New tool against an ancient enemy

QuantiFERON Latent TB New Jersey
To protect patients and control the spread of tuberculosis, a world-class TB clinic replaced the antiquated skin test with QIAGEN's innovative QuantiFERON-TB Gold In-Tube test.
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René, a 45-year-old man from Haiti, became very ill last summer while visiting his brother’s family in Newark, New Jersey. He began coughing uncontrollably, losing weight, growing more and more weak.

When relatives took René to a hospital emergency room, doctors quickly recognized the symptoms of tuberculosis (TB), one of the oldest and most stubborn infectious diseases. A chest X-ray showed telltale damage from this bacterial infection to his lung tissue. René was sent to the nearby clinic of the Global Tuberculosis Institute, where physicians started him on four high-powered antibiotics. TB is curable but demands a rigorous nine-month course of drug therapy.

At the same time, the TB clinic immediately sought out close contacts of René – seven relatives who share the house in Newark – and brought them in for screening with the most sensitive test available for latent tuberculosis infection, QIAGEN’s QuantiFERON-TB Gold (QFT). A sister-in-law, niece and nephew tested positive, placing them at high risk of developing active TB disease. All three went on a shorter three-month antibiotic regimen that kills the bacteria before it can develop into active disease.

René, his name changed to protect his privacy, is overcome by emotion when outsiders ask about his disease. He does not want other Haitians to learn of his illness because in his home country, which has the highest rate of TB in the Americas, the disease strikes fear into people’s hearts. René pours out his fears in Creole, while his sister-in-law speaks for him in English.

“In Haiti, when somebody gets TB, they often die. It costs a lot of money to get treatment, and most people cannot afford it. René is getting a lot of help here, a lot more than he would back home,” says his sister-in-law, who works as a nurse’s aide and periodically moves back and forth from Haiti with the family. “Once we found out about his condition, I quickly went to get my kids tested. I knew I needed to act fast to protect them.”

QuantiFERON transforms TB control

Protecting families, co-workers and others at risk from tuberculosis is what QuantiFERON-TB Gold does, and QIAGEN has emerged as a leader in the global effort to control TB.

QuantiFERON-TB Gold is a highly accurate modern method of screening for TB infection, and it has begun to rapidly replace the 105-year-old tuberculin skin test. Though still widely used, the skin test is fraught with shortcomings: subjectivity, a high rate of “false positives,” and the need for two patient visits to complete one test.

QuantiFERON-TB Gold avoids those issues and provides an early warning by aiding the detection of TB infection before it becomes an active disease. QIAGEN is expanding market acceptance for this unique technology following the August 2011 acquisition of Cellestis Ltd., the Australian biotech company that developed the QuantiFERON technology.

Although tuberculosis can be cured, it remains difficult to eradicate. TB still rages in the poor countries of Asia, Africa, Eastern Europe and the Americas, killing more than 1 million people a year. Even in wealthy countries the ancient disease remains a threat for vulnerable groups of people – those who have recently been exposed to active TB or whose immune system is compromised.

“Tuberculosis is a global disease. Today you can go anywhere in the world in 20 hours. So if you want to control TB anywhere, you have to control it everywhere,” says Dr. Lee Reichman, executive director of the Global Tuberculosis Institute. He travels the world teaching TB detection, treatment and control. At home in Newark, his Institute’s clinic provides world-class diagnosis and treatment for TB.

One of the toughest aspects of tuberculosis is that its bacteria can lodge in a person’s lungs and stay “latent” (inactive) for months or years. About one-third of the earth’s population – 2 billion people – carry the TB bacteria in this latent mode, the World Health Organization says. About one in 10 people with latent infection will someday develop active, contagious TB – often when their immune systems are weak.

QuantiFERON-TB Gold detects latent TB with a novel and highly accurate technology, which enables potentially fatal pathogens to be identified before its DNA or RNA are present in amounts that can be measured with molecular technologies. This is achieved by analyzing blood samples to measure the body’s own immune response to any infection with TB bacteria. Authorities worldwide are embracing QFT to screen people who are particularly susceptible to developing active disease, as well as those who work or live with people who could be endangered if active TB emerges.

