Atlanta lawyer Andrew Speaker sparked a media frenzy and public outrage, when—despite having been told he had active and extensively drug-resistant (XDR) tuberculosis (TB)—he flew to Europe for his 2007 wedding and honeymoon and put his fellow air travelers at risk.
When a federal order—the first of its kind in more than 40 years—quarantined him, further testing revealed he had less-severe multidrug resistant (MDR) TB. The subsequent furor over the case served as a wake-up call to the medical community.
“The Andrew Speaker story reminded hospitalists that Mycobacterium tuberculosis infects up to one-third of the world’s population, about 2 billion people,” says Stephen J. Swanson, MD, a staff physician with Hennepin County Medical Center in Minneapolis.
Dr. Swanson, who works as a pediatric hospitalist and completed a two-year fellowship with the Epidemic Intelligence Service (EIS) for the Centers for Disease Control and Prevention from 2004-2006, would like to see tuberculosis more on hospitalists’ radar screens.
Jay Routson, MD, a teaching hospitalist and clinical assistant professor of medicine in the Idaho State University Department of Family Medicine in Pocatello, says he does not feel entirely up to date on TB testing and MDR TB. “I rely on [infectious disease] and pulmonary specialists if I need the assistance,” he says. The last time he treated a case of suspected TB, the protocol called for four-drug therapy while awaiting sensitivities. He presumes this is unchanged. “I am comfortable with the [purified protein derivative (PPD) test], [polymerase chain reaction (PCR) test], and a bronchoscopic approach, but I’m ready for a review of newer testing modalities.”
New cases of tuberculosis in the United States have declined since 1993. As of 2006, almost 14,000 cases of active tuberculosis disease were reported—about 4.6 cases per 100,000 population. Foreign-born patients represent a greater proportion of these cases—50% of cases of tuberculosis in all age groups.
“In Minnesota, one-quarter of our foreign-born tuberculosis patients have been in the U.S. for less than a year before they were diagnosed,” Dr. Swanson says. “Most are not arriving with active tuberculosis; they are developing tuberculosis disease and being diagnosed years after their arrival in the U.S.”
In the United States, active tuberculosis often develops in people who acquired latent TB infection in their country of birth and then came to the U.S. Or, they have been exposed to infected people who have recently arrived in the U.S. About 1 million international travelers arrive in the U.S. each day.
But active TB also occurs in U.S.-born individuals (see Fig. 1, above). Risk factors include immunosuppression (e.g., HIV) and being older than 50, reflecting probable exposure to someone with active TB when it was more prevalent in the U.S.
—Stephen J. Swanson, MD, staff physician, Hennepin County Medical Center, Minneapolis.
Hospitalists should remain aware of the following erroneous beliefs about TB:
Active tuberculosis is primarily being seen with immunocompromised individuals, particularly those with HIV/AIDS. “Not true,” says Dr. Swanson, who is also a pediatric tropical medicine and infectious disease specialist. While the risk of TB disease is greatly increased in the immunocompromised, it occurs most commonly among the immunocompetent.
Tuberculosis is predominantly a pulmonary disease. Also not true. “At least in Minnesota, we know that more than 50% of our reported cases of tuberculosis disease are extrapulmonary,” says Dr. Swanson. “The rate of extrapulmonary tuberculosis is, in fact, much more common in the foreign-born than in the U.S.-born patients.”
Infants and young children with TB frequently have extrapulmonary manifestations such as meningitis, says Samir S. Shah, MD, MSCE, pediatric hospitalist and pediatric infectious disease specialist at the Children’s Hospital of Philadelphia.
Extrapulmonary tuberculosis is more likely among foreign-born individuals, even if they have been in the U.S. for five years or longer. This phenomenon also occurs among the elderly and immunocompromised patients, including those receiving corticosteroid therapy.
A negative PPD skin test rules out tuberculosis. A PPD can easily be falsely negative, says Dr. Swanson. “In fact, among normal adults, probably 25% of all cases of active pulmonary tuberculosis will have a negative PPD, even when their sputum demonstrates acid-fast bacilli,” he says. “The incidence of a false-negative PPD is even higher in children, and also higher if it is extrapulmonary tuberculosis. In half of these children with extrapulmonary tuberculosis you may easily have a falsely negative PPD.”
With that said, hospitalists should approach TB treatment while being mindful of these caveats:
Because tuberculosis may be extrapulmonary, it may not be identified with a chest X-ray. Almost every organ structure and body site can be a site of infection for tuberculosis, including the central nervous system, pericardium, bone, joints, skin, lymph nodes, and gastrointestinal tract.
Whether tuberculosis bacilli can be detected in sputum is a key determinant of transmissibility. “The reality is that Andrew Speaker, as it turns out, was smear negative, so they didn’t see any organisms with acid-fast stains,” says Dr. Shah. “[But] if individuals are smear-negative, they are they are still capable of transmitting disease.”
