Tuberculosis has earned the undesirable distinction of being the world's top infectious disease killer — a mantle it took back from COVID in 2023. TB claimed the lives of 1.23 million people in 2024 and sickens about 10 million people each year.
Research is now casting doubt on the true number of TB cases.
A new study published in Nature Medicine found that many TB diagnoses may be incorrect — and that this could carry significant implications for patient care and well-being.
The study analyzed data from 111 low- and middle-income countries in 2023. Since nobody knows the true number of TB patients, Nicolas Menzies — a co-author on the paper and an associate professor of global health at the Harvard T.H. Chan School of Public Health — says he and his colleagues used data on the number of TB cases submitted to the World Health Organization and came up with a formula to estimate false negatives and false positives. However you slice the numbers, he says, the headline conclusion is the same: There are an awful lot of incorrect diagnoses.
Menzies and his colleagues estimate that, of those who seek medical care for symptoms that could indicate a TB infection, about a million people have the disease but aren't given that diagnosis. They are false negatives. On the flip side, the estimated number of false positives was even worse: 2 million or more people each year are erroneously told they have TB when they actually have something else.
"Amongst all of those individuals who are diagnosed and treated for TB every year, perhaps a quarter of them — and maybe even higher — might not have TB disease," Menzies says. He says that in the most serious cases, these patients could have a potentially fatal disease like pneumonia, lung cancer or chronic obstructive pulmonary disease. He says this type of misdiagnosis has been a "blind spot" in the TB world.
The study has been both praised — and criticized — by outside experts.
Its attention to incorrect TB diagnoses is an important step, says Dr. Marcel Behr, a professor of medicine at McGill University who was the founding director of the McGill International TB Centre. "The issue about whether we have false positives has been understudied," he says, adding that he was impressed with the research's "rigorous approach."
But to Dr. Lucica Ditiu, a pulmonologist who is head of Stop TB Partnership, that emphasis on false positives could backfire. She worries that the study could cast doubt on TB statistics, prompting governments and global health funders to shift their dollars elsewhere. Ditiu also fears that the misdiagnosis angle could make clinicians reluctant to diagnose the disease lest they make a mistake.
The reason for the misdiagnoses
Why are there so many false positives and missed cases?
Menzies' theory: less-than-perfect diagnostic tests — and human error.
There are a variety of ways to diagnose TB but most tests rely on sputum — mucus coughed up by a patient — that is then analyzed for signs of the tuberculosis bacterium. The accuracy rate varies hugely, with the newer PCR machine analysis far more accurate than traditional methods of examining a sample under a microscope.
However, a significant number of diagnoses are made without a positive test result. Well over a third of diagnoses in low- and middle-income countries are the result of a physician, nurse or another clinician looking at a patient's symptoms — like a persistent cough, weight loss, night sweats — and then following guidelines to make their best medical guess.
Menzies believes those clinical assessments, while well-intentioned, are responsible for many of the cases where people are told they have TB but actually have something else.
Behr — who runs a diagnostic TB lab — has a theory about what's going on.
He believes that lots of health workers "grew up in an era where there were not good TB diagnostics" and are accustomed to trusting their gut instinct over the test results. He admits it "takes a little while for doctors to adapt" and embrace the improved tests.
Ditiu hopes that the impact of this study is to improve access to tests — and the tests themselves — and not to deter clinicians from making a diagnosis, especially in remote areas with underfunded medical facilities.
"If the purpose of the paper is to say that we need better tools, better diagnostics — that, I think, is spot on," she says. "If it is to say: Oh my goodness, clinical diagnosis is so bad, then this is very damaging. Because the reality of the world, like it or not, is that our biggest problem in TB is we have a huge number of people that are not diagnosed, at all, in any shape or form."
The consequences?
Whatever the future holds for the diagnosis of TB, Menzies believes an important message from his study is about the perils of misdiagnosis.
Failing to diagnose TB in an early stage can be problematic — both for the individual's treatment and for the safety of those who could catch the bacterial infection. Those risks have received a lot of attention, he notes. In contrast, he argues, the downside of incorrectly telling someone they have TB has received less attention.
He can tick off a long list why this is so problematic: the costs of the treatment and missed work, the side effects of the drugs — particularly liver damage from strong TB drugs — and the stigma faced by TB patients.
And another major one: The patient is not treated in a timely fashion for whatever they do have.
In Brazil, Menzies partnered with the Ministry of Health to run a study of patients who were diagnosed with TB and then, later, had a change of diagnosis. Those patients were nearly twice as likely to die in the follow-up period compared to patients whose diagnosis of TB was accurate at the outset.
"I always sigh when I read, you know, stories like: 'The analysts were surprised by a finding.' But this was actually something that we were surprised by," says Menzies.
His conclusion? "Some people who have false positive diagnoses actually have some quite serious conditions that would benefit from prompt diagnosis and treatment."
This finding led Menzies to take incorrect TB diagnoses much more seriously. Behr is hoping that Menzies' new study — quantifying those incorrect diagnoses on a global scale — will do the same to the TB field more broadly. Behr says this is a topic that's been discussed quietly and it "needs the volume to be turned up a bit."
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