Cape Town

The 11 cities most likely to run out of drinking water – like Cape Town

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Dripping tap

Cape Town is in the unenviable situation of being the first major city in the modern era to face the threat of running out of drinking water.

However, the plight of the drought-hit South African city is just one extreme example of a problem that experts have long been warning about – water scarcity.

Despite covering about 70% of the Earth’s surface, water, especially drinking water, is not as plentiful as one might think. Only 3% of it is fresh.

Over one billion people lack access to water and another 2.7 billion find it scarce for at least one month of the year. A 2014 survey of the world’s 500 largest cities estimates that one in four are in a situation of “water stress”

According to UN-endorsed projections, global demand for fresh water will exceed supply by 40% in 2030, thanks to a combination of climate change, human action and population growth.

It shouldn’t be a surprise, then, that Cape Town is just the tip of the iceberg. Here are the other 11 cities most likely to run out of water.

1. São Paulo

Brazil’s financial capital and one of the 10 most populated cities in the world went through a similar ordeal to Cape Town in 2015, when the main reservoir fell below 4% capacity.

At the height of the crisis, the city of over 21.7 million inhabitants had less than 20 days of water supply and police had to escort water trucks to stop looting.

Image copyright Getty Images
Image caption At the height of the drought, Sao Paulo’s reservoirs became a desolate landscape

It is thought a drought that affected south-eastern Brazil between 2014 and 2017 was to blame, but a UN mission to São Paulo was critical of the state authorities “lack of proper planning and investments”.

The water crisis was deemed “finished” in 2016, but in January 2017 the main reserves were 15% below expected for the period – putting the city’s future water supply once again in doubt.

2. Bangalore

Local officials in the southern Indian city have been bamboozled by the growth of new property developments following Bangalore’s rise as a technological hub and are struggling to manage the city’s water and sewage systems.

To make matters worse, the city’s antiquated plumbing needs an urgent upheaval; a report by the national government found that the city loses over half of its drinking water to waste.

Like China, India struggles with water pollution and Bangalore is no different: an in-depth inventory of the city’s lakes found that 85% had water that could only be used for irrigation and industrial cooling.

Not a single lake had suitable water for drinking or bathing.

Will Cape Town be the first city to run out of water?

Image copyright Getty Images
Image caption Pollution in Bangalore’s lakes is rife

3. Beijing

The World Bank classifies water scarcity as when people in a determined location receive less than 1,000 cubic metres of fresh water per person a year.

In 2014, each of the more than 20 million inhabitants of Beijing had only 145 cubic metres.

China is home to almost 20% of the world’s population but has only 7% of the world’s fresh water.

A Columbia University study estimates that the country’s reserves declined 13% between 2000 and 2009.

And there’s also a pollution problem. Official figures from 2015 showed that 40% of Beijing’s surface water was polluted to the point of not being useful even for agriculture or industrial use.

The Chinese authorities have tried to address the problem by creating massive water diversion projects. They have also introduced educational programmes, as well as price hikes for heavy business users.

4. Cairo

Once crucial to the establishment of one of the world’s greatest civilisations, the River Nile is struggling in modern times.

It is the source of 97% of Egypt’s water but also the destination of increasing amounts of untreated agricultural, and residential waste.

Image copyright Getty Images
Image caption The Nile provides 97% of Egypt’s water supply

World Health Organization figures show that Egypt ranks high among lower middle-income countries in terms of the number of deaths related to water pollution.

The UN estimates critical shortages in the country by 2025.

5. Jakarta

Like many coastal cities, the Indonesian capital faces the threat of rising sea levels.

But in Jakarta the problem has been made worse by direct human action. Because less than half of the city’s 10 million residents have access to piped water, illegal digging of wells is rife. This practice is draining the underground aquifers, almost literally deflating them.

As a consequence, about 40% of Jakarta now lies below sea level, according to World Bank estimates.

To make things worse, aquifers are not being replenished despite heavy rain because the prevalence of concrete and asphalt means that open fields cannot absorb rainfall.

Image copyright Getty Images
Image caption Illegal well-drilling is making the Indonesian capital more vulnerable to flooding

6. Moscow

One-quarter of the world’s fresh water reserves are in Russia, but the country is plagued by pollution problems caused by the industrial legacy of the Soviet era.

That is specifically worrying for Moscow, where the water supply is 70% dependent on surface water.

