IT might be an unfashionable part of London鈥檚 East End, but on a fresh spring
morning, the borough of Newham looks cheerful enough, dapper even, with its
leafy park and Victorian terraced houses standing as neat as ninepins. You鈥檇
never guess you were strolling through the tuberculosis capital of the affluent
Western world鈥攂ut unless the statistics are lying, that鈥檚 Newham鈥檚 current
claim to fame.
Tuberculosis. TB. The rod-shaped microbe that famously wrecked the lungs and
lives of John Keats, Emily Bront毛 and others. In case you hadn鈥檛 heard,
it鈥檚 back and enjoying a new lease of life in the era of Puff Daddy and Lara
Croft. A couple of months ago came news of the largest TB outbreak ever recorded
at a British school, in Leicester, then a cluster of suspected cases in
Aberdeen. And this is just the small beer.
Every day around 3000 Londoners swallow the cocktail of powerful antibiotics
needed to purge their lungs of TB, while seven more show the first
symptoms鈥攃hest pains or a stubborn cough. London now has double the cases
of New York, a city that spent $1 billion and much of the past decade
fighting an epidemic in Manhattan (see Diagram).
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Newham is the new Manhattan. Its prevalence of 108 cases per 100,000 of its
population puts it ahead of India (41 per 100,000) and even impoverished,
chaotic Russia (91 per 100,000). What鈥檚 happening? Talk to local nurses and
doctors and you hear the familiar story of TB thriving among the homeless and
disenfranchised, among drug addicts and the malnourished, people living in
unsanitary, overcrowded houses, sleeping on floors and chairs. But importantly,
you also hear something else.
Around half of Newham鈥檚 TB victims are asylum seekers, fleeing conflicts and
poverty in sub-Saharan Africa, India and Bangladesh, where resurgent TB has been
a growing problem for the past two decades. Most arrive carrying the bug in a
harmless latent form. It鈥檚 the poor conditions they encounter in Britain that
spring the microbe from its hideouts in the lungs.
In other words, London鈥檚 worsening TB problem is not home-grown. It is a
symptom of globalisation鈥攐f the fact that in an interconnected world of
cheap air travel, one nation鈥檚 epidemic can quickly become another鈥檚. During the
heyday of the empire, Britain exported TB. Now it鈥檚 back and baying for
blood.
鈥淲e鈥檝e always let the developing world rot,鈥� says Liverpool University鈥檚
Peter Davies, one of Britain鈥檚 foremost TB experts. 鈥淏ut for the first time the
diseases of that world鈥攑articularly TB鈥攁re impinging on us. And
we鈥檝e got a choice. We can do something or just sit back and hope.鈥�
Unfortunately, sitting back as the bodies pile up has become a habit in our
dealings with TB. One person infected every four seconds, one dying every ten
seconds. The global statistics are almost too grim to shock. TB claims more
lives, often young and productive ones, than malaria, more even than AIDS.
And yet TB lacks the pull of HIV, Ebola or malaria. No Hollywood movie
dramatises its workaday carnage. The disease conjures up not drama but humdrum
images of Asian and African poverty, fuelling a complacency and ennui that
drives TB specialists to despair.
鈥淭hree million people are dying every year,鈥� exclaims a visibly troubled
Mario Raglivione, head of TB control for the World Health Organization. 鈥淎nd
virtually the whole of sub-Saharan Africa is infected.鈥� Infected with a latent
version of a microbe that can hibernate for years before attacking; a microbe
you can catch simply by sleeping in the same room as someone; a microbe that if
it gets out of control will eat your lungs and make you cough up blood before it
spreads to your kidneys, spinal cord and even your brain. TB is not humdrum,
says Raviglione鈥攊t鈥檚 鈥淓bola with wings鈥�.
Perfect niche
And now it is flying like never before. TB鈥檚 first big break came in newly
industrialised Britain, where it rose rapidly up the league table of killers as
the undernourished rural poor flocked to the cities to fill squalid houses and
prisons. It was a near-perfect niche for an airborne microbe that preys on the
weak, and today we鈥檙e recreating it on a global scale and with added
dangers.
Look at Russia, Eastern Europe, Estonia and Latvia. Ten years ago, no serious
TB problem. Now, in the wake of social and economic collapse, TB is so rampant
in former Soviet prisons that to be thrown in the slammer means almost certain
infection combined with a hit-and-miss approach to drug treatment. Result: these
countries are now the world鈥檚 chief breeding grounds for drug-resistant strains
of the bacterium.