If you encounter a pediatric case of tuberculosis, transmission most likely has occurred from a household contact. Up to 17% of new cases of tuberculosis came from contact with someone with a negative acid-fast bacilli smear. If a sputum sample contains fewer than 1,000 bacteria/mL, the organism may not be detected on acid-fast staining, but still hold enough tuberculous bacilli to infect a person, especially with close and prolonged exposure. It takes only one to five bacilli arriving at the terminal pulmonary alveolus to infect an individual.
“We believe that roughly one-third to two-thirds of people exposed to a smear-positive individual with pulmonary tuberculosis will become infected,” says Dr. Swanson. “Although most will develop only latent tuberculosis infection, some will progress to active disease, particularly infected infants and young children.”
Because young children do not produce sputum, TB diagnosis in children is problematic. Infected children will present with malaise, fever, failure to thrive, and possibly erythema nodosum. Presentation is atypical: cough is infrequent except with endobronchial disease.
“One has to have a low index of suspicion and actively look for tuberculosis in children,” says Dr. Swanson.
Using gastric aspirates is one method, but is probably not more than 50% sensitive. The test is not ideal because it is time consuming, uncomfortable for young children, and aspirate samples must be collected on three consecutive early mornings.
Other approaches include ultrasound-guided transesophageal biopsies or computed tomography (CT)-guided biopsies of primarily hilar or paratracheal lymph nodes evident on CT.
There are also molecular diagnostic methods. In older children and adolescents, hospitalists can collect sputum induced with hypertonic saline. Even when acid-fast stains are negative, PCRs can be used to rapidly detect the presence of M. tuberculosis complex in sputum samples, tissue samples, and gastric aspirates, and stool samples when looking for intestinal tuberculosis.
The QuantiFERON TB Gold test (Cellestis International) is used to measure the interferon gamma released when blood samples are mixed with TB antigens and incubated. Although it has been around a number of years, it has just been incorporated into practice in the past two. The test is highly sensitive and specific but does not distinguish active from latent infection.
“It’s a pretty good test, although certainly not 100%,” says Dr. Shah, who is also an assistant professor of pediatrics and epidemiology at the University of Pennsylvania School of Medicine. “It can be used as an adjunct to skin testing to help exclude or confirm tuberculosis disease, but it should not replace clinical judgment.” Further, it is not clear how reliable the test is in children.
PPD tests are valuable when positive. False positive PPDs are rare; they generally develop from exposure to environmental non-tuberculosis mycobacterial species. A false-positive PPD can result from prior vaccination with the Bacillus Calmette-Guérin (BCG) vaccine used overseas. “Generally speaking, I do not let a patient’s BCG status influence how I interpret their PPD, especially when I am suspecting tuberculosis in the patient,” says Dr. Swanson. “Furthermore, a positive PPD is useful in confirming infection with tuberculosis, but a negative PPD will not definitively exclude TB infection.”
Although molecular diagnostics can verify the presence or absence of the tubercular bacillus, drug susceptibility testing is crucial to determine whether and how the organism should be treated. MDR TB is resistant to at least the first-line drugs rifampin and isoniazid. XDR TB is also resistant to any fluoroquinolone and at least one of three injectable second-line drugs: amikacin, kanamycin, and capreomycin.
Between 1993 and 2006, 49 cases (3% of evaluable MDR TB cases) met the revised case definition for XDR TB from the World Health Organization’s Emergency Global Task Force on XDR TB. Roughly 3% of TB cases in the U.S. are multidrug resistant, says Dr. Shah.
Emergence of drug resistance is more likely in cases of incomplete or intermittent therapy, or when an adequate treatment regimen was not begun after learning the initial two-month treatment phase has been done incompletely, inadequately, or with the incorrect medications.
“I will delay initiation of therapy on a patient so that I can get adequate samples from sputum, gastric aspirates, or tissue for mycobacterial isolation and susceptibility testing. This is because of the recognition that our hospital treats a large population of foreign-born individuals with a higher prevalence of drug resistance,” says Dr. Swanson. “You need to know your susceptibilities before blindly embarking on a treatment regimen.”
In the end, for all the renewed focus on the disease, “[drug resistance with tuberculosis] is not a new phenomenon … it has been flying under the radar,” says Dr. Shah.
Dr. Swanson serves up this analogy: “XDR tuberculosis is like Britney Spears. It gets a lot of attention. But there’s a lot more dysfunction and psychopathology in Hollywood than just Britney Spears, and a lot more disease and debilitation produced by non-XDR tuberculosis.” TH
Andrea Sattinger is a medical writer based in North Carolina.