Global threat calls for TB screening

Two decades after the World Health Organization (WHO) declared tuberculosis a “global public health emergency,” the disease persists in spite of progress in the availability and quality of care. Around the world, 8.7 million patients developed active TB in 2011 and 1.4 million died – ranking tuberculosis second only to HIV/AIDS among the deadliest infectious agents worldwide.

Tuberculosis is endemic in many developing countries and thrives amid malnutrition, cramped living conditions and diseases like AIDS that suppress the immune system.

Drug-resistant tuberculosis is a growing problem because patients in low-resource areas often stop therapy before finishing the demanding antibiotic regimen. Nonprofit groups and governments are fighting TB in developing regions by implementing WHO’s ambitious strategy for “directly observed therapy” – which means that a healthcare worker must be present for each patient’s daily dosing with antibiotics.

In the United States and Western Europe, incidence of active TB is relatively low thanks to a century of TB control programs. Treatment is spearheaded by public health organizations like the Global Tuberculosis Institute’s clinic at the New Jersey Medical School in Newark. Protecting latent TB-infected patients from active disease – and preventing contagion – are top priorities in the modern war on TB.

The risk in industrialized markets is highest for specific, identifiable groups – and these are the people most in need of screening with QFT. The first line of containment is to identify and test contacts of active TB patients, who may have infected those around them. People with weakened immune systems – such as HIV-positive, rheumatoid arthritis and chemotherapy patients – are vulnerable to TB infection, whether from recent or past exposure, and can more readily develop the active disease.

Immigrants, international students and travelers, especially involving countries with a high TB burden, are statistically more likely to be infected with the TB bacteria. People living or working in cramped situations – prisoners and staff, military members, some members of other occupations – also are vulnerable.

Healthcare workers themselves are a high-priority target for screening because of the double risk: Nurses and doctors can face on-the-job exposure from patients with undiagnosed active TB, and if they progress to active TB they become a potential threat to other patients.

QIAGEN’s outreach strategy for QuantiFERON-TB Gold focuses on reaching these targeted groups through healthcare providers and employers. Dr. Reichman advocates a “screen and treat” approach that can diminish by about 90% the risk of latent TB patients developing active disease.

QIAGEN estimates the need for latent TB testing at 15 million tests per year in the United States and 50 million worldwide. Screening has only begun to address the need.

Latent TB Active TB
TB germs in the body are walled off TB germs in the body are active and spreading
Person can't spread TB germs to others Person can spread TB germs to others
Person does not feel sick Person usually feels sick
Chest X-Ray usually normal Chest X-Ray usually shows damage to lungs
Sometimes has to be treated with medicine to prevent active TB Always has to be treated with medicine to cure the disease and prevent spread to others
Usually treated with 1 medicine, for 4-9 months Usually treated with 3 or 4 medicines, for 4-9 months

Tuberculosis goes to a school

When active TB surfaces in the general community – such as in a crowded workplace or school – Mark Wolman, program manager for TB control at the Institute in Newark, experiences his scariest moments. It may begin with a call to the public health hotline, which rings 10 feet from his desk, that a 17-year-old high school student has arrived in a hospital with signs of active TB.

“If they are contagious, we jump on it,” Wolman says. “We go to the hospital and talk with the patient and family about tuberculosis. Even if the disease is not yet confirmed, because bacteriology results can take weeks to come back, we want to make them aware of TB and how it works.”

Wolman or his colleagues go next to the school – to communicate directly with students, teachers and parents and to develop a list of contacts of the sick student. The TB control officer draws seating charts in each class to see who was close enough to inhale droplets from a cough or sneeze. Students who share several classes or “hang out” with the sick student are more at risk. Teachers also can be vulnerable.

As many as 70 students and staff may be tested in a typical school outbreak. In a workplace, it’s often not that many, because workers have a limited number of close contacts. But schools need a lot of outreach, with letters and meetings to inform and motivate all stakeholders.

