Blood markers may predict risk for active TB, study finds

SEATTLE – In an advance that could change tuberculosis treatment worldwide, researchers in Seattle and South Africa have identified markers in the blood of infected people that may predict those at high risk for developing an active – and potentially fatal – form of the disease.

A signature pattern of 16 genes, detected in analysis of samples from more than 6,000 South African adolescents, may one day help create a test to identify and treat people likely to develop active TB – more than a year before they get sick.

That’s according to researchers at the Center for Infectious Disease Research in Seattle and the South African Tuberculosis Vaccine Initiative at the University of Cape Town, who led a decadelong effort to find what may become a crucial screening tool. Their results were published Wednesday in the journal The Lancet.

“Since we’ve known about TB, it’s been the holy grail,” said Daniel Zak, the study’s first author and an assistant professor at CIDR who specializes in analyzing big data sets to identify markers to predict disease risk.

About one-third of the world population – 2.4 billion people – is infected with the bacterium that causes latent TB, which shows no symptoms. A fraction, less than 10 percent, actually develop active illness.

“Our immune-system response to TB is actually pretty good,” Zak said. “If you don’t have HIV or other risk factors, then 90 percent of the people who get TB infection will hold it in check for their whole lives. They won’t get sick, and they won’t spread it.”

In 2014, nearly 10 million people around the world fell ill with TB and 1.5 million died, according to the Centers for Disease Control and Prevention.

In the United States more than 9,400 TB cases are reported annually. Identifying those most likely to develop active disease – and to spread it to others – has been difficult. TB can be treated and cured with first-line antibiotics, but it’s not possible to treat millions of people just in case they eventually get sick.

In the new study, funded in part by the National Institutes of Health and the Bill & Melinda Gates Foundation, researchers identified the blood biomarkers in two stages.

First, they collected samples for two years, 2005 to 2007, from more than 6,000 South African adolescents infected with latent TB. They monitored the young people, testing their blood every six months, to see who eventually developed active disease.

Analysis of the samples revealed different genetic patterns in those who got sick and those who didn’t develop illness, Zak said. Researchers eventually realized that the risk signature – a set of 16 genes – could be detected as early as 18 months before onset of illness. Symptoms of TB include cough, fever, night sweats and weight loss.

Armed with the gene signature, the researchers tested the blood of more than 4,500 volunteers in South Africa and The Gambia. The second group included people who were healthy but lived with others who had been diagnosed with active TB. They were also more varied than the first group in terms of age, health status, ethnicity and the strains of local TB to which they were exposed.

Despite the differences, the same genetic signature was found in those in the second group who eventually developed active TB.

“I’m really excited that this worked,” Zak said. “It’s an important incremental development.”

The challenge now is to prove that the genetic signature can predict active disease in a real-world population, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, who reviewed the study.

“I think that conceptually it’s quite important,” Fauci said. “Whether or not it gets translated into the field remains to be seen.”

South African investigators launched a large clinical trial this year to determine whether providing targeted drug therapy to people who test positive for the blood biomarkers will prevent them from developing active TB.

“The hope is that if we’re catching it so early, the amount of the bacteria is less, it’s easier to treat and there are more people being monitored,” Zak said.

CIDR and partners have started early talks with companies that make convenient tests, called assays. If all goes well, a test for those at high risk for active TB might be available within five or 10 years, he estimated.

It’s gratifying to think about decreasing the burden of a devastating disease in such a big way, Zak added.

“These massive diseases of global health – TB, malaria, HIV – are such problems because they’re challenging biologically,” he said. “With the new revolution in biology, we’re starting to make some inroads.”