And being infected with one of these is no joke. Ten dollars鈥� worth of
antibiotic pills taken for six months will cure you of bog-standard TB. A
drug-resistant infection can mean two years鈥� of daily injections and hospital
care costing up to 拢100,000. Yet still patients throw away their pills as
soon as they feel better, not recognising that the bugs are still there and
likely to pop up later in drug-resistant form.
From the south comes a different warning. Across Africa latent TB infections
are flaring up as HIV strips people of the immunity they need to keep the bug
down. HIV is to TB what matches are to kindling, and Africa could be just the
start of the wildfire. 鈥淭he spread of HIV in India and China, where TB is
endemic, will be a disaster,鈥� says Barry Kreiswirth of New York University.
As might HIV鈥檚 ongoing march into Eastern Europe. 鈥淚n Samara, in the Volga
region, there鈥檝e been 10,000 HIV cases in two years, from virtually nothing
before that,鈥� says Richard Coker, a TB researcher at the London School of
Hygiene and Tropical Medicine who spends a lot of time in the former Soviet
Union. 鈥淭he epidemic of HIV is clashing with TB, which means things could get
monumentally out of control.鈥�
If so, the TB of old will look mild by comparison. All those drug-resistant
strains cooking in Russian jails could get a new chance to spread and the
microbe may reinvent itself in other ways as it adapts to its new global niche.
Ominously, some experts think they can see the first signs of a new, more
virulent TB emerging from China (see 鈥淎 superbug you can catch in a crowd鈥�).
For a decade, the main weapon against TB has been a programme called DOTS.
Standing for 鈥渄irect observed treatment short course鈥�, it鈥檚 run by the WHO and
involves getting nurses in TB hot spots both to prescribe TB drugs and supervise
patients to make sure they finish the course. Unfortunately, while DOTS has won
a few battles, it is losing the overall war against TB.
And losing it big time. Back in 1990 the aim was to get the 22 worst affected
countries detecting 70 per cent of TB cases and curing 85 per cent of them by
the year 2000. This simply hasn鈥檛 happened. Only two countries, Peru and
Vietnam, have met the target, most are not even close, and 10 years into the
programme only 1 in 5 people worldwide have access to basic TB drugs. Even the
WHO, in its latest report on TB control, admits 鈥減rogress has been slow鈥�. What鈥檚
more, the poor countries are largely footing their own bill, providing 75 cents
of every dollar needed for treatment.
The WHO insists it can get DOTS back on course if donor countries like the US
and Britain stump up an extra $400 million a year. Others say cash alone
is no longer enough. 鈥淢uch as DOTS is a good programme,鈥� says Mohta Smith, an
expert on drugs and poverty at Oxfam, 鈥渋t鈥檚 very difficult to get people to
comply .鈥� As Tom Frieden, the former head of New York鈥檚 eradication programme
warns: 鈥淎 poorly run programme can create multidrug-resistant TB faster than you
can eradicate TB.鈥�
Rapid-fire
In short, the war against TB needs better ammunition. First, drugs that work
in weeks rather than months and trigger far less resistance and fewer side
effects (one front-line TB drug causes fatal liver failure in some patients).
And second, a vaccine that actually works. No major infectious disease has ever
been beaten without one, yet the existing 80-year-old vaccine for TB, while it
offers some protection in developed nations, is virtually useless in many parts
of the world.
On present form we鈥檙e in for a long wait. In the past 30 years just one new
drug (rifapentine) has been introduced specifically to treat TB and even that is
just a derivative of an old antibiotic. There have been no major clinical trials
of any new vaccines. And the standard tuberculin screening test is more than 100
years old. Worse, claim campaigners like Oxfam鈥檚 Smith, promising compounds
languish on the shelves of drugs companies unwilling to gamble large sums
developing treatments for patients unable to pay much for them.
One example is a class of antibiotics known as the oxazolidinones. First made
by DuPont in the 1970s, the compounds wiped out a wide range of bacteria in the
testtube鈥攊ncluding TB. Expectations soared among TB specialists. The US
drugs giant Pharmacia bought the rights to the compounds and developed one,
linezolid, as a treatment for pneumonia and the 鈥渟uperbugs鈥� that sometimes
infect surgical wounds in hospitals. So far, none of the compounds has surfaced
as a TB treatment.