Official regulatory bodies admit that 35% to 60% of total drinking water reserves in Russia do not meet sanitary standards

7. Istanbul

According to official Turkish government figures, the country is technically in a situation of a water stress, since the per capita supply fell below 1,700 cubic metres in 2016.

Local experts have warned that the situation could worsen to water scarcity by 2030.

Image copyright AFP
Image caption A 10-month long drought dried up this lake near Istanbul

In recent years, heavily populated areas like Istanbul (14 million inhabitants) have begun to experience shortages in the drier months.

The city’s reservoir levels declined to less than 30 percent of capacity at the beginning of 2014.

8. Mexico City

Water shortages are nothing new for many of the 21 million inhabitants of the Mexican capital.

One in five get just a few hours from their taps a week and another 20% have running water for just part of the day.

The city imports as much as 40% of its water from distant sources but has no large-scale operation for recycling wastewater. Water losses because of problems in the pipe network are also estimated at 40%.

9. London

Of all the cities in the world, London is not the first that springs to mind when one thinks of water shortages.

The reality is very different. With an average annual rainfall of about 600mm (less than the Paris average and only about half that of New York), London draws 80% of its water from rivers (the Thames and Lea).

Image copyright Getty Images
Image caption London has a water waste rate of 25%

According to the Greater London Authority, the city is pushing close to capacity and is likely to have supply problems by 2025 and “serious shortages” by 2040.

It looks likely that hosepipe bans could become more common in the future

10. Tokyo

The Japanese capital enjoys precipitation levels similar to that of Seattle on the US west coast, which has a reputation for rain. Rainfall, however, is concentrated during just four months of the year.

That water needs to be collected, as a drier-than-expected rainy season could lead to a drought. At least 750 private and public buildings in Tokyo have rainwater collection and utilisation systems.

Home to more than 30 million people, Tokyo has a water system that depends 70% on surface water (rivers, lakes, and melted snow).

Recent investment in the pipeline infrastructure aims also to reduce waste by leakage to only 3% in the near future.

11. Miami

The US state of Florida is among the five US states most hit by rain every year. However, there is a crisis brewing in its most famous city, Miami.

An early 20th Century project to drain nearby swamps had an unforeseen result; water from the Atlantic Ocean contaminated the Biscayne Aquifer, the city’s main source of fresh water.

Miami's sea font

Although the problem was detected in the 1930s, seawater still leaks in, especially because the American city has experienced faster rates of sea level rise, with water breaching underground defence barriers installed in recent decades.

Neighbouring cities are already struggling. Hallandale Beach, which is just a few miles north of Miami, had to close six of its eight wells due to saltwater intrusion.

Poor More Likely to Suffer During South Africa’s Dire Drought

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Cape Town, South Africa is in the throes of a years-long drought that could earn it a truly alarming distinction: the first major city in the developed world to run out of water.

South Africa as a whole is experiencing its worst drought in a century. The six dams that supply Cape Town’s water have dropped to just 15.2 percent capacity of usable water, according to the Los Angeles Times, down from 77 percent in September 2015. Enforcement of strict water restrictions – which cut permitted daily consumption from 23 gallons per day to just 13.2 gallons – begin February 1.

Shravya K. Reddy, principal at Pegasys Strategy and Development and Climate Reality’s former director of science and solutions, lives in Cape Town and says that while several factors – including relatively rapid population growth, poor planning, and people ignoring previous water restrictions – have all contributed to this crisis, officials’ failure to recognize the role that climate change plays in exacerbating drought has made the situation even more dire.

“Decision-makers well-versed with climate science would have taken it seriously and would have started treating this drought, even in 2015 or 2016, as if it would last longer than usual,” Reddy tells Climate Reality. “Instead, they seemed to never escalate the preparations for additional water supplies or accelerate water augmentation projects in the belief that taking drastic action would be overkill, since the rains would come. If they had taken more concerted action two years ago or early last year, then they would not need to be on such war footing right now.”

Climate change worsens drought because as temperatures rise, evaporation increases. When this evaporation happens over land, soils dry out. Many places are also experiencing both decreases in annual precipitation and longer periods without significant rain, resulting in reduced water levels in streams, rivers, lakes, and (importantly) reservoirs. When rains do come, much of the water runs off the hard ground and is carried back to the ocean before it can fully replenish dams, reservoirs, or the water table.

All of Cape Town’s citizens are feeling the impact of the drought, but the city’s lower-income residents are already bearing the brunt. Should the city, which has a population of more than 4 million people in its greater metropolitan area, run out of water on April 21, as many are predicting, their plight will become truly desperate.

