Antiretroviral reaction can spark scary symptoms
Experts: Look out for paradoxical response
TB patients with HIV can experience a marked, though short-lived, worsening of TB symptoms following the initiation of antiretroviral therapy (ART) as often as 20% to 30% of the time, a team of researchers in Florida has found.1
Clinicians should be alert to the phenomenon so they won't mistake what's essentially a heightened and newly reconstituted immune response for a sign that the therapeutic regimen has gone awry, says David Ashkin, MD, medical adviser to Florida's TB control program.
"We were concerned that people in the field might not know what this was," he says. "Often, your first inclination is to stop the meds. When you do that, the problem goes away, all right, but for the wrong reason - because your immune system's going down again."
With the increasingly widespread use of the more powerful combination therapies, in particular highly active antiretroviral therapy (HAART), Ashkin says he suspects paradoxical responses may occur even more frequently and began to wonder exactly how often such responses occur in dually infected patients undergoing concurrent treatment for TB and HIV when his TB hotline started ringing off the wall.
Fever, lymphadenopathy, pleural effusions
Typically, the conversation on the hotline went like this:
"You know, I've got a couple of cases where. . ."
"Let me guess. They're having a fever of 104, their necks are swelling up, and you think they've got MDR-TB, right?"
"Hey! How'd you know?"
Over the years, researchers have noted a wide variety of paradoxical reactions, some in response to anti-TB therapy and some in response to anti-HIV treatment. "It's nothing unique to TB," says Michael L. Tapper, MD, chief of infectious disease and epidemiology at Lenox Hill Hospital in New York City. "Something similar has been described with other opportunistic infections, such as CMV retinitis and MAC [mycobacterium avium complex]. People who aren't AIDS-ologists certainly need to be aware of it and to know it's time-limited. They especially need to realize it's not an indication to stop treatment."
In Ashkin's study, 36% of HIV-infected TB patients (who received treatment for TB as well as ART) had paradoxical reactions. In a second group - TB patients who weren't HIV-infected and received TB therapy only - just 2% had a paradoxical response. In an historical control group, where HIV-infected patients had gotten only TB therapy, an examination of the patients' records indicated that 7% experienced a paradoxical response.
In all, three of the 88 patients in the study (two in the first group and one in the second) had such strong reactions that they needed supportive therapy, including high doses of steroids, Ashkin says. "I call it the gas-and-brake phenomenon," he says. "You're watching your patient, and suddenly he or she can't breathe or swallow and his or her lymph nodes are encroaching on the trachea and esophagus. And you're thinking, 'Oh, no, I've created a monster!'"
Steroids to calm immune response
It sounds a bit counterproductive to give steroids to someone whose immune system is already taking a beating - but the treatment works just fine, Ashkin adds. "It reminds me of this new stuff from [AIDS researcher] David Ho, who's talking about using immuno-modulators like steroids to suppress the immune system, so HIV can come out of its dormant state in the T cells, and then we can kill it with drugs." Whether or not that describes what's happening, patients who need steroids should continue to get their anti-HIV therapy, and - as further proof - their viral loads will continue to drop, Ashkin says.
Most of the patients in Ashkin's study needed no more than a steady hand on the wheel, not steroids. Even patients whose reactions were quite marked generally reported feeling fine, says Ashkin's collaborator, Masahiro Narita, MD, regional TB consultant for the state.
The researchers used a fairly inclusive definition for paradoxical reactions, Narita adds, including persistent fevers of indiscernible origin; and the appearance or worsening of intrathoracic lymphadenopathy, cervical adenopathy pleural effusion, pulmonary infiltrates, or other tuberculous lesions.
Since researchers were careful to start ART several weeks after TB treatment had been begun, they could distinguish side effects from the two kinds of treatment. Clearly, patients in the first group (HIV-infected TB patients getting treatment for both infections) were reacting to the ART, not the TB treatment, Ashkin says.
Plus, it was no surprise some patients in the second group (TB patients without HIV) reacted paradoxically to their TB therapy, Ashkin says, since clinicians have noticed such reactions ever since Robert Koch first injected his patients with killed TB virus.
As for the handful of paradoxical reactors in the third group (the HIV-infected TB patients who were treated for TB but before antiretrovirals had become available), perhaps those reactions can be written off to some inadvertent immunological boost resulting from the synergism between TB and HIV. If so, then treating patients' TB might have restored immune function, thus generating a paradoxical response to TB therapy.
Implications for public health?
One segment of the study may eventually have implications for public health practices, Ashkin says.
As he and his co-workers periodically checked patients' anergy status and PPD response, they found that after a few weeks of ART, patients who had initially tested anergic were able to muster vigorous reactions to the tuberculin skin test. The conversions didn't coincide with rapidly rising CD4 counts, however. Instead, CD4 counts often stayed in the basement, well below 200.
To Ashkin, this suggests that recovery of skin-test reactivity coincided precisely with the onset of reconstituted T-cell function, he says. It follows, perhaps, that anergy status may be a better gauge of immune-system recovery than CD4 counts alone. "We think T-cell function is probably more important than sheer numbers," he says.
If a second study Ashkin plans shows that ART calls forth the same hidden response to PPD skin tests in anergic, HIV-infected patients not being treated for TB, perhaps clinicians should check a patient's anergy status once ART is under way, he suggests. In certain high-risk groups (an example in Florida would be Haitian immigrants) such a check could call forth a previously hidden response to the TB skin test, and appropriate treatment could be begun.
Reference
1. Narita M, Ashkin D, Hollender E, et al. Am J Respir Crit Care Med 1998; 158:157-161.
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