Tuberculosis. The ‘romantic disease’ afflicting artists like Chopin and Keats. Yet if TB remains the quintessential Victorian affliction, it remains a brutal illness even now. According to the WHO, around 1.2 million people died of the disease in 2022, making it more dangerous than AIDS and second only to Covid-19 as an infectious killer. Things are especially stark in the developing world: Gabon, Mongolia and Uganda are just three of the nations to suffer from the scourge of tuberculosis. Once you add the crucial link between TB and HIV, a combination that blights countries like Angola and Chad, and John Bunyan’s evocation of TB as “the captain of all these men of death” still seems apt.
From ethambutol to pyrazinamide, doctors do have a number of antibacterial medications to combat tuberculosis. But before that, they must first identify it – and here the situation is rather more frustrating. Though a range of diagnostic tests certainly exist, slow results, poor performance and false positives are just three problems among many. That, in turn, makes it harder to understand exactly which drugs a patient needs – hardly immaterial when many cases are resistant to first-line treatment.
All the same, the situation is far from hopeless. With new tests capable of detecting genetic particles of the bug responsible for TB – all within just a few hours – doctors are increasingly able to get their charges treated fast. That’s echoed by broader work around when TB tests are administered, with HIV-positive individuals at the front of the queue. In the background, meanwhile, scientists are honing a new range of tuberculosis vaccines, potentially presaging a future where the ailment is stamped out completely.
Conspicuous consumption
To understand why TB diagnostics are so indispensable, you must first appreciate how the illness works. An infectious disease spread through the air, Professor Kogieleum Naidoo emphasises that “shared air spaces” are a particularly effective means of transmission. As the deputy director of the Centre for the AIDS Programme of Research in South Africa explains, simply sharing a meal or a bedroom with an infectious individual can be dangerous, with just four hours of contact heightening the risks considerably. Nor are the risks merely personal. In the first few years after contracting TB, untreated patients are liable to pass on their illness to another eight or ten others.
And if that makes early diagnosis vital, so too is the fact that not all TB is created equal. Encompassing a trio of different stages – exposure, latent and active disease – 5–10% of people infected with the Mycobacterium tuberculosis bug will end up developing full-blown TB. Rapid detection is therefore crucial, particularly for people who are already immunocompromised. As work by USAID shows, the numbers here are clear. If you have HIV, for instance, your weak immune system means you’re 18 times more likely to catch the disease than the general population. All told, around 6% of TB cases are among people living with HIV, while 2022 saw the deaths of 67,000 ‘HIV/TB’ patients.
Given the urgent need for robust TB diagnostics, what tools does the medical profession have at its disposal? Historically speaking, the picture has been mixed. As Naidoo says, doctors long relied on a technique called sputum smear microscopy, whereby a person “expectorates” into a tube, before it’s sent to a lab and tested for traces of TB. The main problem with this approach is time: results will generally only arrive in seven to ten days. In the interim, of course, individuals have ample opportunity to infect their friends and neighbours. Another long-standing tactic involves culture testing, whereby technicians use a sample to grow any TB bacteria that may be present. Though accurate – culture tests offer insights into how infectious you are, and whether your TB is antibiotic resistant – the growing process can take up to eight weeks.
1.2million
The number of people who died of TB in 2022.
WHO
NAAT a bad idea
Given these limitations, it’s no wonder that scientists have rushed ahead with alternatives. For Naidoo, one of the most exciting developments of recent years has been so-called nucleic acid amplification tests (NAATs). An increasing staple of the TB profession over the last decade, perhaps their strongest suit is speed. In the hands of an experienced lab technician, NAATs can offer results in just 90 minutes. As Naidoo continues, that dovetails with their simplicity. Earlier generations of lab-developed assays were labour intensive, both wasting time and risking incorrect results. Nowadays, however, the whole process is done through easy-to-use cartridges, even as result quality remains high. As Naidoo says: “It’s going to tell you whether the organism will respond to the first-line treatment, or require second-line treatment, because it’s a drug-resistant organism.”
