Grew up in India, which took decades of time. Millions of tuberculosis cases occur every year, Lalita Ramakrishnan knew all too well how devastating this disease could be. The world’s biggest infectious killer, comparable to SARS-CoV-2. Mycobacterium tuberculosis It spreads through the air, infiltrating the airways and often destroying the lungs. It can also cause inflammation in other tissues and wear down bones and joints. Ramakrishnan witnessed this erosion of his mother’s body. The only available vaccine has been lackluster. Microbes have rapidly evolved resistance to the drugs used to fight them. And the disease had a particularly insidious character. Once inside the body, the bacteria can stow away for years or even decades, before causing a full-blown illness without warning.
This condition, called incubation, is thought to have affected around 2 billion people. quarter of the world’s population. Ramakrishnan, now a tuberculosis researcher at the University of Cambridge, has heard that fact many times and passed it on to his students. That was what all the experts at the time did according to established theory. This group of 2 billion people is thought to account for the majority of the world’s infections and is one of the most formidable obstacles to eradicating the disease. To end tuberculosis for good, it was thought, the world needed to find and treat every potential case.
In the years since then, Ramakrishnan’s stance on latent tuberculosis has changed considerably. Over the last 30 years, she argues, the extent of this has been exaggerated by at least an order of magnitude, confusing priorities, leading scientists to wild bird chases, and needlessly subjecting people to tedious treatments that take months. It got to a point.In her view, the term latency It’s so useless and full of misinformation that it should go away. “I taught that nonsense forever,” she told me. She’s now spreading the word that tuberculosis’s biggest and most gaudy numbers may actually be its biggest and most persistent myths.
Ramakrishnan is not the only one who thinks so.Along with her colleagues Marcel Bear of McGill University in Quebec and Paul Edelstein of the University of Pennsylvania (“We call ourselves the Three BERs,” Ramakrishnan said) ,she long crusade to set a record straight. Their promotion attracted a significant proportion of supporters and opponents. “I don’t think they’re wrong,” Carl Nathan, a tuberculosis researcher at Cornell University, told me. “But I’m not sure they’re right.”
Several researchers have told me that they generally agree with the basic premise of the BER argument. Less than 2 billion It’s not that hard to get behind. But how little is important. If your current latency estimates a small amount of overshoot, no practical changes may be necessary. However, the greater the overestimation, the more treatment recommendations may need to be changed. Further reprioritization of research and funding may be necessary. Plans to control, eliminate, and ultimately eradicate the disease may need to be completely and permanently reconsidered.
Confusing numbers about wait times appear to be based primarily on incorrect assumptions about specific TB tests. One of the main ways to screen people for this disease is to prick the skin with a harmless bacterial derivative and wait for an inflamed lump to appear. This indicates that the immune system is familiar with the microorganism (or the TB vaccine) but is not. This is direct proof that the bacteria themselves exist. That is, the only thing that can guarantee a positive result is that the immune system encountered something similar to her MTB. at some point-Maybe it was a long time ago, epidemiologist Laine Hoven of the London School of Hygiene and Tropical Medicine told me.
But for a long time, researchers believed that all tuberculosis infections had the potential to last a lifetime, Behr said. The idea wasn’t entirely far-fetched. Other microbial infections can be lifelong, and there are historical reports of persistent MTB infections, including cases in which men developed tuberculosis. over 30 years after his father passed the germ on to him. Following the logic that those who were infected before are likely to be infected now, the researchers added everyone who is still reacting to this bug to the group of people actively fighting this bug. Did. By the end of the 1990s, Behr and Hoeven told me, a prominent epidemiologist had used this premise to arrive at a large figure of 2 billion, estimating that: Approximately one-third of the population An MTB was lurking inside.
Once its eye-catching appearance took root, it quickly spread.that repeated in textbook, academic paper lectures and news articles, press release, government websiteflat Official treatment guidelines.of who I parroted that too.has repeatedly called for research into vaccines and treatments that could reduce the world’s large latent tuberculosis population. “We were all taught this doctrine when we were young researchers,” Soumya Swaminathan, former chief scientist at the WHO, told me. “Each generation passed it on to the next.”
But it makes little sense that tuberculosis is a life sentence, as the BERs claim. Decades of epidemiological data show that the vast majority of illness occurs within the first two years after infection, most commonly within a few months. Beyond that, progression to symptomatic, contagious disease is unlikely.
