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TB Wars

Quick, Simple and Inexpensive: The Holy Grail in TB Diagnosis

Most people infected with TB worldwide have latent infections, meaning the TB bacteria in their bodies are controlled by their immune systems and are not causing disease. A long-sought global health goal is a simple, quick and inexpensive test for active TB infections, in which multiplying bacteria overwhelm the immune system, threatening patients’ health and posing a risk for spreading the infection.

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Dr. Achkar describes her research that could lead to a dipstick test for tuberculosis.

Such a test is especially needed in poor countries, where the vast majority of cases occur. But the simple and affordable tests now available are not very accurate for detecting active infection, and tests that are more accurate are expensive, complex or time-consuming.

Sputum-smear microscopy is now the most commonly used point-of-care test for active TB infection. A patient coughs up a sputum sample, which is smeared onto a glass slide and stained with a dye. If M. tuberculosis, the microbe that causes TB, is visible under the microscope, the patient almost certainly has an active infection.

The problem with this test is that someone with no observable bacteria in the sputum can still have an active TB infection. “Only about half of all people with active infections have detectable M. tuberculosis in their sputum smears,” says Jacqueline M. Achkar, M.D., M.S., associate professor of medicine (infectious diseases) at Einstein and an attending physician in medicine at Montefiore, the University Hospital and academic medical center for Einstein. “So people with active infections but who are smear-negative often aren’t diagnosed.”

This isn’t such a problem in developed countries. “In the United States, if the clinical signs and symptoms point to TB, we usually don’t stop at negative sputum smears,” Dr. Achkar explains. “But in resource-limited settings, people with negative smears would get sent home until they get so sick that they become smear-positive. Obviously, that’s not ideal.”

A possible alternative test would look not for M. tuberculosis itself but for antibodies the immune system makes in response to an active infection. This approach has been tried, but with disappointing results. “Many scientists believe that M. tuberculosis doesn’t produce a significant antibody response, but new evidence shows otherwise,” says Dr. Achkar. “It’s likely that people have been looking for the

An assay that detects three antibodies has shown promise for quickly and inexpensively diagnosing active TB infections. The assay was based on the discovery that TB bacteria actively infecting human lungs shed tiny pieces of their membrane vesicles into the bloodstream, causing patients to produce three different antibodies in response.
Illustrated by Nirja Desai
Dr. Achkar’s Einstein colleagues previously discovered that when M. tuberculosis multiplies in the lungs, the bacteria shed tiny pieces of their membranes into the bloodstream, making the infection more virulent and triggering a small but detectable antibody response—at least in mice.

Dr. Achkar then showed that these bacterial “membrane vesicles” triggered the same effects—but with even more pronounced antibody production—in people with active TB. She found that these patients produce antibodies against three specific types of vesicle proteins, suggesting that this antibody trio might serve as a highly sensitive and specific biomarker for active TB infection.

Dr. Achkar recently devised an assay for the three antibodies and tested its accuracy in 28 patients known to have active TB infections, plus a control group of 16 people with latent TB. Among the actively infected patients, the test correctly diagnosed all 16 smear-positives. And—particularly important—the antibody test was positive for 9 of 12 smear-negatives (people actively infected but with no M. tuberculosis in their sputum). No one in the control group tested positive.

“If we can sustain these numbers in large-scale testing and turn our assay into a simple ‘dipstick’ blood test, that would be phenomenal,” she says.

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