The New York Times’ website has a little list of "most e-mailed articles". It is sometimes frightening. The list is often topped by stories related to furniture decision dilemmas, private schools for macramé, 100 recipes with cauliflower, or the latest Apple iGadget. These subjects appear to be of utmost importance, setting aside news.

Every once in a while, however, a few important stories make the "most e-mailed" list. Some of them recently have related to public health, often the belated articles about a recent pandemic threat, which portray the sense that we yet again escaped a "superbug"–bird flu, SARS–that never really seemed to happen anyway (well, not to "us" at least), or just fizzled off like the latest winter storm. The most recent of these has been extensively drug-resistant (XDR) tuberculosis, a form of TB that is resistant to most available medications, and is therefore more difficult to treat than its drug-susceptible counterparts [1]. Americans were recently told of two separate incidences of XDR TB among airline passengers–an American defense lawyer, and an Indian national–both of whom knew about their disease status and chose to fly anyway [2]. The sense was one of appall–a kind of "How could you put us in danger? What right do you have…" and yet in many ways, the sense of appall could be directed at those who seemed shocked.

That reasoning is more understandable if we look closely at the worldwide picture of XDR TB, and its causes. The disease has appeared on every continent, and in nearly every country that has TB, including the United States [3-5]. Many locations have just a few cases, and most cases are not linked to one another. Drug-resistant TB typically arises within individuals when they don’t take their medications properly (giving the bacteria a chance to mutate). This perspective has been the mantra of TB programs for years. The biological theory was that drug-resistant TB is too weakened by mutations to be directly transmitted from one person to another [6], and that the real problem is that patients don’t take their medicines correctly, acquiring their own individual drug-resistant bacteria. Patient-blaming is convenient for those of us in the medical system; it requires little effort on our part, because it’s not our fault [7].

But increasingly, we are finding that "non-complaint" patients are not the origin, but the side-effect, of inadequate medical care. Many patients are not prescribed an adequate regimen by their doctors. In fact, the World Health Organization’s (WHO) guidelines instruct physicians to use a regimen that is often ineffective when patients are failing therapy [8]; this regimen often amplifies the drug resistance [9]. But it’s cheap to use this regimen, and avoid rapidly testing patients for drug-resistant TB to give them "second-line" therapy. Indeed, XDR TB in South Africa increasingly became resistant to drugs as the WHO guidelines were implemented in the country [10, 11]. But guidelines for treatment often privilege cost over disease outcomes. South Africa is also a good example for why these drug-resistant strains arise, as it has both a high burden of drug-resistant TB generally, and has reported the most XDR TB cases to date (several hundred as of November 2006) [12, 13].

We can understand why this is the case if we take the patients’ perspective. Patients with TB in many regions of South Africa are typically too poor to see a doctor for a simple cough or cold symptom. So it is only when they are very symptomatic, or too weak to work, that they visit the local health post, where they are assumed to have TB and are given a standard medication regimen. They usually return home with this regimen, then get refills that require several return trips to the health post (because TB treatment takes months to complete). The added travel expenditures do not seem worth the lost work time, since the initial regimen generally makes the patients feel better [14]. So patients often discontinue therapy. Unfortunately, this is often the time that residual TB bacteria become resistant to drugs, by responding to subtherapeutic levels of medications in the body [9]. Months pass as this residual–now drug-resistant–TB builds, and the patient’s condition worsens. Finally they are tested for drug-resistant TB, usually after half a year or more has passed [15]. Their sputum samples are sent to national labs for testing, which takes at least one month [16]. Many die at this stage. A few will be detected and sent to a centralized referral hospital, which requires several days travel (and associated expense) and has a 70-person or longer waiting list [16]. Most patients then die or get intermittent therapy with "second-line" drugs from the referral center. Because these centers are far from patients, people typically miss refills, and continue to acquire more drug-resistance until death [17].

What complicates the picture is that some of these drug-resistant TB strains are transmissible, so the problem is not merely the build-up of resistant bacteria due to treatment interruptions and the difficulties of accessing effective drugs. Rather, some people catch already drug-resistant TB bacteria [18, 19]. South Africa‘s largest reported epidemic of XDR TB appears to be caused by a common strain of TB that infected people who were resistant to drugs they were never given [20, 21]. These people could not have gotten XDR TB by improperly taking their treatments. They caught the disease from TB bacteria that was already XDR.

What is particularly frightening is that the number one risk factor for them to have XDR TB was "hospitalization" [22]. In many of these regions, patients are admitted to hospital wards if they are too ill to stay home. Sometimes, given the media attention received by XDR TB, health officials will try to "quarantine" such patients out of fear that they may infect people in the community [23]. But there are rarely isolation facilities available. Patients will be detained in large rooms (often without adequate ventilation) with 40 or more other "suspects", many of whom are HIV-infected and therefore at greater risk of getting active, potentially infectious, TB [24]. It takes months to determine who has XDR, who has TB at all, and who just has a cough and possibly a pneumonia. During the time these patients stay together, many patients who did not have XDR TB will become "superinfected" with XDR TB, on top of whatever they already have [22]. A few bigger hospitals have a spare trailer home or additional room to put XDR TB patients, but the detection system takes a month or more to determine who has drug-resistant TB, while the median survival time of the XDR TB patients has been just 16 days after arrival getting tested at the hospital [21]. Most XDR TB patients die after they have been placed in circumstances where they could transmit the disease on the hospital ward, and before they can be isolated from other patients. That explains why so many patients who presented to hospitals with non-XDR TB or some other condition later returned and died with XDR TB, after being hospitalized with XDR TB patients but not exposed to XDR TB in the community [22].