The lab work continues. A 1996 study hailed one of linezolid鈥檚 stablemates a
鈥減otent鈥� TB killer with a 鈥渇avourable toxicity profile in rats鈥�. And this year a
university team in Texas concluded that linezolid itself has 鈥渆xcellent
potential for therapy of rapidly growing mycobacteria鈥�. But Pharmacia has no
plans to move any of the drugs into clinical trials. When asked why not, a
spokesperson simply told 快猫短视频 that 鈥淭B is not an indication we
are currently pursuing鈥�.
Meanwhile, the fate of another potentially revolutionary weapon against TB
hangs in the balance鈥攁 compound code-named PA-824. Identified by a small
Seattle-based company called PathoGenesis in the mid-1990s, the drug, hailed as
the first truly novel anti-TB drug in three decades, invades TB microbes,
blocking the production of a fatty chemical they need to make their cell wall.
In the test-tube it demolishes colonies; in mice it rapidly clears infections
without causing nasty side effects. Not even the mighty defences of multidrug
resistant strains keep the drug out. And unlike most antibiotics, it continues
to dispatch bugs speedily, long after they鈥檝e given up dividing and slunk into
hibernation, waiting for better times. In short, says Rick O鈥橞rien, leading TB
expert at the world famous Centers for Disease Control in Atlanta, Georgia,
compound PA-824 could 鈥渟horten tuberculosis treatment significantly鈥�.
If it ever reaches any patients. Last autumn PathoGenesis was swallowed up by
a bigger company called Chiron and the future of PA-824 now looks uncertain. The
lab research continues, but 快猫短视频 understands that clinical
trials are only likely if another company or non-profit organisation agrees to
split the bill or buys the right to develop the drug from Chiron. Smith is not
optimistic. 鈥淭hey either dump the research or use the drugs for something else,鈥�
she says鈥攖ypically a disease that affects richer people.
Nobody has ever claimed TB is a pushover. The microbes鈥� thick waxy shells
protect them from many run-of-the-mill antibiotics. And once inside the lungs,
they dodge the body鈥檚 defences by hiding inside macrophages鈥攖he very
immune cells that are supposed to destroy them. All the body鈥檚 defences can do
is seal the microbe off inside the nodules, or tubercles, that give the disease
its name.
Once there, TB can lie low for years or even decades, waiting for the moment
to attack. But disease is not inevitable: nine out of ten infected people never
develop symptoms or infect others. Nor are poverty and poor living conditions
the only triggers. Genes and even lack of sunshine can play a part. For example,
Gujarati Indians who move from Africa to live in affluent areas of London are
three times as likely to develop symptoms as those who stay put. Lack of vitamin
D is what seems to trigger their disease.
It would also be inaccurate to say drugs companies and scientists are doing
nothing about TB. The companies that make the expensive second-line drugs have
just struck a deal with the WHO to supply those drugs at cost price to the
countries that need them (see 鈥淭he ultimate weapon鈥�). More generally, after decades in the
scientific wilderness, the microbe is now being studied in more labs.
A crucial step forward came three years ago when scientists finished
sequencing the bug鈥檚 genome. Already that blueprint, with its 4000 genes, has
enabled teams to identify new enzymes from tuberculosis that might be vulnerable
to drugs. And at Colorado State University a team led by Ian Orme has recently
screened some 50,000 compounds for signs of activity against TB. About 100 of
the most promising are now being tested in mice. Other teams are working on ways
to rouse the hibernating microbe prematurely from its tubercles so the body鈥檚
defences can attack it. On the immunisation front, there are several
experimental vaccines that, in the words of one expert, 鈥渨ork quite well in
animals鈥� (see 鈥淭he ultimate weapon鈥�).
One day we might even have the TB equivalent of the malaria pills travellers
take to ward off infection. Last year a team in New York discovered that a TB
enzyme called isocitrate lyase plays a key role in enabling the microbe to bed
down in the lungs. Now drugs giant GlaxoSmithKline is looking for compounds to
block the enzyme. Ultimately, it could lead to a revolutionary new generation of
TB pills, safe enough to give to healthy people who want to lock out the
bug.
Or it could just lead to more shelves filled with abandoned TB treatments.