The trio is confident that the majority of people are clearing this bug from their bodies rather than leaving it there indefinitely.Concepts supported by recent modeling studies. If the bacteria persisted, researchers would expect to see a surge in illness later in life as the immune systems of people with positive skin tests naturally weaken. Furthermore, the rate of progression to full-blown tuberculosis is expected to be higher in people who have started taking immunosuppressants or who have been infected with HIV. And yet, Neither trend works: No more than 5 to 10 percent of people whose immune systems are affected by a positive skin test will develop TB disease within about 3 to 5 years. This suggests that for almost everyone else, tuberculosis disease may never develop. MTB remains. “If there was a perfect experiment, that would be it,” said William Bishai, a tuberculosis researcher at Johns Hopkins University.
Cornell’s Nathan wasn’t a big seller. Immunosuppressants and HIV flip a very specific switch in the immune system. If MTB is suppressed by multiple branches, losing some immune defenses may not be enough to release the bacteria. However, most experts I spoke to are convinced that lingering cases are extremely rare. “Some people run into problems in old age,” said tuberculosis researcher Bouk de Jong of the Institute of Tropical Medicine in Antwerp. “But is mountain biking for everyone? I don’t think so.”
If anything, people with positive skin test results Might be so few Ramakrishnan told me that they are more likely to eventually develop the disease, either because they have protection against MTB or because they have a genetic predisposition to clear the microbes from their respiratory tract. In either case, a positive test could fundamentally change the outcome, especially in countries such as the United States and Canada, where MTB transmission is rare and most TB cases can be traced from abroad. Traditionally, people in these regions with positive skin test results and no obvious symptoms have been told, “‘This means you have dormant bacteria inside of you,'” Behr says. he said. “‘It could come out at any time and cause harm.'” Instead, health care workers should communicate to the public that there may be up to a 95 percent chance that these patients have already cleared the infection. That’s what he told me. If you are far removed from your last exposure and a medication regimen may not be necessary.Tuberculosis drugs are safe, but not completely benign: standard treatment lasts for monthsmay interact with other drugs and cause serious side effects.
At the same time, researchers disagree about how much risk remains years after exposure to MTB. “We’ve known for decades that we were overtreating people,” said Madhu Pai, a tuberculosis researcher at McGill who was not directly involved in Behr’s research. . But treating many people with positive skin tests was the only way to ensure that those with symptoms were treated. teeth Robert Horsburgh, an epidemiologist at Boston University, said people with live bacteria can get the medicine they need. This strategy also applies to the goal of elimination where infestation is rare. “Clinicians may be more cautious” to weed out as many bugs as possible, says Joanne Flynn, a tuberculosis researcher at the University of Pittsburgh.
In other parts of the world, MTB infections are widespread and repeat infections are common, but “to be honest, no one cares if you have latent TB,” Flynn told me. I did.Many people have very sick and highly contagious cases Not yet diagnosed or treated; in too many places, the availability of medicines and vaccines is spotty at best. Eradication remains a long-term goal, but active outbreaks require initial attention. Perhaps whining about latency now is like trying to put out a stray spark next to an untamed conflagration.
One of the main goals of BER could be to help address the larger problem of tuberculosis. Despite decades of research, the disease’s best detection tools remain “fundamentally flawed,” said Keertan Deda, a tuberculosis researcher at the London School of Hygiene and Tropical Medicine and the University of Cape Town. he says. Tests that can directly detect viable microorganisms in tissues, rather than a surrogate for immunity, have the potential to definitively diagnose and prioritize ongoing infections for all people. disease spectrum For treatment. Such a diagnosis is also the only way to finally end the uproar over the spread of latent tuberculosis. Without it, researchers are still scrutinizing only indirect evidence to understand the global burden of tuberculosis, which is likely still in the “hundreds of millions” of cases, Houben said. he said. But until the data improves, the numbers will remain fuzzy.
The two billion number still exists, although it’s not everywhere. Thanks in part to the efforts of BER. The WHO’s latest annual tuberculosis report notes that currently a quarter of the world’s population has tuberculosis. I got infected Not MTB infected Comes with MTB.The organization also officially retired the term Potential Because of that guidance Dennis Falzon of the WHO Global Tuberculosis Program told me about the disease via email. These changes, however subtle, indicate that even the world’s greatest authorities on tuberculosis are abandoning old wisdom.
Losing this large number technically reduces the infectious range of tuberculosis. This may seem to minimize the effects of tuberculosis. Mr. Behr argues the opposite. Because of the large denominator, the mortality rate for tuberculosis ends up being very small, suggesting that most infections are benign. So quantifying the 2 billion statistic reinforces that “this is one of the most troublesome pathogens in the world, and it’s not a symbiotic organism that we live in peace with,” Behr said. Ta. Fewer people may be at risk than once thought. However, for such people, teeth When microorganisms lurk, the danger becomes more real.