Together with more specialised tests like the interferon-gamma release assays – together with old stalwarts like x-rays and stethoscopes – these diagnostic breakthroughs are making a difference in the fight against TB. Once again, the figures here are illuminating. As WHO statistics show, the percentage of people diagnosed with TB based on bacteriological confirmation jumped from 55% in 2018 to 63% three years later. That, in turn, has helped save the lives of millions of people worldwide since the turn of the millennium.
Yet if 2021 alone saw investment in better diagnostics top $1bn, better tests aren’t enough to squash TB. Think of it like this: whatever the advantages of NAAT and its fellows, kits still need to be matched to patients. With that in mind, Naidoo unsurprisingly describes the importance of integrating TB diagnostics into HIV treatment. “It’s been an amazing advancement over the last 15 years that we recognise that HIV and TB are linked,” she says. “If you’ve been diagnosed with HIV, you should be screened for TB at every visit to the healthcare worker.” That’s shadowed, Naidoo adds, by observing for specific symptoms: weight loss, night sweats and fevers are just three hallmarks of tuberculosis, and doctors should assess patients accordingly.
63%
The percentage of people diagnosed with TB based on bacteriological confirmation in 2021, up from 55% in 2018.
WHO
Even if patients ultimately end up testing negative, healthcare workers can still take action. Given, after all, that 25% of the world’s population carries Mycobacterium tuberculosis – even as a far smaller number ultimately develop proper TB – diagnosis can prevent infectious but otherwise healthy individuals from passing the bug on to others. And if that leads Naidoo to advocate for “targeted universal testing” of the population at large, preventative care is increasingly available too. As a recent article in The Lancet explains, a three-month course of weekly rifapentine plus isoniazid, alongside three months of daily rifampicin, can be highly effective here. Naidoo agrees, noting that preventative medication can protect individuals for up to three years.
Vaccine passports
As the talk of pre-emptive treatment implies, diagnostics isn’t the only path to a TB-free future. One of the most interesting areas of work are vaccines. Like in the testing space, researchers aren’t starting totally from scratch. The earliest tuberculosis vaccine, for its part, was developed in France during the First World War. But – just like previous generations of diagnostic tests – these older vaccines aren’t perfect. For one thing, they’re not always very effective. For another, they risk infecting the very individual they’re meant to protect, meaning they’re generally only deployed in countries where tuberculosis is common. Even so, Naidoo remains optimistic. “The TB vaccine landscape is extremely promising,” she says, adding that there are 16 candidates in clinical development, 11 of which are at the trial stage.
Beyond the obvious health benefits, the real strength of TB vaccines once more lies in how the illness functions. With a quarter of everyone on Earth tuberculosis carriers, a safe and efficient vaccine would slash latent transmission at a stroke. As Naidoo says, a jab with an efficacy of just 50% would protect up to 75 million people from tuberculosis between 2025 and 2050, something researchers are edging towards across a range of trials.
Yet, as is so often in the long fight against TB, what’s really needed is a holistic approach. Whatever the benefits of some future vaccine, millions of people will remain vulnerable, both in developing countries, and among HIV sufferers, drug addicts and other immunocompromised groups. Fortunately, there are plenty of signs that diagnostic tests are going from strength-to-strength too. Of particular interest, to quote a recent WHO report, is “targeted next-generation sequencing for detecting drugresistant TB directly from sputum specimens” – in simple terms, giving doctors the ability to understand exactly which drugs are suitable for which patient.
And if that once more hints at the lively interplay between diagnostics and treatment, it makes sense that Naidoo is so enthusiastic for the future of her field. A decade from now, she predicts, we’ll have developed a TB vaccine effective for people living with HIV. More than that, comprehensive tuberculosis screening will have become far more common, cutting new infections and leading to faster care for those already sick. “If,” Naidoo summarises, “we were to just implement some of these strategies, in addition to investing in new technologies, we will certainly break the back of this epidemic.” Given how long we’ve been fighting it, that’s surely a relief.
