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Tuberculosis: the problem we could have avoided

People went on red alert about SARS, where the fatality rate was approximately 10%. Bird flu doesn’t even spread between people (yet), but we’re on red alert about bird flu. Don’t get me wrong. Prevention is way better than cure. But it would make sense to deal with actual current threats before panicking about possible ones.

Tuberculosis is a much bigger problem than SARS, and it’s here, now, and killing millions. Untreated TB has a fatality rate of around 55%. TB treatment in the days before drugs reduced that rate to around 30%. In developed countries, with anti-TB drugs, the fatality rate was around 7%. (TB stats from the CDC.) Most of the current fatalities worldwide are people who had ordinary TB and couldn’t afford the cure. From a callous perspective, that’s not a problem in developed countries. But the drug-resistant strains that evolve in people who can’t or don’t take the full course of treatment is everybody’s problem.

As if that wasn’t bad enough, drug-resistant TB just took a turn for the worse.

There are three different factors to keep in mind with bacteria and viruses: virulence (the severity of the symptoms caused by that specific strain), infectivity (how likely you are to catch it), and drug resistance. These are not correlated. A disease can be virulent, but not highly infective or drug resistant, or totally resistant to drugs, but not virulent, and so on.

So far, drug resistant TB has been rather low on infectivity. (Even bacteria have a hard time being good at everything all at once.) The guy I will always think of as The TB Lawyer had an extremely drug resistant strain (XDR, worse than the MDR, multiply drug resistant, strains you commonly hear about). But it was a strain with low infectivity. (I guess, when they told him that, he heard only the good news, and figured he was good to go.) [Update: Turns out he has MDR TB. See footnote for a bit more detail.] I haven’t seen anything about where he picked it up (an interesting question, no?) or how virulent it is. They say he has a 30% chance of succumbing, which is what you’d expect for “normally” virulent TB when drugs aren’t — or as in this case — can’t be used.

Well, now comes news from South Africa of a hyper-virulent, extremely drug resistant strain. When these medical types say hyper-virulent, they mean it. Fifty two out of the 53 people with confirmed diagnoses died. Average survival after the diagnostic samples were taken was 25 days. Median survival (i.e. the length of time the largest number of people survived) was 16 days.

Now, these particular people also had AIDS, which doesn’t help, but this is not the way AIDS patients react to “normal” TB. There is no reason to think the hyper-virulence would be different in people without AIDS. It’s also not an experiment where I’d like to be the guinea pig.

The strain is not, from what I see, hyper-infective. If it’s like “normal” TB, it spreads rather like a cold.

Great, huh?

The World Health Organization is so freaked out by this combination of characteristics, they’d like to see people go on a SARS-type alert to prevent global transmission. They also want South Africa to receive as much aid as is necessary to make sure all cases are identified, isolated, and treated. (See the excellent PLoS article for that and many other links.)

(Factoid via CDC, March 2006: “XDR TB was identified in all regions but was most common in South Korea … and countries of eastern Europe/western Asia.” These strains are not (yet) hyper-virulent.)

Following the steps indicated by the WHO would be the intelligent thing to do. Not to panic. Not to hoard (probably useless) drugs, not to join Cheney in a bunker and shoot all comers. No, just to address the issue and do what it takes.

Instead, the reaction in the developed world could be summarized as, “Another disease in Africa?” *Yawn*

We won’t be yawning when (it’s when, not if) the strain gets here. Then we’ll be flapping around in a useless panic, probably with fascist overtones, if past experience is any guide.

MDR TB: resistant to the two main TB drugs (rifampicin and isoniazid). XDR TB is resistant to those as well as the quinolone class of antibiotics, and at least one of the second-line antibiotics (kanamycin, capreomycin, or amikacin). (These drugs are more toxic to the patient and usually(?) or always(?) have to be given by IV.) The older definition of XDR TB was resistance to three or more of the second-line drugs. (From Wikipedia) The definitions are clearly divided, but the bacteria are not. Resistance is not all or nothing. So a TB infection could be 100% resistant to the two main drugs, 90% resistant to one of the second-line drugs, 80% to another one, 65% to another one, and so on. What are you going to call that? MDR? XDR? I suspect this is the problem the CDC was having. They tested the diagnostic samples, found plenty of resistance, and tried to find the guy. Further tests showed some susceptibility, so now they’re calling it MDR.)

Tuberculosis: The Solution?

Is there a solution? The short answer is yes, if we give it the time, attention, and money it needs. So the long answer is, “No.”

I’m not really joking. People do have a way of getting their act together when faced with death, but the problem here is that once we’re faced with it, it’ll be too late to do anything effective.

Short term, for instance, we could be doing what the WHO says: prevent global transmission with a SARS-type effort, and make sure everyone with TB is successfully treated. That’s including if it costs actual money and requires actual aid. All I can think is, “What are the chances of that?” (Those of you who have better ideas than me about how we can take our little teaspoons and start digging at the mountain of stupid, help us out in comments.)

What I’m so pessimistic about is people having the sense to take preventive measures. Those are the only kind that will really do us any good long term, because the usual solutions to a disease crisis, drugs, are becoming ineffective as we speak. If we wait for outbreaks, drugs may not save us.

