TB repairman’ proves good predictor of relapse
Handy early marker opens window onto latency
Measuring amounts of a protein produced by the TB mycobacterium — apparently as a way to repair damage done to its cell wall by isoniazid — someday may be a handy way for clinicians to predict whether patients will respond " to therapy, says Robert Wallis, MD, associate professor of infectious diseases at Case Western Reserve University in Cleveland.1
The protein, antigen 85 complex, turns out to be significantly higher at a point two weeks into therapy among patients who continue to have positive cultures after other patients become culture-negative or ultimately fail therapy altogether.
Along with providing an early marker to help clinicians predict how their patients will respond to therapy, Wallis’ findings also may open what he calls a "window" that lets scientists peek into the hidden workings of TB latency.
Latency a survival strategy
And why not? Latency, like the antigen 85 complex, represents a survival strategy of a sort, Wallis points out. "When people are first infected, only a minority develop rapidly disseminated disease and die," he says. What happens in most people — a period of latency, followed sometimes by some unknown signal that activates the bug — makes sense from the bug’s point of view, since most TB transmission occurs from patients with chronic cavitary reactivation disease.
But how, exactly, does the TB bug achieve a state of latency? It’s tough to say, latency being what it is.
Wallis reasoned it might be possible to look at what is afoot during a state of artificial latency. By that, he means the period of drug-induced latency among patients on anti-TB therapy who are adherent, respond well to treatment, aren’t plagued by drug resistance, and yet go on to relapse.
What he found surprised him, he says. The protein is secreted by metabolically active bugs in log-phase growth, leading him to expect it would decrease rapidly during therapy.
"Instead, it turns out that isoniazid transiently increases the expression of this protein in cultures," he says. "But to really see that, the bacilli have to remain viable." That continuing viability probably points to which strains will be difficult to eradicate, he adds.
Results of treatment
In fact, subjects in Wallis’ study who did relapse (along with those who simply persisted longer than others) showed rising levels of antigen 85 complex. Concentrations of the protein peaked, at levels ³ 60 pg/ml, around day 14 of therapy, he found.
On the other hand, those with levels below 60 pg/ml by day 14 showed rapid response to treatment and ultimately were cured. (Of subjects with day 14 levels above 60 pg/ml, 33% showed persistence of TB beyond the ninetieth day of therapy, and 17% ultimately failed treatment.)
"I find it exciting to think there might be a point-of-care assay you could use after only two weeks or so of treatment to predict outcome," Wallis explains. "That way, you could see whether you’d need to make adjustments [to the regimen]."
Neither compliance nor drug-resistance in the conventional sense of the word was implicated in the relapses and persistence, Wallis emphasizes. Strictly speaking, of course, he says the antigen’s presence represents a TB bug’s attempt to "resist" the effects of isoniazid.
A combination of factors
In practice, Wallis says persistence and relapse probably can be explained by a combination of biological factors (such as elevated levels of antigen 85 among some hardier strains of bug) coupled with human factors (such as poor adherence).
That explanation might help account for why even patients who seem to adhere well still relapse sometimes and, conversely, why patients blessed with "a wimpier bug," even though they don’t comply as well, may do just fine, he says.
Reference
1. RS Wallis, M Perkins, M Phillips, et al. Induction of the antigen 85 complex of Mycobacterium tuberculosis in sputum: a determinant of outcome in pulmonary TB treatment. J Infect Dis 1998; 178:1,115-1,121.
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