While for the past 30 years, the incidence of active tuberculosis (TB) in the US has been lower than the global incidence, untreated latent TB infection (LTBI) is thought to account for the majority of domestic infections. In fact, about 80% of US active TB cases may have progressed from LTBI that was untreated, according to the CDC. Respiratory medicine and public healthcare clinicians can play an important role in screening, diagnosis, treatment, and addressing misconceptions to improve treatment adherence.

An often asymptomatic condition in which the patient carries the disease-causing bacteria Mycobacterium tuberculosis, the disease can potentially be harmful to the infected individual and others if it becomes activated. According to the CDC, approximately 7 in 8 cases of TB in the US are believed to be associated with transmission from individuals with untreated LTBI.

“Many people mistakenly believe that TB is not a concern in the US or that only active TB matters when, in fact, most cases come from untreated latent infections,” said Shruti K. Gohil, MD, infectious disease specialist and associate medical director of epidemiology and infection prevention at UCI Health in Orange, California.

“This makes it very important that patients get appropriate screening and treatment, if needed, at this stage to reduce their risk of developing serious consequences of an active TB infection,” said Gohil. “Patients should know that latent TB treatment is not as difficult as they have been in times past because we now have shorter, more convenient treatments that most patients are able to complete.”

Scope of Screening

According to Michael J. Davis, DO, MPH, AAHIVS, a physician in the Department of Infectious Diseases at Parkview Health in Fort Wayne, Indiana, a lack of universal LTBI patient screening mandates among the majority of healthcare systems underlines the importance of individual providers. Providers with direct access to susceptible populations should be conscientious about identifying those with risk factors, he explained.

These include individuals who have had close contact with patients diagnosed with active TB, are living in congregate settings, are living in regions with high prevalence, and have recently immigrated from countries where active TB is more common and patients with weakened immune systems.

There is some sense of urgency to having this population screened, given the increased risk for reactivation, said Davis. “Although LTBI screening is a Grade B recommendation by the US Preventive Services Task Force for at-risk populations, this population can often be a missed screening opportunity for various reasons,” said Davis.

“Some of those reasons may include patient access to care, language barriers, competing health maintenance priorities, or unawareness of the screening recommendation and reactivation risk. To better address the fallout in LTBI screening and treatment, there needs to be more education on the provider side, health system prioritization of the screening, and collaboration with public health departments.”

Dipak Chandy, MD, professor of medicine and neurology at Westchester Medical Center in Valhalla, New York, and chief of the Division of Pulmonary, Critical Care, and Sleep Medicine, also suggested that patients be tested before being prescribed TNF inhibitors.

“Any one of these drugs will increase the risk of latent TB becoming active TB,” explained Chandy. “Anybody who’s going to be put on these medications typically will get tested before they are started because if they are positive, we would consider starting treatment just before or simultaneously in that kind of regimen.”

Treatment Tactics Toward Adherence

Patients identified with LTBI should be treated to prevent the development of active TB. According to the CDC, providers can consider several recommended regimens for LTBI treatment, which can span 3-9 months and will utilize one or more of the drugs isoniazid (INH), rifapentine, and rifampin.

In conjunction with the National Tuberculosis Coalition of America, the CDC preferentially recommends short-course, rifamycin-based, 3- or 4-month LTBI treatment regimens over 6- or 9-month INH monotherapy because the short-course regimens have higher completion rates than longer regimens and likewise offer effective, safe treatment. Chandy and other providers agree, saying they see evidence of better adherence over time as treatment has evolved into cycles that are briefer than they previously were — especially when considering the traditional method of INH therapy as a first-line antibiotic treatment that required a 6- to 9-month prescription and monitoring for side effects including liver damage and neuropathy.

“INH is a challenging regimen for people to follow,” said Chandy. “These days, very few people would even consider something like that. The vast majority of our patients now use a much shorter regimen, which is typically rifamycin for 4 months. I think people are more willing to accept a shorter-duration prescription. The change in duration has been a big plus in terms of acceptance.”

Chandy also noted there has been a general increase in no-show rates currently across the community clinic for LTBI treatment.

“For most patients, it’s very difficult to force somebody to treat for latent TB compared to active TB,” he said. “It’s more difficult to argue this as a direct social consequence. It is more about protecting oneself for reactivation down the road.” Observed therapy via video and self-administered therapy are among options to consider, according to the CDC, once it’s confirmed that active TB is not present.

No Active Disease

“Administering latent TB treatment when the TB is active would be very detrimental to that patient,” said Chandy. “The first thing you want to ensure is that the patient is asymptomatic and that they don’t have anything on an x-ray that even remotely suggests active TB.”

Other signs to assess for during the patient’s history and vitals include fever, insidious onset of cough, recent weight loss, night sweats, and enlarged lymph nodes. “These might be suggestive symptoms,” said Chandy. “Now all of these can have other explanations not related to TB, but these might make our ears perk up. That’s why TB is such a dangerous disease. Plenty of people with active TB really have minimal to no symptoms.”

In addition to x-rays, other reliable diagnostic tests include blood tests such as QuantiFERON-TB Gold Plus and T-SPOT.TB, as well as skin tests such as the tuberculin skin test and purified protein derivative, the latter of which is not universally recognized for accuracy. 

Additional warning flags to consider related to treatment beyond side effects include heavy alcohol use, history of hepatitis, and taking any other liver-toxic medications.

Baseline liver function testing is recommended before treatment, said Chandy. “People who are elderly are at increased risk as well. There is no hard cutoff in terms of age, but if someone is 70 years old, you’re probably thinking about that before prescribing treatment.”

Carlos H. Zambrano, MD, an infectious disease specialist at Loretto Hospital in Chicago, touted the capabilities of rapid molecular testing, such as nucleic acid amplification, Xpert MTB/RIF assay, and Truenat, that detect M tuberculosis DNA within hours. “Digital tools and mobile applications can help in contact tracing and monitoring compliance with treatments,” said Zambrano.

“Community healthcare workers can help support the delivery of medications and directly observed treatment to enhance completion rates.” According to the CDC, those with no known risk factors for TB may be considered for treatment of LTBI if they have either a positive interferon gamma release assay result or if their reaction to skin testing is 15 mm or larger.

Awareness and Prevention

Despite all the successes related to TB, Chandy and others believe there’s a need for better awareness of LTBI to maintain the momentum.

“The concept of latent tuberculosis is a complicated concept to begin with,” said Chandy. “I think that if you went out into the population, awareness is probably minimal to none and has probably always been that way.”

With increasing globalization, more awareness of infection exposure risks is needed, especially with infections such as TB, said Davis. “While public health departments have taken on most of the burden of treating both active and latent tuberculosis, there should be enhanced surveillance and prioritization by health systems to identify cases and connect patients to treatment,” he said.

“If the US is going to continue to be a country with lower TB rates, there needs to be enhanced surveillance and collaboration between health systems and public health departments.”

Chandy, Davis, Gohil, and Zambrano reported having no relevant financial disclosures.