“Socio-economic disparity is evident in both peoples’ access to critical information, as well as in the measures people are taking to prepare for ‘Day Zero,’ the day when the city has to shut off municipal water and taps literally run dry,” Reddy says. “In speaking with people who typically have to work the longest hours just to financially survive, it seems to me that they simply don’t have access to the same levels of information we do, and thus are less empowered to make informed decisions about how they will cope and manage.”

This disparity, she adds, can often be traced back to a lack of computer and internet access among many of South Africa’s lower-income communities.

Another imbalance has become clear: Wealthier citizens have the resources to prepare and safeguard themselves from the worst of the water crisis’ impacts.

“Those with more disposable income can stock up on more bottled water. We can also invest in more water-saving devices,” Reddy explains. “Many of Cape Town’s most under-resourced residents live in what we call townships or informal settlements – what the West would call shanty towns or even slums – and they’re lucky if they have a communal water source amongst eight to 10 families. They certainly cannot buy and hoard bottled water.

“People with means – transportation as well as leisure time – can drive farther out of the city to areas where clean, potable water comes out of natural springs and can collect water to take home. Those who don’t have the luxury of a car and time to drive around are less able to take advantage of such natural springs hours away.”

She notes that some retailers are even taking advantage of the situation, increasing the price of common water conservation tools like buckets, pitchers, and other water storage units because of higher market demand, making them even less accessible to the people who may need them the most.

And beyond the obvious necessity of clean drinking water, Reddy worries that “significant public health challenges will emerge as a result of people not being able to maintain individual and institutional hygiene.” The risk of water-borne diseases and other bacterial infections may also rise sharply, elevating the risk of serious public health issues.


“Money buys other adaptation means too. The wealthy have greater ability to buy more new clothes as a response to less clothes washing, ordering takeout food as a response to less cooking and dishwashing, buying ‘chemical toilets,’ tons of wet-wipes, hand sanitizer, and leaving the city for long stretches of time to escape elsewhere – either by renting places in other cities or staying with friends and family who can afford to accommodate long-term guests,” she continues.

“Based on what several people in my circles have been saying, it is clear that some people will have the ability to temporarily leave the city and move to their second homes out in the countryside, to parts of the province that are not as water stressed. Some may even temporarily move to Johannesburg or leave the country until some semblance of normalcy is restored. The majority of the city’s residents do not have that immense privilege.”

Reddy concludes on a note that has become all too familiar for many already experiencing the climate crisis firsthand: “Certainly in the case of climate change adaptation in any community, anywhere in the world – those with greater means at their disposal will fare better.”

With each new natural disaster, the truth becomes clearer: The most vulnerable among us are on the front lines of a crisis they had the least to do with creating – and if we don’t act now to support solutions and end climate change, we may reach a point of no return.

Is Cape Town Thirsty Enough to Drink Seawater?

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Cities like Cape Town may now have to rely on desalination to help them survive drought.

Cape Town is withering. If current projections hold, the South African city of 4 million will run out of water on May 11, known as Day Zero. It’s been three long years of drought—we’re talking a once every 1,000 years kind of problem that Cape Town’s water infrastructure just wasn’t built for.

The irony is that a whole sea of water laps at the shores of the coastal city. But if you wanted to drink it, you’d have to build an expensive, energy-intensive desalination facility. Cape Town is indeed rushing to bring such projects online, at least on a temporary basis, and in so doing is exposing a dire reality: Pockets of humanity around the world may have to rely on the sea to survive drought in the very near future. Because it’s likely that climate change is exacerbating this drought.

Models show that for certain parts of the world, things are going to get real hot and real dry. The American South, for instance, could see a tripling of 95-degree-plus days per year by 2050. “Cape Town is a warning shot for us,” says Michael Kiparsky, director of the Wheeler Water Institute at UC Berkeley. “What we can see is that it’s very possible for water crises—which emerge all the time around the world—to get close to the point of real, massive human disaster.”

The key to managing water is diversifying. Think of it like stocks—if you’re all in on Enron and Enron implodes, so does your money. But invest in a range of companies and you can hedge against uncertainty. Same goes for water sources. Dams, however ecologically terrible their impacts, let you save up a stock of water. You may even decide to treat wastewater to boost your supply. And you’ll of course want to convince your populace to save water, even in times of plenty.

