Tag Archives: public health

Betrayals of Trust

I wish I’d been wrong about polio eradication. Really, I do. Against the ever-extending deadlines, outbreaks of vaccine-associated poliomyelitis, and deadly violence, there’s no comfort in having anticipated failure.

Way back in 1997, when Vincent Racaniello and I penned the first major scientific criticism of the World Health Organization’s polio eradication campaign, we were actually naïve enough to think that our objections might make a difference. Instead, we were waved aside and assured that everything would work out fine.

But the goalposts had already started moving. The original plan was to eradicate polio by the year 2000. When Vincent and I wrote our critique of the campaign’s reliance on oral polio vaccine (OPV), the WHO had already adjusted the deadline to 2005. As that year approached, the date slid further. Bill Gates now thinks that his foundation can help the WHO finish the job by 2018, continuing a longstanding tradition of keeping the goal at least five years in the future.

Don’t get me wrong, there is a chance we might eventually eliminate this virus. There’s even a tiny chance we might get it done with just OPV, but I wouldn’t bet a dollar on it, let alone the billions of dollars the WHO’s funders have pumped into that dream.

The problem is that OPV, originally developed by Albert Sabin, contains live attenuated viruses that routinely revert to wild-type, paralytic strains in vaccinated people. It’s the only vaccine in general use that can cause exactly the disease it’s meant to prevent, and it does so in one of every few million vaccinees. For the eradication effort, a bigger problem is that many, if not all vaccinees secrete the reverted virus for some time. Kids take the vaccine, and a few days later they’re pooping out live, potentially paralytic virus. That’s not a big deal if everyone around them is vaccinated, but in areas where vaccine coverage is spotty it can – and does – lead to outbreaks of polio caused by vaccine-derived strains.

There’s no obvious way to end an OPV-only campaign. People with immune disorders can excrete vaccine-derived poliovirus indefinitely. Eradication mandates eliminating OPV because it’s a source of new infections, but if we stop vaccinating then the existing reservoirs of infection will start new outbreaks. That’s why even the eradication campaigners now admit, more than a decade after we told them so, that switching to the inactivated vaccine may be an essential step.

Unfortunately, inactivated polio vaccine (IPV) is much more expensive to make, transport, and administer than OPV. The price differences aren’t noticeable in developed countries with plenty of pediatricians, but they become prohibitive if your goal is to vaccinate the whole world right now. Getting IPV to every child would require building a functional public health infrastructure everywhere, but we can get OPV to them without having to make that commitment.

In other words, the WHO and its supporters have made a deliberate choice to value the quick elimination of a single disease over establishing lasting improvements in public health.

Back in 1995, when I first heard a presentation about the eradication campaign from a WHO/CDC representative at a conference, the rationale was that eradication is much easier to “sell” to developing countries than the hard, unglamorous work of building public health infrastructure. Eliminate polio in five years and you can claim a distinct, easily defined victory. Spend the same time and money building rural clinics and covering urban sewers, and nobody will notice. I was told that polio eradication was an achievable goal that politicians could understand. I also inferred the subtext: that it was the kind of career-defining accomplishment that WHO and CDC officials would love to put on their resumés. I had a problem with that rationale then, and I still do.

I’m certainly in favor of people advancing their careers, and I’d love to see infantile paralysis eliminated from the world. Public health is chronically strapped for cash and people, though, and pouring huge sums and millions of person-hours into a quixotic charge against one disease inevitably entails shortchanging other, more pressing needs.

There’s also another price that’s only become clear recently. In order to make the eradication campaign work, the WHO has enlisted thousands of volunteers all over the world. The Rotarians committed themselves to the effort early, and have provided an astonishing amount of logistical support. But in the last polio-endemic countries, the real ground troops are local volunteers, mostly women, who’ve had a short course in vaccine delivery. These dedicated individuals are motivated by nothing but a desire to help their neighbors. Their reward is a mother’s thanks, a child’s smile … or a bullet:

Nine female polio vaccinators have been killed in two shootings at health centres in northern Nigeria, police have told the BBC. In the first attack in Kano the polio vaccinators were shot dead by gunmen who drove up on a motor tricycle. Thirty minutes later gunmen targeted a clinic outside Kano city as the vaccinators prepared to start work.

