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Bad news in the global village: Are U.S. hospitals ready for XDR-TB strain?
Emerging bug truly capable of untreatable infections
Tuberculosis has been reduced to record lows in the United States since the major hospital outbreaks in the 1980s and '90s, but there is growing concern that deadly strains of extensively drug-resistant (XDR) TB may arise at a point of U.S. disinterest and waning funding, the very trough of the so-called "U-shaped curve of concern" that historically precedes TB resurgence.
"We are concerned about that kind of scenario," says Peter Cegielski, MD, team leader for drug-resistant TB in the international branch of the Centers for Disease Control and Prevention's division of TB elimination. "We [could be] facing another one of those situations based on the fact that federal funding for TB control has decreased over the past several years and the rate of decrease of TB in the United States has also slowed. It is not decreasing nearly as fast as it used to."
From 30,000 feet, it appears tuberculosis has met its public health match in the United States, where TB rates fell to an all-time low in 2006. In addition, the CDC detected only 49 cases of XDR-TB in a review of data back to 1993. Though the case count is low, it should be considered a "minimum estimate," the CDC emphasized. In addition, the epidemiology of drug-resistant TB appears to be changing. "XDR-TB presents a global threat and a challenge to TB-control activities in the United States," the CDC stated in reporting the data. "To prevent the spread of XDR-TB, renewed vigilance is needed through drug-susceptibility testing, case reporting, specialized care, infection control, and expanded capacity for outbreak detection and response."1
U.S. hospitals have faced outbreaks of multidrug-resistant TB (MDR-TB) before, but XDR-TB is like MDR-TB on steroids. Though only a small number of XDR-TB cases have been documented in the United States, there is concern because some of the cases were clearly the result of recent transmission — not prior failed drug therapy in a TB patient.
"It appears that transmission is occurring," Cegielski says. "Many of the individuals who have been reported in the U.S. with XDR-TB had never been treated before for TB, suggesting that they were in fact infected with XDR-TB in the first place."
By the current definition, XDR-TB is resistant to at least isoniazid and rifampin among the first-line anti-TB drugs and among second-line drugs, is resistant to any fluoroquinolone and at least one of three injectable drugs. The clinical reality, however, actually is worse than that definition sounds. Even in a time when such terms as "superbugs" and a looming "post-antibiotic era" are used routinely, the prospect of patients and health care workers exposed to XDR-TB is sobering. Common descriptions such as "virtually untreatable" are not exaggerations, Cegielski says.
"To treat TB, you have to use multiple effective drugs," he explains. "Even though not every anti-TB drug is in the definition of XDR-TB, in practice what you have left are ineffective drugs. What lab tests show might be an effective drug is very limited [in efficacy]. In effect, [clinicians] are limited to weaker drugs and an insufficient number of them. That is where the concept of 'virtually untreatable' and 'practically untreatable' comes from. That is not an overstatement."
The general consensus is that current hospital infection control measures for TB — if they are indeed in place and enforced — should be protective against the XDR strain. The problem is that there is little margin for error for health care workers and patients if a nosocomial outbreak occurred. Such an infection is immediately life-threatening, particularly for those with HIV or other immune-compromising conditions.
"An individual who has XDR-TB has a poorer prognosis than one who has multidrug-resistant TB without the additional drug resistance," Cegielski says. "I don't think there is a substantially increased risk to health care providers of getting XDR-TB, but if they do get it, then it is probably worse than MDR-TB."
Indeed, unpublished CDC data indicate that the chances for long-term survival — even in a person without HIV — are worse than 50/50 after an XDR-TB infection. "It appears that mortality rates are greater than 50% within four years," he says. "That means less than 50% of individuals [with XDR-TB] survive four years based on limited, unpublished data. For comparative purposes, the cancer survival [rate] is 55% in five years."
XDR-TB reported in 17 countries
Though only a smattering of XDR-TB cases have been reported in the United States, the dramatic emergence of such a dangerous infectious disease anywhere cannot be ignored in the "global village." XDR-TB has been identified in 17 countries from all regions of the world, most frequently in the former Soviet Union and Asia, Julie Gerberding, MD, MPH, CDC director recently told Congress.
"Given the increasing proportion of the burden of TB in the United States among foreign-born persons, there is a strong need to improve the quality of overseas medical screening of U.S.-bound immigrants, including the ability to detect and treat XDR-TB in this population," she said at a March 21, 2007, meeting of the Committee on Foreign Affairs Subcommittee on Africa and Global Health. "Equally important will be the strengthening of program infrastructures, both domestically and abroad, through training and sustained support."
Indeed, public health officials are taking the threat so seriously that, as this issue went to press, a 27-year-old man who acquired XDR-TB in Russia was sitting in a negative pressurized jail cell in Phoenix for allegedly refusing to wear a mask in public. That action was taken by state officials, but the federal government is looking to head off incoming cases through aggressive screening policies that are just now making their way into regulatory reality.
"We have developed new and stronger procedures of screening individuals who are entering this country as immigrants, refugees, and other applicants for permanent status," Cegielski says. "There is no screening for TB among visitors, students, tourists, and businessmen on shorter-term stays. Better procedures and stronger screening measures have been developed and are being implemented in practice. The policies are working their way through the system to be codified."
Of course, people entering the country illegally may slip through any screening efforts for XDR-TB, but the CDC is carefully stepping around that political issue while trying to beef up surveillance. "I would be very loathe to create the impression that we should keep more visitors out the United States," Cegielski tells Hospital Infection Control. "I don't want to this to be some xenophobic response."