Cape Town does not have a stellar portfolio. “The diversification of our water sources would have helped a whole lot earlier,” says environmental scientist Kevin Winter of the University of Cape Town. “It’s difficult to do that because you need sometimes these triggers to be able to change the budgetary system and be able to think differently about a long-term strategy.”

The city is certainly triggered now. (The local government was unable to provide comment before this story published.) And what it’s been able to do in recent months is pretty remarkable, at least from a public education perspective: A city that once consumed 290 million gallons of water a day now uses 160 million gallons. But that’s still a whole lot of water in a region where rain just refuses to fall.

So Cape Town is turning to desalination to tackle the shortfall. Specifically, temporary reverse osmosis plants that’ll spin up in the coming months and provide fresh water. Not much of it in the grand scheme of things—4 million gallons a day—but still a start.

Desalination is not a new idea. For decades now, researchers have been doggedly exploring the technology, which comes in two flavors. The first you can do at home if you like, just boiling water to collect steam and leave salt behind. The second is reverse osmosis, and involves forcing water through a permeable membrane to filter out the salt. Problem is, boiling water takes a ton of energy, as does pumping water.

The technology is improving. Fancy new materials, like membranes just an atom thick, are making reverse osmosis more efficient. (That is, making it easier to push that water through.) “Desalination technology is going to change considerably in the coming years,” says Winter. “I think what the city is currently doing right now is to go slowly with its experiments and it will start to ratchet those up in time.”

Which has some scientists crying foul. Late last year, a group of researchers published a paper detailing how desalinated water could theoretically be tainted by sewage piping into the waters off Cape Town. In their samples of seawater they found 15 pharmaceutical and household chemicals, as well as nasty microbes like E. coli. These are not things you’d want to suck into a desalination plant and turn into drinking water without some serious testing and purification if necessary.

On top of the potential pollutants coming out of a desalination plant, there’s also the byproduct of brine (lots and lots of salt), which is pumped back out to sea, potentially disrupting ecosystems. That and desalination plants can kill sea critters by hoovering them up. “It doesn’t make sense to me to solve one ecological problem by creating a whole lot more,” says the University of Cape Town’s Lesley Green, co-author of the paper, “which is saltier seawater and not managing the discharge of medicinal compounds and persistent organic pollutants.”

Desalination may also present unexpected social costs in Cape Town, because not every citizen would benefit from it. “At home I have water, it flows out of the tap,” says the University of Cape Town’s Tom Sanya, an architect who specializes in sustainable design. “But we have a significant number of people in the informal settlements of Cape Town who don’t have water flowing in their homes. If the city has up to now failed to supply each individual resident in Cape Town with water, then I can’t be convinced that after investing heavily in technologies we’ll have enough money left to invest in distribution.”

Still, in Cape Town, the ecological and social costs of desalination may pale in comparison to the consequences of not turning to the sea for help. The energy costs of the technology are still huge, but Israel has proven it can be done on a massive scale: The nation now makes more freshwater than it needs. And as certain parts of the world descend into a new era of heat and dryness, desalination is going to look like a mighty tempting solution.

“It kind of depends on how bad you need the water,” says engineer Amy Childress of the University of Southern California. “And that’s exactly where South Africa is, and it’s where California would have been if we didn’t have a rainy last year. It really is pure and simple—how bad you need the water and how unlucky you are with the drought.”

Cape Town has been very, very unlucky. But it’s taking steps to diversify its water portfolio, and the rest of the world would be wise to follow. Otherwise it’ll be Enron for the lot of us.

Archbishop Desmond Tutu asks for the right to an assisted death for himself

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Archbishop Desmond Tutu celebrating mass at St George's Cathedral, Cape Town, on his 85th birthday
Archbishop Desmond Tutu celebrating mass at St George’s Cathedral, Cape Town, on his 85th birthday 

Archbishop Desmond Tutu – whose life and struggles have inspired millions around the world – has said he wants to have an assisted death and end his life by his own choosing.

Writing on the occasion of his 85th birthday Archbishop Tutu said he does not want to be kept alive “at all costs” and maintains his right to decide when to depart from this world.

The Archbishop first spoke of his support for assisted dying two years ago, but this is the first time he has said explicitly that he would choose it for himself.

He said: “I have prepared for my death and have made it clear that I do not wish to be kept alive at all costs. I hope I am treated with compassion and allowed to pass on to the next phase of life’s journey in the manner of my choice.”

The Archbishop’s words come after he was admitted to hospital last month for surgery to treat a series of recurring infections related to his long running battle with prostate cancer, and it is understood the experience brought into sharp focus the imminent prospect of death.

