Two collaborating research teams — one studying tuberculosis in humans and the other examining zebrafish genes — have identified a genomic variation that could differentiate between TB meningitis patients who are likely to respond to anti-inflammatory therapies and those who aren't.
The researchers, an international team from the United Kingdom, Vietnam and the US, published the results of their study in the journal Cell this month, demonstrating that changes in the gene LTA4H can stratify patients with TB meningitis into distinct groups with divergent responses to anti-inflammatory therapy. Patients with forms of the gene associated with excess inflammation respond well to anti-inflammatory steroid treatment. Meanwhile, patients harboring gene changes that caused them to experience median inflammation or reduced inflammation do not benefit, and may even be negatively affected.
The group hopes their findings will translate into personalized treatment strategies for TB meningitis based on a patient's genotype. The results may also hold promise for targeting treatments for other, more common types of TB and other infectious diseases with inflammatory implications, the researchers reported.
Guy Thwaites of Kings College London, who led the clinical section of the study in Vietnam, told PGx Reporter that the group's findings will have to be confirmed in a trial measuring whether genetic testing actually improves patients' outcomes before any such strategies can be put into clinical practice.
"It was a nice finding because, while the world of cancer is so infinitely more advanced than infectious disease, now for the first time, really ever in tuberculosis, you have a gene that predicts treatment response," Thwaites said.
In their study, the researchers discussed how they combined work investigating the function of LTA4H in zebrafish with clinical research in Vietnam of anti-inflammatory treatment in humans to discover the link between the gene and treatment response.
The meningitis form of TB only makes up about one percent of cases, but is particularly hard to treat, and is often fatal. Patients generally are treated with a combination of antibiotics and steroids to dampen the inflammation.
Thwaites said his clinical research team initially investigated dexamethasone, an anti-inflammatory steroid, as an adjunct to TB meningitis treatment in a 2004 trial, finding that it modestly benefitted patients. "We tried over a few years to understand what the mechanism was," Thwaites said. "But we were unable to find [it.]"
Meanwhile, the zebrafish researchers had been studying how changes in the LTA4H gene in zebrafish are associated with the animals' susceptibility to a mycobacterial infection similar to human TB. They found that alterations within LTA4H can lead to either excessive or inadequate inflammation in patients by promoting growth of the bacteria through different pathways.
Interested in exploring the significance of this finding for human disease, the zebrafish team approached the Vietnamese study group, hoping to examine whether patients from its 2004 trial showed a response to the corticosteroid treatment based on their LTA4H genotype.
"We still had DNA from a large number of these patients, and so we said we'd have a look," Thwaites said.
The authors reported that they tested samples from 182 Vietnamese patients who participated in the earlier research. They found that individuals who were either homozygous mutants or homozygous normal at a particular SNP location on LTA4H, rs17525495, were more likely to die from their infection than those who were heterozygous.
Among patients not treated with dexamethasone, the group found that those with a homozygous mutant genotype had the highest mortality. Among those treated with the anti-inflammatory steroid meanwhile, homozygous mutants had the lowest rate of death. This suggests the LTA4H genotype has a "critical influence on response to standard-of-care adjunctive anti-inflammatory therapy in TB meningitis," the group wrote.
Because only those patients having the homozygous mutant genotype benefitted from dexamethasone treatment, the study results suggest that genotyping could help define which patients should be treated with the drug and which should not, potentially saving money and reducing unnecessary treatment for those unlikely to gain from the therapy.
Additionally, the researchers found that the steroids could have adverse effects for those with a homozygous genotype associated with reduced inflammatory response, though this result was not statistically significant, Thwaites said.
In a release describing the discovery, Thwaites's colleague Dr Sarah Dunstan, head of human genetics at Oxford University Vietnam, described this variation as a "Goldilocks" effect. Heterozygosity sees a "just right" amount of inflammation, while each homozygous state causes either too much, or too little.
Thwaites, meanwhile, stressed that more research is required before clinicians might use genotyping to guide treatment for TB. "This was a one-off finding in a single center with a relatively small number of people," he said. "We need randomized-controlled trials to assess the effectiveness of performing early host genotype with or without a particular intervention and seeing whether that improves outcome."
His group now plans to expand their investigations to additional patients in Vietnam. "That will give us a greater indication if this gene is determining response to treatment," he said.
Thwaites said that it is also possible the findings could apply to more common forms of TB, as well as other infections, because the inflammatory pathways affected by LTA4H are known to be implicated in a number of infectious diseases.
"The question is now about other forms of TB, where it is quite common to get excessive immune response, for example pulmonary disease which is very much more common," he said. Thwaites's group is also interested in examining whether the same association holds true for other diseases like bacterial meningitis.
In the meantime, the results in TB meningitis already suggest that rapid genotyping tests could be used to guide steroid treatment for these patients.
Although widespread testing could be a challenge, according to Thwaites, the success of simple molecular diagnostic tests for TB is growing in the developing world, and this bodes well for performing regular clinical genotyping in this population.
"Right now it’s a long way off from … being rolled out, but we said the same about molecular diagnostic tests for TB five years ago," Thwaites reflected. "Now, there are PCR one-tube assays that have been rolled out through some parts of Africa."
Although these tests are still not quite affordable enough to facilitate routine testing in the developing world, the technologies already in place could likely also be used to molecularly guide treatment strategies for TB meningitis, he added.
Finally, Thwaites said the study results have opened up hypotheses about current and developing therapies that could more specifically target the pathways identified in the two extremes of inflammatory response.
"One is thalidomide," he said, "which has been used, and is still used to treat leprosy and has also been used in small numbers to treat complications of brain tuberculosis."
Another, he said, is aspirin, which can inhibit TNF, an important molecule in the pathogenesis of TB. Promising results with aspirin in the zebrafish research suggest the drug may also act in a genotype-specific manner in humans.
"Drugs like thalidomide, corticosteroids, and aspirin are all off-patent," Thwaites said. "You just have to persuade people to do trials."
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