In any case, heightened surveillance and increased drug susceptibility testing on all TB cases are being urged. "One of the most important things is that health care providers follow established guidelines for drug susceptibility testing and reporting," he says. "[Testing] guidelines state that if resistance is detected for any two anti-TB drugs then that patient's culture should be tested for the full panel of the anti-TB drugs. Those results should be reported promptly. I don't know for what reasons, but we are finding that testing for additional drugs sometimes is selective and the timing of the reporting could be improved."
Of course, improving susceptibility tests has implications for both individual patient treatment and larger public health concerns. "At an individual [patient] level, the full set of results are necessary in order to choose the best treatment," he says. "But this also has public health implications because as soon as you give that person effective treatment, then they stop spreading the infection. The broader issue is being able to accurately monitor and describe what is going on in this country with regard to the occurrence of XDR-TB."
The deadly nexus with HIV
Any emergence of XDR-TB would particularly threaten those living with HIV and AIDS, who appear to be extremely vulnerable to advancing infection with the strain. In describing an outbreak last year in KwaZulu-Natal Province in the Republic of South Africa, Gerberding reported a staggering 98% mortality rate among 53 people with XDR-TB. "[The] median survival period [was] only 16 days from the time health care workers collected their sputum for analysis," she testified. ". . . Among those patients with XDR-TB, 55% had no prior history of TB treatment, which indicated they had contracted their TB directly from other infected individuals. Forty-four of the XDR-TB patients also underwent testing for HIV, and 100% were found positive. Of these, 15 were receiving antiretroviral therapy, which is an important caution as we succeed in providing anti-retroviral therapy to more and more HIV-infected persons."
That latter point is particularly disconcerting because there has been a general perception that XDR-TB would not be as devastating in countries such as the United States where a large proportion of HIV-positive patients are on antiretroviral therapy. "One would expect that an HIV-infected individual is more vulnerable if they are not on antireterovirals," Cegielski says. "Certainly with MDR-TB and TB in general, widespread use of highly antiretroviral treatment has had a very positive effect on the occurrence of tuberculosis both in individuals and populations. One would expect the same situation to be true with XDR-TB, but having said that, some of the South African patients were on good antiretroviral treatment and had good virological responses but still died with XDR-TB."
In addition, apparently most of the cases in the South African outbreak were hospital-acquired. "The evidence, I think, clearly points to nosocomial transmission of a very lethal organism," Gerald Friedland, MD, an epidemiologist at Yale New-Haven (CT) Hospital and collaborating investigator on the outbreak said last year at the 37th World Union on Lung Health Conference in Paris. Of course, hospital infection control measures in South Africa are not comparable to the United States, but XDR-TB also caused devastating nosocomial outbreaks in Spain in the 1990s. During a recent update of that situation, clinicians warned that the "strain responsible for the 1991-1995 outbreak in Spain fits the XDR-TB case definition. No effective medical treatment was available for these patients. In two of the hospitals affected, all patients died, with a relatively short survival time of 40-some days between diagnosis and death."2 As a result of the XDR-TB outbreaks, Spanish hospitals have implemented rigorous infection control measures such as maintaining respiratory isolation units under negative air pressure, they reported.
"What happened with XDR-TB in South Africa and apparently in Spain is reminiscent of what happened in the United States with MDR-TB back in the late 1980s and early 1990s," Cegielski says. "There were a number of hospital outbreaks with high mortality rates, generally among HIV-infected individuals. So reasoning by analogy, yes, there certainly is concern about the potential for hospital transmission of [XDR-TB], but we don't have evidence that that has occurred or is occurring in the U.S. After those outbreaks of the 1990s, there are generally much better control measures."
Michael Tapper, MD, hospital epidemiologist at Lenox Hill Hospital in New York City, dealt with those early U.S. TB outbreaks and has seen cases of XDR-TB. "I don't think it changes anything [for infection control], but it is a warning," he says. "Obviously in a shrinking world, it certainly is possible if not likely that some additional cases will be imported from Africa. People will leave Africa and bring in that particular strain. The question is if there are patients with clinical infection and active disease, how quickly they are going to be recognized, how quickly they will be placed in appropriate facilities for isolation and put on effective treatment? I would like to think that the systems in the U.S. are prepared to recognize this and would find the isolated case."
In addition, the fact that more U.S. HIV patients are on antiretroviral treatment means there is less progress to full-blown AIDS, which required more aggressive treatments such as aerosolized pentamidine in the 1990s. "Aerosolized pentamidine facilitated transmission by making patients cough," Tapper notes. "There are far fewer people like that because they are far fewer people who have advanced to clinical AIDS. Most of them are on therapy, but in a vulnerable population, such as an inner-city population where there are a high number of HIV-infected people who have not yet been treated, there is always the potential for [TB transmission]."
And what about that "U-shaped curve of concern" — is XDR-TB arising at a low point of U.S. interest and corresponding vigilance to preventing a disease that is widely perceived as vanquished?
"Hospitals have certainly moved on to other issues, concerns about bioterrorism and pandemic influenza," Tapper says. "There are still pockets of high rates of TB, for example, in Harlem or in other inner cities. I do think though that some of the work that had to be done to get better negative pressure rooms and some of the other lessons learned [from the 1990s outbreaks] are still in place. Whether they would be adequate to protect us were XDR-TB to happen here is a very difficult question."