Archbishop Tutu won admiration across the globe for his steadfast and courageous campaigning against apartheid in South Africa during the 1980s and early Nineties.

Following the introduction of democratic rule he went on to campaign against corruption, poverty and HIV, remaining a steadfast advocate of human rights across the continent.

For those suffering unbearably and coming to the end of their lives, merely knowing that an assisted death is open to them can provide immeasurable comfort.Archbishop Desmond Tutu

His words, in an essay for the Washington Post, will renew the debate over the rights and wrongs of assisted dying, an issue which still causes deep divisions within the worldwide Anglican Church and the wider community.

Archbishop Tutu wrote: “Just as I have argued firmly for compassion and fairness in life, I believe that terminally ill people should be treated with the same compassion and fairness when it comes to their deaths. Dying people should have the right to choose how and when they leave Mother Earth.”

He went on to state that he had reversed his lifelong opposition to assisted death in 2014, but had remained more ambiguous about whether he desired it for himself.

Now, however, he says: “Today, I myself am even closer to the departures hall than arrivals, so to speak, and my thoughts turn to how I would like to be treated when the time comes.”

Archbishop Emeritus Desmond Tutu arrives in a wheelchair for a church service in celebration of his 85th birthday at St. Georges Cathedral, Cape Town
Archbishop Emeritus Desmond Tutu arrives in a wheelchair for a church service in celebration of his 85th birthday at St. Georges Cathedral, Cape Town 

Archbishop Tutu goes on to argue forcefully that while he believes in the sanctity of life, people – especially those in pain – should not be denied the right to make their own choice as to when they die.

“For those suffering unbearably and coming to the end of their lives, merely knowing that an assisted death is open to them can provide immeasurable comfort,” he said.

The Archbishop, who received the Nobel Peace Prize in 1984, celebrated his birthday on Friday by presiding over Eucharist at his home church, St George’s Cathedral, in Cape Town.

In his essay he repeated his support for the former Archbishop of Canterbury Lord Carey’s attempts to introduce a bill allowing doctors to help terminally ill people take their own lives in this country.

“In refusing dying people the right to die with dignity, we fail to demonstrate the compassion that lies at the heart of Christian values,” said Archbishop Tutu.

“I pray that politicians, lawmakers and religious leaders have the courage to support the choices terminally ill citizens make in departing Mother Earth.”

The then Bishop Desmond Tutu, in May 1980
The then Bishop Desmond Tutu, in May 1980 

But Baroness Finlay of Llandaff, a former Welsh government adviser on palliative care and an opponent of assisted dying, questioned the burden the responsibility for assisting someone to end their life would place on the individual tasked with carrying it out and on a country’s medical services.

She said: “Suicide is not illegal and pain free methods are widely known, so the real question is who Archbishop Tutu wants licenced to assist his death?

“That person would have the responsibility of judging that he has the mental capacity to make such a decision, they would have to decide that the prognosis is correct and won’t change and they would have to carry the burden of helping him die.”

Tuberculosis: Test Speeds Diagnosis, Time to Treatment.

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The Xpert MTB/RIF (Cepheid) test improved tuberculosis (TB) diagnosis and reduced time to treatment, but not long-term TB-related morbidity, according to the results of a multicenter, randomized, controlled trial.

“Despite already being rolled-out in many countries, our study is the first to look at the feasibility of the Xpert test in a real-life clinical setting in southern Africa,” lead author Keertan Dheda, MBBcH, from the Department of Medicine, University of Cape Town, South Africa, said in a news release. The study results were published online October 28 in the Lancet.

The researchers enrolled adult patients with symptoms suggestive of active TB at 5 primary care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. They randomly assigned patients to either Xpert MTB/RIF testing, performed at the clinic by a nurse who received 1 day of training, or to sputum smear microscopy. On the basis of local World Health Organization–compliant guidelines, participants with a negative test result were managed empirically.

The main study endpoint, analyzed by intention to treat, was TB-related morbidity, measured with the TB score and Karnofsky performance score at 2 months and 6 months after randomization in culture-positive patients who had started anti-TB treatment.

Of 758 assigned patients to smear microscopy between April 12, 2011, and March 30, 2012, 182 were culture positive, as were 185 of 744 patients assigned to Xpert MTB/RIF. Among culture-positive patients, median TB score and median Karnofsky performance score in culture-positive patients did not differ between groups at 2 or at 6 months.