Some Nigerian Muslim leaders have previously opposed polio vaccinations, claiming they could cause infertility. On Thursday, a controversial Islamic cleric spoke out against the polio vaccination campaign, telling people that new cases of polio were caused by contaminated medicine.

This is the latest in a string of such killings, but it’s the first I’ve heard of in Nigeria. It’s become fashionable to blame the CIA for causing this spate of anti-vaccinator violence, but as I’ve pointed out before that’s an oversimplification. The latest incident underscores that point.

If any agency is to blame for these deaths, it’s the WHO. They’ve recruited women to do a job that makes them stand out, in places where armed religious fundamentalists fly into a rage whenever women stand out. Then the WHO has trained these women to administer a vaccine that can cause the very disease it’s meant to prevent. When a local cleric claims that new cases of polio were caused by “contaminated medicine,” what are these volunteers supposed to say? He’s sort of right. Finally, all of this is being done in the service of a public health campaign that’s probably doomed. Meanwhile, malaria, tuberculosis, and HIV remain rampant and vaccines for other preventable diseases can’t be distributed because of a lack of infrastructure.

Perhaps it is much easier to convince politicians to back an eradication campaign than to build real public health systems. But it’s not cheaper.

Polio vs. bin Laden

Like most Americans, I felt a visceral surge of patriotic pride when I heard that we’d killed Osama bin Laden: pride in the President who ordered and orchestrated the bold raid, pride in the military that carried it out, and pride in a nation that, after nearly a decade of half-measures and absurd distractions, finally hit the primary target in the battle against Al Qaeda. We got the sonofabitch. I loathe violence and oppose capital punishment, but I’m pragmatic enough to understand that in some very, very rare cases, the only correct solution is a bullet. This was one of those cases.

But we have to be wary of surges of patriotism. They come from a place beyond reason, a primitive part of our tribal psyches, and leaders of all sorts have exploited them ruthlessly throughout history. As soon as the initial cheering dies down, we must set aside the easy jingoism and force ourselves to ask some hard questions. Exactly what did we just do, what did it cost, and was it really, objectively worth it? While asking those questions, though, we have to appreciate the conditions under which the decisions were made.

Fortunately, more than a year after that fateful night in Abbottabad, this phase of post-game analysis is still in full swing. Many foreign policy wonks bemoan the precedent the raid set: landing troops inside a sovereign nation without permission to carry out what can only be described as an assassination. US relations with Pakistan were fragile before; the two nations are barely speaking now.

Public health and infectious disease geeks like me, meanwhile, have been wringing our hands over a Central Intelligence Agency operation that took place before the raid. At the time, the Agency had a major problem. They’d pinpointed a residential compound where they strongly suspected bin Laden was holed up, but they couldn’t be sure. The man they saw pacing the courtyard in reconnaissance photos could have been him, or could have been some wealthy hermit with no connection to terrorism. When you’re on the cusp of dropping dozens of Navy SEALs into someone’s yard in the middle of the night and triggering an international incident, you really want to be sure you have the address right. The spooks decided to get creative.

Enlisting a Pakistani doctor named Shakil Afridi, the CIA mounted a campaign to collect DNA samples from children in Abbottabad, under the cover of a hepatitis B vaccination program. Afridi deployed nurses first in the slums of the city, then moved the campaign closer to the suspected bin Laden residence. If children from the target house carried bin Laden DNA, it would mean that Osama was most likely there. The effort appears to have failed, but the President ultimately took an enormous risk and authorized the raid anyway.

The public health community has been fiercely critical of this “fake” CIA vaccination campaign ever since. This recent post from infectious disease blogger Maryn McKenna typifies the general sentiment, which was exactly how I felt when I first heard about this incident. Laurie Garrett, meanwhile, took a more sensationalist tone in a shrill (and inaccurate) rant last month.

