Blog posts from the Laboratory for Microfluidic Bioengineering
Blog posts from the Laboratory for Microfluidic Bioengineering
What I didn’t know about tuberculosis (TB) after over two years of research on technology development for TB diagnostics
Bonjour… While generally used as a common greeting in French, its usage as the first word of this article is rather symbolic. I spent the last week in Montreal, Canada. It being a city in North America, I had imagined it to be a fully English-speaking city that resembled any other city I had visited in the United States in terms of the language used for communication. I was quite wrong. Montreal is a bilingual French-English city with a heavy bias towards French. All signs at public places are in French and the common form of greeting is Bonjour. This is what I had not known about a North American city after living in North America (the United States) for almost a decade.
It turns out there were many things about tuberculosis I had not known up until the last few weeks, despite having worked towards developing point-of-care TB diagnostic tests for over two years. Being an engineer by training (and at heart), the focus of my research over the past two-and-a-half years has been on technological innovation to assist in the diagnosis of tuberculosis in low-resource settings like those in rural India. The primary domain of my lab’s work is development of novel device design, novel biochemical assays, and their integration. Buried deep in biochemistry and technology, we are generally unaware of many aspects of TB from the point of view of the patient, the clinician, the diagnostic lab, the government’s TB control programs, and policy makers (e.g. the WHO). Recently, I have been very fortunate to get to attend two eye-opening events that have really broadened my perspective on the global epidemic of TB. I have learnt many lessons that technology innovators like us rarely get to learn and I thought it was only fair for me to write an article about them so others like me may benefit from it. But before I begin I would like to thank the organizers of these events, without whose immense efforts these events couldn’t have happened. A 4-day UK-India Joint Researcher Links Workshop on Tuberculosis Diagnostics was organized in Chennai by Dr. Sesha and Dr. Mark Bradley (University of Edinburgh) and Dr. Srikanth Tripathy (NIRT, Chennai). A 3-day course on ‘Advanced TB Diagnostics’ was conducted as a part of the McGill Summer Institute in Infectious Diseases and Global Health in Montreal and was directed by Dr. Madhukar Pai.
Lesson #1: Numbers dehumanize people
In the year 2017, 10 million people around the world became infected with TB and 1.3 million died of it. About a quarter of these deaths occurred in India. Many of us are used to hearing these numbers. I have myself used these numbers on several occasions to convince grant funding agencies about the scale of TB infection and why our research in developing point-of-care TB diagnostics is important. However, none of these inordinately large numbers communicate the agony that every single patient faces in dealing with this disease. Numbers dehumanize patients. In addition, because most of us rarely hear about someone we know contracting TB, we are under the impression that TB is a disease of the poor, restricted to the economically backward class. This is far from the truth. No one is immune to TB – not you, not me, nor anyone else alive. However, TB infection is tabooed enough that people who get it rarely talk about it and because it is often curable, survivors lead a perfectly normal life after getting treatment without ever telling anyone. While in Montreal, I got to meet a few incredible people who not only survived TB but are now strong advocates of raising TB awareness. It was heart-wrenching to hear every single person’s story of how they dealt with TB and came out strong. Guess what, all of these incredibly strong people are from an affluent background, many from western countries.
Lesson #2: National tuberculosis programs
Contrary to what one may think based on the massive TB burden in the world, most countries have very well-planned national tuberculosis programs (NTPs) that provide detailed guidelines to be followed for TB diagnosis and treatment. The current TB control program in India is called the Revised National Tuberculosis Control Program (RNTCP) and was launched in 1997. The RNTCP program has a vision of achieving a “TB-free India” and aims to achieve universal access to TB control services. The program provides free-of-cost high quality diagnosis and treatment services across the country through the government healthcare sector. The RNTCP employs WHO recommendations for TB treatment known as DOTS (Direct Observed Treatment, Short Course). When in Chennai, I got the opportunity to visit both a government primary healthcare center and the National Institute for Research in Tuberculosis (NIRT), one of the six TB national reference laboratories. A common observation at both sites was that there was a very high level of education and competence among all staff members, down to the technicians performing microscopy. The diagnostic algorithm for TB diagnosis was clearly defined and there did not seem to be any ambiguity among the folks who ran the facilities. All diagnostic tests are conducted free of cost to the patient. In fact, the facilities were being run so efficiently and with so much clarity of thought and action that it made me question where the real pitfalls were and why TB continues to be a massive health burden. I had to travel to Montreal to find out.
RNTCP-recommended TB diagnostic algorithm
Lesson #3: The public versus the private healthcare sector
It turns out that one of the major roadblocks in effective TB case finding in any country is the mismanaged and unregulated private healthcare sector. Despite government-run NTPs being well-oiled machines, as many as 60% of all TB patients seek initial care in the private sector in any country. If you live in India, you would not find this surprising – it is but common for most Indians to visit their private practitioner for any ailment. In addition, not many people infected with TB go to the doctor suspecting they could have it so the first point of contact is always the family doctor. Private practitioners may not abide by the NTP guidelines and, in general, have no inclination to refer these patients to DOTS centers. The quality of TB care provided at government-run health centers that follow the NTP guidelines is substantially better than in the private sector. There is a fundamental misalignment between where good TB care is provided and where patients seek care. Why is this the case, one wonders. The reason, as quoted by some patients in a publication by Chakravarty et al, is that even though government-run hospitals provide good care free of cost, there is too much bureaucracy, time delay between tests, and having to “run from one place to another”. Patients have to wait in long queues, at times for an entire day. As a result they often fall back to the private sector where they have to pay for diagnosis and treatment, but things move faster. Just look at the long and winding pathway Bina had to take to seek treatment for drug-resistant TB in Mumbai (see figure below). Bina was made to seek TB treatment from 6 different facilities/providers spanning four and half months, even within the public sector. Despite this conundrum, it is the opinion of global health experts that the private healthcare sector is the single largest roadblock in effective TB case detection and treatment. If we cannot control the private sector, we cannot control TB.