Diagnostic Performance of Point-of-Care MTB/RIF

Compared with microscopy, point-of-care MTB/RIF had higher sensitivity (83% vs 50%; P = .0001), but similar specificity (95% vs 96%; P = .25). Compared with laboratory-based MTB/RIF, point-of-care MTB/RIF had similar sensitivity (83%; P = .99), but higher specificity (92%; P = .0173).

Of 744 tests with point-of-care MTB/RIF, 34 (5%) failed, as did 82 (6%) of 1411 with laboratory-based MTB/RIF (P = .22). More patients in the MTB/RIF group than in the microscopy group had a same-day diagnosis (24% vs 13%; P < .0001) and same-day treatment initiation (23% vs 15%; P = .0002).

Because of the lower dropout rate, more culture-positive patients in the MTB/RIF group were receiving treatment by study end (8% untreated in the MTB/RIF group vs 15% in the microscopy group; P = .0302). By day 56, however, the proportions of all patients receiving treatment were similar (43% vs 42%, respectively; P = .6408).

“Although earlier diagnosis by the Xpert test did not reduce overall severity of TB-related illness, and moreover did not reduce the overall number TB cases treated over the course of the study, it has substantial benefits over smear microscopy including improved rates of same-day diagnosis and reducing treatment drop-out,” Dr. Dheda said in the release.

Cost-Effectiveness May Be a Concern

Limitations of this study include about 20% loss to follow-up of patients with culture-confirmed TB, mostly resulting from staffing problems at 1 site, and possible lack of generalizability to seriously ill patients or those with extrapulmonary TB.

“Whilst Xpert may not be the ideal point of care TB test in particularly poorly resourced settings, in countries like South Africa where the clinic infrastructure is relatively good, rates of drug-resistant TB are high, and patient drop-out are significant problems, within clinic placement of Xpert in TB hotspots might be appropriate and enable earlier diagnosis of drug-resistant TB thus likely reducing community-based transmission,” Dr. Dheda noted. “Nevertheless, prevention of TB and adherence to TB treatment is critical and remains a major priority.”

In an accompanying comment, Christian Wejse, MD, PhD, associate professor, GloHAU, Center for Global Health, Department of Public Health, Aarhus University, Denmark, wonders about the cost-effectiveness of Xpert testing.

“At a cassette cost of US$10 (reduced price for low-resource settings), testing large numbers of people with suspected tuberculosis will put substantial pressure on already resource-limited tuberculosis programmes in which the drugs for treatment might not always be available,” Dr. Wejse writes. “Hence, the provocative question raised by this study is whether tuberculosis elimination is most likely to be advanced by distributing GeneXpert machines to all peripheral health facilities in the world, or by investing the same amount in ensuring that health facilities have the set-up available in this study—ie, well trained and paid staff, electricity, and reagents.”

Tuberculosis: Test Speeds Diagnosis, Time to Treatment.

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The Xpert MTB/RIF (Cepheid) test improved tuberculosis (TB) diagnosis and reduced time to treatment, but not long-term TB-related morbidity, according to the results of a multicenter, randomized, controlled trial.

“Despite already being rolled-out in many countries, our study is the first to look at the feasibility of the Xpert test in a real-life clinical setting in southern Africa,” lead author Keertan Dheda, MBBcH, from the Department of Medicine, University of Cape Town, South Africa, said in a news release. The study results were published online October 28 in the Lancet.

The researchers enrolled adult patients with symptoms suggestive of active TB at 5 primary care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. They randomly assigned patients to either Xpert MTB/RIF testing, performed at the clinic by a nurse who received 1 day of training, or to sputum smear microscopy. On the basis of local World Health Organization–compliant guidelines, participants with a negative test result were managed empirically.

The main study endpoint, analyzed by intention to treat, was TB-related morbidity, measured with the TB score and Karnofsky performance score at 2 months and 6 months after randomization in culture-positive patients who had started anti-TB treatment.

Of 758 assigned patients to smear microscopy between April 12, 2011, and March 30, 2012, 182 were culture positive, as were 185 of 744 patients assigned to Xpert MTB/RIF. Among culture-positive patients, median TB score and median Karnofsky performance score in culture-positive patients did not differ between groups at 2 or at 6 months.