The problem is that getting promising compounds and experimental vaccines is the
cheap part. It鈥檚 the clinical trials that need the big bucks and are the real
test of a company鈥檚 commitment to TB. And here the news isn鈥檛 good. Out of
literally hundreds of promising treatments, 快猫短视频 found not a
single drug, and only two vaccines, with firm dates for small-scale human safety
trials (see 鈥淭he ultimate weapon鈥�). Most are five to ten years off even
being considered for a trial.
The poor relation
快猫短视频s at the bench say that鈥檚 because the renaissance in TB research is
too recent to deliver new treatments. Doctors say it鈥檚 because if you scratch
the surface you find the will and money to tackle TB aren鈥檛 really there.
鈥淒erisory鈥� is what Davies calls the sums being invested. 鈥淭hey鈥檙e doing no
more than they need to buy some immunity against attack and get the press off
their backs.鈥�
Is that fair? Take GlaxoSmithkline. As a leading maker of drugs to treat
respiratory diseases, you鈥檇 expect it to be doing more than most. And indeed it
is. Since 1993 it has spent the equivalent of 拢2 million a year on what
the company鈥檚 latest annual report calls an 鈥渆xtensive research programme鈥� on
TB.
Not bad say critics鈥攗ntil you weigh it against the 拢2.4 billion
the company spent in total on R&D last year; or the 拢2.8 million in
salaries and bonuses paid to its two chief executives; or the 拢2.7 billion
the company earned from sales of its six-strong fleet of asthma and hay-fever
drugs. TB might claim 3 million lives a year compared to asthma鈥檚 180,000, but
in the drug development stakes asthma, a disease of affluence rather than
poverty, wins hands down. While GlaxoSmithkline鈥檚 programme 鈥淎ction TB鈥� has yet
to deliver a single new treatment, the company has 10 new asthma products in the
pipeline.
According to Davies, the commercial bias against diseases like TB is now so
out of control that it鈥檚 contributing to serious errors of diagnosis. In the
recent outbreak of TB in Leicester, the source was an Asian teenager with an
active TB infection. Yet for nine months he was prescribed asthma drugs鈥攁
delay that led him to infect many people. Davies says: 鈥淒octors don鈥檛 think of
TB because there isn鈥檛 a company producing goods saying 鈥榯hink of TB鈥�.鈥�
To be fair, drugs companies are not charities. Nor did Big Pharma create the
vast inequalities that fuel diseases like TB. And there鈥檚 one barrier to
launching new TB products it certainly can鈥檛 be blamed for鈥攖he generic
drugs currently used to treat conventional TB are now so cheap that any new drug
would have to be dramatically more effective to compete in the marketplace. It鈥檚
naive to expect the companies to deliver without more incentives from
governments and their taxpayers.
Hotting up?
TB has begun moving up the political agenda of late, piggybacking on growing
concerns about HIV and the globalisation of disease. The UN has set up a Global
Health Fund specifically to tackle HIV, malaria and tuberculosis, while in
Britain the government says it will give tax breaks to companies that invest in
research into drugs and vaccines for these diseases. There is a lot of talk
everywhere about 鈥減ublic-private鈥� partnerships. And even the World Trade
Organization has begun to discuss ways to force companies to hand over the
promising compounds sitting on their shelves so that others can develop them. So
is the war on TB about to hot up?
The signs are less than overwhelming. So far, Britain has contributed
拢75 million to the new fund, the US $200 million鈥攍ess than
one-third of what it will spend this year funding research into the harmful
effects of recreational drugs. The WHO, remember, needs an extra $400
million a year just to salvage its TB treatment programme.
Meanwhile, a report from the US Institute of Medicine in Atlanta has
advocated screening for TB all applicants for US citizenship from hot-spot
countries. Could the US be contemplating a political solution to TB?
If so, they should forget it, says Frieden. 鈥淲e鈥檙e all connected by the air
we breathe, that is not going to change, the solution is not to build a perfect
moat.鈥� In today鈥檚 world, diseases are global. No country, city or neighbourhood
is an island.
Not New York. Not even Newham.
Why do we need a new TB vaccine when we鈥檝e already got one? Because the
existing BCG jab, made from cattle tuberculosis, protects no more than 80 per
cent of those who have the jab鈥攁nd often not even that.
In fact, in India, Malawi and many other tropical countries, the vaccine is
next to useless at stopping adult lung disease. That鈥檚 possibly because children
in the tropics are exposed to soil bacteria very similar to TB. The natural
immunity they build up to these bacteria may be enough to kill off the weak BCG
vaccine before it can trigger much immunity to TB. But whatever the explanation,
we need a new vaccine that provokes a much stronger response from the body鈥檚 T
cells鈥攖he white blood cells that coordinate our immune defences, as well
as seeking out and destroying infected cells.