The sinister thing is that bacteria learn a lot faster than bureaucrats. [more] Drug resistant TB is a symptom of broken medical care. Cost-cutting results in anemic anti-TB programs without adequate follow-up to make sure patients take the full course of treatment. Taking only some of the antibiotics, enough to kill the susceptible bacteria but not enough to kill all of them, very quickly leads to populations of drug-resistant TB. MDR TB (multiply drug resistant) began appearing in the early 1990s. By the late 1990s, XDR TB (extremely or extensively drug resistant) had appeared. In 2006, people noticed that XDR TB was appearing everywhere, but they took heart from its low infectivity. Then the South African cluster appeared among AIDS patients. We don’t know whether it would spread as easily among people with healthy immune systems. But now that we’re breeding lots of XDR TB, it’s only a matter of time before one of those is highly infective for everybody. Maybe it’s already here. Maybe it isn’t. But the matter of time is on the order of a year, or three.

The only way to deal with a disease that has no cure is to prevent it. And the only way to do that for TB is to have a vaccine. We have no really good vaccines. If a full-scale effort started now, and was successful, it’ll be a decade or three before it’s ready for use.

There are some good scientific, reality-based reasons why vaccine development takes time. But there are also some regulatory reasons which are nothing but bureaucratic inertia. (For a taste of the complexity, read this Nature commentary.)

For instance, since the early days, the only way to get regulatory approval was to incubate some of the essential components in chicken eggs. Once upon a time, that was the only way to do it, but for the last decade or more, tissue culture and yeast incubation have been the cheaper, better, and much faster method. But regulatory approval stayed stuck in the chicken era until (I believe) the SARS scare. I think at that point they got off their duffs and tried to streamline procedures a bit, but I’d be surprised if there wasn’t still a lot of room for improvement.

The vaccine that we do have right now has issues.

In the US, there’s very little TB, comparatively speaking, so most people haven’t been exposed. That means a very cheap and simple skin test can identify the few people who have been exposed. However, after vaccination, the skin test comes up positive. It can’t tell the difference between people with the disease and people who have fought it off (which is what a vaccine actually does). It takes a more expensive and time-consuming test to make that distinction. Needless to say, the public health authorities would rather keep things simple. For them.

There are also real reasons why it’s not that good an idea to get vaccinated. The effectiveness of the usual BCG vaccine varies. Sometimes in children it gets up to about 85%. However, in a 1966 US government study, it was as low as 14% in adults. Those aren’t very impressive numbers. (Although, maybe, if you’re flying long distances and there are lawyers from Atlanta on the plane, you’d prefer to have some chance of immunity rather than none?) Furthermore, surviving an actual case of TB does not guarantee immunity against new infections, so it’s not surprising that the BCG vaccine can’t either.

Then there’s the fact that unless you’re traveling to a country with serious TB problems, US doctors don’t hand out the BCG immunization. The CDC’s recommendations go so far as to say that if you’re going overseas to spend time in hospitals or prisons, you should get tested before and after to see if you caught TB. No suggestion that immunization might make sense, even if all it does is reduce the chance of catching it. So getting the vaccine probably involves traveling to a country where they do provide it.

Other vaccines besides BCG have an even bigger disadvantage. They’re not available yet. MVA85A is the closest to delivery. It’s a virus engineered to carry important bits of TB and to improve the effectiveness of BCG vaccination. It’s in testing, and although a Nature article makes it seem it’ll be out Real Soon Now, a 2004 BBC report said actual use was expected in 2014. (Update 2014-01-25: Link to Nature article no longer available. Similar link here Unfortunately, MVA85A did not pan out.)

If effective vaccines aren’t there yet, then what do we do when an outbreak happens? (Note the “when.” It’s intentional.) There is one preventive measure that antibiotics have allowed us to forget about: quarantine.

Forcible quarantine has been mentioned recently only in connection with AIDS (and, of course, the TB lawyer). For a sexually transmitted disease, it makes zero sense. STDs are simple to stop IF you can get people to cooperate. (You see why I’m so pessimistic about anything that depends on cooperation.) But for a lethal disease that’s transmitted like a cold, quarantine makes a lot of sense from an epidemiological standpoint.

Quarantine also makes a whole hornet’s nest of civil liberties and humanitarian issues.

Can you deprive anyone of liberty who has committed no crime? Who’s responsible for the person’s welfare? That’s a non-trivial question when you’re putting a sick person into surroundings with other sick people, who may have different strains of the disease that can cause infections on top of existing infections. Who pays for the enforced hospital stay? If it’s a disease with a high fatality rate (as drug-resistant diseases tend to be), what are the merits of taking someone from her or his family, incarcerating them in a perhaps distant facility, and never allowing direct contact so that the person has to die surrounded by strangers? Who pays for the extra medical personnel and enforcers to look for sick people being hidden by their families?

I’ve put those things as questions because I honestly don’t know the answer. In my healthy, unthreatened state, I want to make sure the sick person is helped to the full extent of modern medicine.

On the other hand, if I’d been on that plane with Mr. “TB Lawyer” Speaker, I’d be livid at him. And at the CDC for not preventing him from flying in the first place.

So, I don’t know how to answer those questions. But what I do know is that all of us, you, me, everyone, have to figure out those answers now. If we wait until people are dying, the answers will be ugly and panicked. Which is the same as saying they’ll be ineffective.

So what would you do?