Diagnostic Performance of Point-of-Care MTB/RIF

Compared with microscopy, point-of-care MTB/RIF had higher sensitivity (83% vs 50%; P = .0001), but similar specificity (95% vs 96%; P = .25). Compared with laboratory-based MTB/RIF, point-of-care MTB/RIF had similar sensitivity (83%; P = .99), but higher specificity (92%; P = .0173).

Of 744 tests with point-of-care MTB/RIF, 34 (5%) failed, as did 82 (6%) of 1411 with laboratory-based MTB/RIF (P = .22). More patients in the MTB/RIF group than in the microscopy group had a same-day diagnosis (24% vs 13%; P < .0001) and same-day treatment initiation (23% vs 15%; P = .0002).

Because of the lower dropout rate, more culture-positive patients in the MTB/RIF group were receiving treatment by study end (8% untreated in the MTB/RIF group vs 15% in the microscopy group; P = .0302). By day 56, however, the proportions of all patients receiving treatment were similar (43% vs 42%, respectively; P = .6408).

“Although earlier diagnosis by the Xpert test did not reduce overall severity of TB-related illness, and moreover did not reduce the overall number TB cases treated over the course of the study, it has substantial benefits over smear microscopy including improved rates of same-day diagnosis and reducing treatment drop-out,” Dr. Dheda said in the release.

Cost-Effectiveness May Be a Concern

Limitations of this study include about 20% loss to follow-up of patients with culture-confirmed TB, mostly resulting from staffing problems at 1 site, and possible lack of generalizability to seriously ill patients or those with extrapulmonary TB.

“Whilst Xpert may not be the ideal point of care TB test in particularly poorly resourced settings, in countries like South Africa where the clinic infrastructure is relatively good, rates of drug-resistant TB are high, and patient drop-out are significant problems, within clinic placement of Xpert in TB hotspots might be appropriate and enable earlier diagnosis of drug-resistant TB thus likely reducing community-based transmission,” Dr. Dheda noted. “Nevertheless, prevention of TB and adherence to TB treatment is critical and remains a major priority.”

In an accompanying comment, Christian Wejse, MD, PhD, associate professor, GloHAU, Center for Global Health, Department of Public Health, Aarhus University, Denmark, wonders about the cost-effectiveness of Xpert testing.

“At a cassette cost of US$10 (reduced price for low-resource settings), testing large numbers of people with suspected tuberculosis will put substantial pressure on already resource-limited tuberculosis programmes in which the drugs for treatment might not always be available,” Dr. Wejse writes. “Hence, the provocative question raised by this study is whether tuberculosis elimination is most likely to be advanced by distributing GeneXpert machines to all peripheral health facilities in the world, or by investing the same amount in ensuring that health facilities have the set-up available in this study—ie, well trained and paid staff, electricity, and reagents.”

Source: Lancet

A Transcriptional Signature for Active TB: Have We Found the Needle in the Haystack?

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Analysis of whole-genome RNA expression in human clinical samples is a relatively novel approach to biomarker development. The pattern of RNA expression (i.e., transcriptional signature) can provide a “biological snapshot” of the immune response to physiological stressors, and specific disease states may produce distinct transcriptional signatures. In this week’s issue of PLOS Medicine, Michael Levin and colleagues report that a blood RNA transcriptional signature can be used to diagnose active tuberculosis (TB) in high HIV/TB prevalence settings. Using blood samples from patients referred for TB evaluation at three sites in Cape Town, South Africa (cases from an outpatient TB clinic; controls from two hospitals) and one district hospital in Northern Malawi, the authors identified a minimal set of 44 transcripts that distinguished patients with TB from patients confirmed to have an alternative diagnosis. They then converted the complex expression data into a simple-to-calculate disease risk score, which was highly sensitive (93%, 95% CI [83–100]) and specific (88%, 95% CI [74–97]) for active TB.

Have We Found the Needle in the Haystack?

This landmark study advances the field in several critical ways. For the first time, a blood transcriptional signature for TB was defined by comparison with patients who have conditions that mimic TB in a high burden setting instead of with healthy controls or patients with sarcoidosis or auto-immune diseases [1]–[4]. The inclusion of controls for whom TB was in the list of differential diagnoses but ultimately excluded increases confidence that the blood transcriptional signature identified may be clinically relevant. Second, the authors developed the disease risk score, which provides a single measure of the degree to which an individual’s RNA expression is consistent with TB. The disease risk score can be calculated by simply subtracting the summed normalized intensities of down-regulated transcripts from those of up-regulated transcripts. By eliminating the need to use complicated bioinformatics to make predictions from the RNA expression data, the disease risk score could simplify the application of transcriptional signatures in clinical settings. Finally, the authors demonstrate convincingly the high diagnostic accuracy of their blood transcriptional signature. The results were impressive in their test set (20% of enrolled patients), including in HIV-infected and smear-negative sub-populations, and in an entirely independent validation dataset published years earlier [1].