Distance travelled by Bina to access care (Purohit et al)
Lesson #4: Extrapulmonary TB
While Mycobacterium tuberculosis primarily infects the lungs, it can infect any other body part, e.g. bone, brain, spine etc. causing extrapulmonary TB. Simply put, this is one of the largest pain points for TB detection and control because in many cases you don’t know where to look. Patients often suffer for months at a stretch and could undergo unnecessary surgeries before the infection is correctly located and diagnosed. The random and haphazard care-seeking pattern for extrapulmonary TB infections was recently illustrated by Purohit et al (see figure below). There is a dire need for a systemic biomarker of TB infection. A blood test that can report active TB infection in any body part will be a holy grail of sorts.
Care seeking behavior for extrapulmonary tuberculosis in rural and urban settings (Purohit et al,)
Lesson #5: Latent tuberculosis infection
Between a quarter to a third of the world’s population is estimated to be carrying the TB-causing bacteria Mycobacterium tuberculosis. Think about that. Between 25% - 33% of the world’s population is carrying it. However, only 5-10% of those carrying the bacteria will develop an active infection over the course of their lives. The state in which bacteria exist in the host but have not caused an active infection is called latent tuberculosis infection (LTBI). In India, as many as 40% of the population is estimated to have LTBI – that’s almost every other person. In slightly more graphic terms, LTBI is a ticking timebomb. A host of research has been conducted to identify biomarkers for LTBI. In high TB burden countries like India, government programs are so overburdened in dealing with active TB infections that LTBI is often ignored. However, the RNTCP in India does recommend treatment for LTBI in high risk patients, e.g. HIV-infected patients and children of parents having active TB infection. On the other hand, in low TB burden regions like the UK, tests for detecting biomarkers for LTBI are conducted. The silver lining here is that treatment for LTBI is now well established and known to be effective.
Lesson #6: TB versus other infectious diseases
On March 23, 2014, the WHO reported the first case of Ebola virus disease (EBV) in West Africa in what became the largest EBV epidemic in history. Over the following two years, EBV killed 11,310 deaths in Guinea, Liberia, and Sierra Leone. EBV was on the front page of every newspaper globally and diagnosis and treating EBV became the top priority of infectious disease and global health researchers quickly. As of today, several EBV vaccines are in clinical trials. During the same two-year period, TB is estimated to have killed about 2.3 million people – that is more than 200-times the number of deaths caused by EBV. Yet, the global response to the epidemic of TB continues to be lukewarm. Another comparison that is often made is between TB and HIV. During the early 1990s, the deadly epidemic of AIDS garnered global attention. The public response to HIV/AIDS was quite different than that for TB. Several celebrities came forward and announced that they were HIV positive and the disease came into limelight. Famous Hollywood actors made movies related to HIV/AIDS (if you haven’t seen Tom Hank’s Philadelphia, it’s a must watch). The publicity triggered rapid corrective action and HIV has now become a manageable condition with the advent of antiretroviral therapy (ART). TB could really use some celebrity voices to promote its cause.
Lesson #7: Supply chain management
I will only comment on this briefly as my understanding of this issue is limited, but it is clear that this is a very important point pertaining to providing TB care. In addition to failure to diagnose accurately and treat properly, inefficient supply chain management plagues the TB care system. According to Dr. Aubid Allah Khan from Pakistan’s NTP, as much as 26% of losses from the Global Fund are because of supply chain management issues. He specifically mentioned long lead times, short shelf lives, and lack of instrument service engineers as major roadblocks to managing TB in Pakistan. A new organization that I was introduced to in regards to supplying TB diagnostics and medicines is the Geneva-based Global Drug Facility (GDF). The mission of GDF is to facilitate worldwide, equitable access to tuberculosis medicines and diagnostics and it is currently the largest purchaser of TB diagnostic tests worldwide, which it then disseminates to several countries at subsidized rates.
Observations from a technology developer
The lessons above have clearly been eye-opening to me as I had only ever thought of TB from a technology developer’s point of view prior to attending these meetings. An important observation I made during these two weeks was that academic technology developers in the area of TB are very siloed from global health experts in TB and vice versa. For example, a portable paper-based nucleic acid amplification technology for TB diagnostics that I presented at the meeting in Montreal was deemed to be very novel and exciting for TB diagnostics by the community. However, the concept of amplifying nucleic acids in paper has been around for over six years now and my research group recently published a review article about the field. Despite being around for a while, the technology has only been reported for detection of TB in literature once (our publication on this topic, currently under revision at an academic journal, would be the second). The marriage of biology and engineering created the field of bioengineering several years ago. I see a tremendously important role of engineering and technology development in the management of TB and I think we should create more opportunities for engineers to interact with global health experts in TB so that together they could work on ‘global health engineering’ for TB care.