“Parents become very concerned, so we try to deal with their anxiety,” Wolman says. “At the same time we want to persuade anyone who is a close contact to get tested, and if they test positive to get treated for TB infection. Otherwise, they can walk around with this bacteria and maybe 20 years later something causes the immune system to be weakened – and they get active tuberculosis.”

New technology drives out old

For more than a century the tuberculin skin test was the accepted way of screening for TB infection, despite being subjective and difficult to use. Now QIAGEN has launched a market conversion strategy to replace the skin test with the QuantiFERON-TB Gold – more accurate, faster and more cost-effective.

Dr. Masae Kawamura, longtime head of tuberculosis control in San Francisco, joined QIAGEN in 2012 as senior director, medical and scientific affairs. The reason: QuantiFERON-TB Gold is making a difference.

“During my time as Director and TB controller of San Francisco, QuantiFERON transformed targeted testing and treatment of populations most vulnerable to TB in our city,” Dr. Kawamura says. “We were able to reduce TB rates and nearly eliminate transmission in homeless shelters, while cutting in half the positive rates in our community clinics.

“QuantiFERON provides the big opportunity to wholeheartedly implement U.S. TB-elimination screening guidelines with a test that is better, more believable and more operationally feasible than the skin test.”

The skin test, first used in 1907, involves injecting a small amount of material from TB bacteria under the skin of a patient’s forearm. Two or three days later, the patient is rechecked. A swollen or red bump may be read as “positive” for TB infection, but the interpretation is a judgment call.

QuantiFERON-TB Gold In-Tube, the third-generation QFT kit, starts by taking a sample of a patient’s blood in three vials: two holding specific TB antigens and one “control.” The vials go to a laboratory, which uses a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the response – and to deliver next-day results.

Timing is important in TB screening. Some patients given a skin test do not return for the second visit, so the test is useless. With QFT, only one visit is needed to produce results.

In addition, the skin test is unreliable in many immigrants because it cannot distinguish an immune reaction to TB bacteria from the BCG vaccine, which is widely used in regions with high TB burdens. QFT is accurate regardless of BCG vaccination.

The skin test yields “false positives” in 20% to 40% of patients – identifying them as infected with TB bacteria and leading to costly but unnecessary follow-up care. QFT positive readings are 99% correct.

“I think QuantiFERON should be used on everybody, but some people still do the old tuberculin skin tests,” says Dr. Reichman, whose Institute has been studying and using QuantiFERON for a decade.

“The only healthcare providers who do skin tests now are people who think that it’s cheaper. Actually, QuantiFERON saves money because it is much more specific, so patients who get a ‘positive’ are people who are really infected with the bacillus. With a more accurate test you have fewer cases to work up through visits to the doctor’s office and chest X-rays, both of which are very expensive.”

Already, leading U.S. laboratory chains have adopted QFT in screening for TB infection – converting from the skin test. The Centers for Disease Control has established this class of test as a benchmark for many patients, including BCG-vaccinated persons and those unlikely to return for a second visit.

Innovation focuses on new applications

QuantiFERON technology is expected to remain a significant growth driver for QIAGEN as anti-TB efforts convert to QFT. The market is far from fully penetrated, and new applications are under investigation.

QuantiFERON-TB Gold, for example, offers promise for screening patients who are candidates for many medications that suppress the immune system. Guidelines for TNF-alpha inhibitors – a widely prescribed class of drugs for rheumatoid arthritis – already require screening for latent TB. Treatments for cancer, HIV/AIDS, diabetes and other diseases may hold similar potential.

Meanwhile, QIAGEN is expanding its footprint in TB control. In 2012, QIAGEN and the Max Planck Institute for Infection Biology launched a collaboration to develop a follow-up test to predict which latent TB patients are likely to progress to active disease – a key question for doctors and patients.

“The ultimate point is to eliminate TB,” says Dr. Reichman. “To do that we need to effectively treat patients with the active disease through directly observed therapy. We need to screen for people with latent TB infection – and treat them so they don’t develop active disease. And we need a tuberculosis vaccine, which is coming, in my view, in five to 10 years. But, globally, we have a long way to go.”