Although the results are promising, key questions remain. First, can the results be reproduced in a truly representative population? State-of-the-art technology and bioinformatics are critical tools for identifying prospective targets, but the rigorous application of fundamental epidemiological principles will be indispensable to advancing these technologies into the clinical arena, where it will be necessary to show their utility in truly representative populations. Levin and colleagues describe an “intention-to-test” recruitment strategy but nonetheless enrolled a highly selected patient population. TB patients generally had advanced disease (over 90% of HIV-uninfected patients [96/106] and over 75% of HIV-infected patients [83/109] were smear-positive) and 28% (207 of 751) of patients were excluded because TB status was uncertain. The control group was recruited entirely from inpatient wards and most patients had non-respiratory diseases. These factors resulted in a spectrum bias towards the extremes of disease manifestations, which is known to inflate estimates of diagnostic accuracy [5]. Second, can a robust threshold be developed for the disease risk score that works in different settings? An inherent limitation of the microarray technology used in this study is that it provides only relative quantification of RNA expression so that intensity values are relevant only within, and not across, experiments [6]. Ultimately, to be clinically useful, a threshold will need to be defined a priori rather than on the basis of experimental data and the selected threshold will have to be consistent across geographic settings. Finally, can a platform be developed to enable measurement of the transcriptional signature in low-income countries? A number of novel technologies for quantitative multi-channel measurement of nucleic acid targets are in development. However, the cost and difficulty of assaying a 44-transcript signature seem prohibitive far into the future. Absent a transformative technology, it is difficult to envision transcriptional profiling having a meaningful impact in parts of the world where novel TB diagnostics are most needed [7].

Triage Testing: A Target for Future Research

As Levin and colleagues suggest, their 44-transcript DRS may be more useful as a triage (i.e., rule-out) test [8] because negative predictive value is high (98%, 95% CI [96–100]), while positive predictive value is sub-optimal (66%, 95% CI [46–87]) when TB prevalence is 20%, as is common in routine settings. The concept of a triage test deserves further attention in the TB diagnostics literature. An ideal triage test rules out disease when negative and triggers further testing when positive (e.g., a mammogram for breast cancer screening). Thus, a triage test requires near-perfect sensitivity (particularly when the consequence of missing disease is high) but only moderate specificity. If rapid and inexpensive, such a test could be used to determine which patients presenting with TB symptoms require confirmatory testing (e.g., automated nucleic acid amplification testing or culture) and for TB screening as is recommended in high-risk populations including people living with HIV and household contacts of active TB cases [9],[10].

The 44-transcript signature identified by the authors shows promise as a triage test and might be further optimized for this purpose during its further development. Indeed, it is likely that any set of host-derived biomarkers, especially if based on generic rather than antigen-stimulated immune responses, will have more difficulty achieving high specificity than high sensitivity. In this regard, the commonly used approach of selecting a diagnostic threshold that maximizes the number of correctly classified outcomes is misguided [11]. This cannot lead to a clinically useful test if neither sensitivity nor specificity is high enough to provide meaningful rule-out or rule-in value. Future work to establish a threshold for the 44-transcript signature as a triage test should focus on maximizing sensitivity, even at the cost of decreased specificity. Furthermore, focusing on developing a triage test at the discovery stage may lead to selection of a different set of transcripts that retains 100% sensitivity while providing even better specificity.

Summary

Levin and colleagues have provided compelling proof of the concept that a blood transcriptional signature can distinguish between TB and clinical mimics in high-incidence settings. The field can now move on to asking more practical questions to determine the feasibility and optimal use for an RNA expression-based biomarker for TB in clinical settings. Finding the right signature—the proverbial “needle in the haystack”—may require additional discovery work involving smaller sets of RNA transcripts and will certainly require validation of candidate signatures in diverse settings. Further discovery and validation studies should adhere to fundamental principles of high quality diagnostic evaluations [12], including enrollment of consecutive patients presenting for TB evaluation in representative health facilities. Even if validated, significant technical hurdles remain to translate these important findings to rapid, inexpensive, and simple assays that can impact patient outcomes in countries where TB is most prevalent. The search continues.

Source:PLOS