Turbocharged versions of the old BCG vaccine are one option. At the Pasteur
Institute in Paris, Brigitte Gicquel, coordinator of the European TB Vaccine
Cluster, is giving the old vaccine new genes. These will enable it to make the
messenger proteins, or cytokines, our bodies use to summon T cells to the site
of an infection.
Others are starting from scratch. Two hundred years ago Edward Jenner
famously used cowpox to inoculate people against smallpox. Today at the Wellcome
Centre of Human Genetics in Oxford, Adrian Hill and his team are turning a
harmless relative of that cowpox virus into a TB vaccine. They鈥檝e given the
virus certain TB genes in the hope it will mimic TB, infecting cells in the body
and churning out tuberculosis proteins to prime the immune system. Small-scale
safety trials are planned for next year.
Another promising vaccine is the brainchild of a Seattle-based company called
Corixa and drugs giant GlaxoSmithKline. It鈥檚 a mixture of two proteins from TB
that seem adept at triggering strong reactions from human T cells. The vaccine
protects monkeys from TB, and is due to start human safety trials in
mid-2002.
鈥淎t this moment, there are nine or ten candidates which work quite well in
animal models,鈥� says Ian Orme, director of the Mycobacteria Research
Laboratories at Colorado State University.
One of the problems facing vaccine developers is the long timescale needed to
prove that a vaccine works鈥攅specially for a disease which can take decades
to develop. But Orme thinks we should get stuck in with trials as soon as
possible. 鈥淭he time is ripe to strike,鈥� he says. 鈥淲e need to get out there and
do it.鈥�
Claire Ainsworth
Super-contagious TB, a strain you can catch on the bus or in the street. It鈥檚
every epidemiologist鈥檚 nightmare, but could it ever really happen?
In the 鈥測es鈥� corner is Dick van Soolingen of the Dutch National Institute of
Public Health and Environmental Protection in Bilthoven: 鈥淎 strain of TB that
spreads more easily is bound to emerge and be selected for.鈥�
In fact, van Soolingen thinks TB is already showing signs of change. One TB
variety, which he dubs Beijing, turned up in northern China sometime in the past
hundred years, and has been on the move ever since. Now it is dominant in Russia
and accounts for half the infections in Indonesia. It鈥檚 not dramatically more
harmful than other strains, says van Soolingen, but it does seem to spread more
easily and seems more likely to develop drug resistance. What鈥檚 more, modern
medicine could be to blame. Van Soolingen suspects the BCG vaccine provides
weaker than normal protection against the Beijing strain, allowing it to
flourish at the expense of other strains.
Adapting to AIDS gives tuberculosis another reason and chance to change. When
people with HIV get conventional TB, the bug usually kills them very
quickly鈥攚ell before it can be passed on to another victim. That鈥檚 not in
the microbe鈥檚 interests鈥攈ence the spread of HIV could hasten the evolution
of new TB strains that are easier to catch.
Alternatively, TB could simply evolve into less harmful forms that would kill
untreated HIV victims more slowly. Indeed, some experts think TB has been slowly
evolving into something less harmful and contagious for thousands of years, long
before HIV came along.
At the National Institute of Allergy and Infectious Diseases in Hamilton,
Montana, James Musser sees the rise of apparently more contagious strains as a
mere blip in this trend. His genetic studies suggest cattle TB jumped into
people about 20,000 years ago. Once there, the microbe evolved into the first
true strain of human TB, from which two more modern varieties branched off. All
three types of TB are still around, but crucially, says Musser, the more modern
varieties are less likely to create clusters of outbreaks鈥攕uggesting they
are less transmissible. 鈥淎ll the evidence shows we are moving towards a
detente,鈥� says Musser.
This view holds that in protecting itself with such a strong cell wall
millions of years ago, TB unwittingly signed its own death warrant. The wall may
keep out drugs, but it also prevents the microbe exchanging DNA with other
bacteria, so it cannot acquire new genetic skills to rid itself of the damaging
genetic mutations that gradually accumulate by chance.
In short, tuberculosis is doing as a species what most of us do only as
individuals鈥攇rowing old and slowly falling apart.
Debora MacKenzie