Indeed, in spite of the focus on travelers on airplanes, the truth of the matter is that ventilation on airliners is actually sometimes much better than ventilation in some of these hospital wards, particularly in the hospitals located in the poorest areas affected by both HIV and TB [25, 26]. The risk of airplane transmission is remarkably low for most passengers [25], but on some hospital wards it would be difficult to avoid catching TB, particularly when being "detained" for a month or more in a stuffy room with several dozen other patients [24]. Some patients in South Africa have tried to protest their conditions and the involuntary detainment–a few "escaped" to see their families for Christmas; one was shot during a patient protest [27, 28].

But ironically, this disconnect between patient realities and health system approaches is highlighted even by the airline passenger cases. In both South Africa and the US, TB diagnosis relies upon technologies that are outdated. In 1882, TB was diagnosed primarily by microscope. In 2008, TB is diagnosed primarily by microscope. There has been little evolution. In the case of one airline passenger, TB was misdiagnosed as another form of drug-resistant TB, then called XDR TB, then again changed to another form of drug-resistant TB [29]. This has implications for what therapy to choose, and emphasizes that even the resource-rich facilities in the US have difficulty analyzing the samples from just one patient, who had extensive resources devoted to him. But even the major initiatives to develop new, rapid, easy-to-use TB diagnostic technologies for poorer locations are in their early stages, and are primarily industry-driven, developing technology that sometimes fails to involve those most in need. Most initiatives have been shoe-horning American and European market-based ideas onto African, Asian and Latin American health systems where the majority of systems have different personnel, electrical, chemical, and operational abilities and needs, let alone financing abilities [30].

Why are these TB systems having so much trouble? South Africa is not a terribly poor country in absolute terms, but those getting XDR TB are usually the poorest of the poor within the country. The largest epidemic of XDR TB has been from a location in the province of KwaZulu-Natal, where the white-owned and developed "Natal" area of beaches and cities and fertile land contrasts remarkably from the Zulu half of the province, which is rocky and can barely support subsistence farming and a small timber industry. HIV was typically imported there by migrant laborers who have no other job options (after being pushed onto infertile land in years past) and who are given alcohol and prostitutes by their European bosses on their one day off from work in the gold mines [31]. Women in situations of economic dependency often have little option but to engage in relationships with these men [32]. And in this context, an existing TB problem has dramatically amplified, given the number of immunocompromised, HIV-infected persons in the population. In the area where XDR TB was first reported, about 1 out of every 5 pregnant women is HIV-positive, and most still do not get antiretroviral therapy [21]. South Africa in particular has an enormous mining industry, fueled by American and European markets that drive migrant labor at low standards (and, in some mines, lead to working conditions that cause laborers to get silicosis, a disease that significantly increases the risk of TB [33]). The existence of migrant labor also destabilizes the effective treatment of TB, as migrants are among the hardest people to provide with a consistent medication supply and treatment monitoring over several months.

Indeed, Americans shocked by the importation of XDR TB into their country should be aware that their economic decisions have fueled, if not rendered inevitable, this drug-resistant pathogen’s emergence. In a large economic analysis of TB incidence, prevalence and mortality, it was found that even drug access was not as large a determinant of TB incidence and outcomes as were International Monetary Fund programs [34]. These programs, funded in part by U.S. taxpayers, typically reduced the number of available doctors and the quality of care, by emphasizing market medicine–which increases emphasis on drugs, diagnostic technologies, and hospitals designed for those who can pay [8]. But those are not the patients with TB. Health systems in the poorest locales have been destabilized, and do not appear to be recovering under the advisorship of American economists for whom the "outcomes targets" are reduced TB prevalence and deaths, but who do not recognize that the "inputs" to reach those targets will have to involve fundamentally allowing people to have control over their own health systems [8, 9, 35].

In the case of XDR TB, we have hope. Improving the standards of care is an accessible strategy; if South Africa, for example, can spend millions on stadiums for the upcoming World Cup, the capacity is there to do simpler things to the TB infrastructure. This means getting patients local care, so that distance and associated expenditures do not fuel new drug resistance [36]. It means supporting healthcare workers and obtaining diagnostic tests available and appropriate to their intended recipients, which will require public financing and communication between developers and those who use these tests [14]. And from our end, it requires that we pay attention to the economic packages directed from our own taxes and consumer decisions that focus on the end product instead of the standards of procurement. XDR TB is not an "untreatable" form of TB–indeed, over half of patients have been cured in some settings [37]. But treating XDR TB will require concerted effort and an eye towards the majority of patients who are affected, rather than the intermittent concern of a few who worry about airplane importation to the American heartland.

Sanjay Basu is at the Yale University School of Medicine. http://omega.med.yale.edu/~sb493

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