means it can sequence several genes as well as several samples at the same time) has rapidly moved into our laboratories.&nbsp;NGS can facilitate rapid diagnosis compared to the traditional practices and provide detailed and accurate sequence information. Using this technology, the entire genome of the Mycobacterium or the whole genome can be scanned to look for mutations in all the genes through which the TB drugs act (WGS is used as an acronym for whole genome sequencing). &nbsp;WGS can rapidly and comprehensively identify the culprit and the underlying drug-resistance mechanism for both existing and novel drugs and that too in a single run! Since the entire DNA is being sequenced, the WGS also gives me really important information if there are more than one pathogen known as co-infection or if there are two different types of the Mycobacteriun strain itself (mixed infections) and it could be that one of them is sensitive and one is resistant in the same individual. Some of the previously mentioned tests are unable to pick this and often can result in poor treatment outcomes as optimally effective drug will not be given to this individual. &nbsp;As a laboratorian I now rely on TB-whole genome sequencing to give rapid, comprehensive, detailed diagnosis and drug resistance profile. &nbsp;This way I am contributing to achieving our goal to ENDTB soon and I foresee this reality as more and more laboratories are adopting this technology to give crucial information about drug resistance in TB patients.&nbsp; &nbsp;

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