Other than a snide remark on Twitter when the news first broke, I’ve kept pretty quiet about this story. That’s because when I learned more details of the operation and started analyzing it, I became – and remain – deeply conflicted about it.

Public health has always been the poor cousin of medicine. When it works perfectly, nothing happens. There’s no dramatic moment when the patient’s heart re-starts, no miraculous recovery as the antibiotics take effect, no made-for-TV journey from sickness into health. The gains from vaccination, sanitation, and prevention are enormous and real, but they accrue on statistical tables that are very hard to explain to non-specialists.

As a result, public health workers have spent decades earning the public’s trust, especially among the poor and marginalized populations that suffer disproportionately from preventable diseases. When the amply-funded CIA made the cynical decision to hijack that hard-won trust for a short-term military objective, people in the field were understandably upset. That said, the Agency’s decision was not entirely arbitrary, and its impact wasn’t necessarily as bad as some commentators have implied.

Let’s get some perspective here. This DNA-collection effort was part of a broader project to stop a prolific mass-murderer. Osama bin Laden did not have blood on his hands; he was swimming in it. This was a man who had directly masterminded the deaths of several thousand innocent civilians, triggered a war that killed and maimed tens of thousands, and continued to promote and design attacks to kill many thousands if not millions more. He made no secret of his desire to annihilate Israel, destroy Western civilization, and roll human rights back to the Middle Ages. The only meaningful distinction between bin Laden and Hitler was that the former did not control sufficient weaponry to scale up his plans – yet. Public trust in vaccination campaigns is certainly important, but it is not all-important. Other priorities do exist.

Nor was the CIA’s betrayal a unique affront to public health. Yes, there have been some setbacks in the World Health Organization’s vaccination campaigns in Pakistan since the bin Laden raid, but it’s not clear the CIA caused those problems. Indeed, the polio eradication campaign, originally slated to be done in the year 2000, has been struggling for years. Pakistan isn’t even the toughest challenge for WHO vaccinators at the moment – Nigeria is. The covert DNA screening surely didn’t help matters, but it’s ridiculous to presume, as Garrett apparently does, that everything in public health would be going perfectly if the CIA hadn’t done this.

Finally, while it certainly wasn’t a very well-structured vaccination campaign, and it was clearly done with ulterior motives, it’s probably not correct to refer to the CIA effort as “fake.” As far as we can tell, the Agency obtained and distributed real hepatitis B vaccine. I presume they chose an injected vaccine because it provided better cover for DNA collection than the oral polio vaccine. A proper hepatitis B immunization requires three doses spread out over six months, but partial immunization still provides some protection against the virus. A handful of Pakistani kids may avoid liver cancer because of this. That’s not a justification, just an observation.

So was the hunt for bin Laden ultimately worth the cost? I still don’t know. I do know that it’s neither fair nor useful to judge the entire operation through a single narrow lens, with information that was only available after the fact. The DNA collection may have failed, but nobody knew it would fail at the outset. The President authorized the raid anyway, but given how thin the evidence was, it would have been perfectly reasonable for him to call it off, leaving the world’s top terrorist alive to plot his next attack.

Foreign policy is full of the nuances, tradeoffs, and uncertainties of a deeply imperfect world. We can and should hold our government to account for its actions, and we can and should point out the real harms that come from undermining public health efforts. But a decision can only be bad if another option was clearly better, and in this case I can’t quite bring myself to condemn the CIA’s choice.

Just don’t make a habit of it, okay guys?

The Other Superbugs: Pesticide Resistant Insects

In 1955, the World Health Organization launched an ambitious campaign to eradicate malaria. The effort relied on new, synthetic antimalarial drugs such as chloroquine and a miraculous new insecticide called DDT. Initially, it went pretty well: several countries’ malaria rates plummeted. Then it fell apart. The malaria parasites became resistant to the new drugs, and the mosquitoes which transmit the disease became resistant to DDT. After two decades of work and a massive expenditure of money and effort, the WHO gave up. Once again, Plasmodium and Anopheles had kicked Homo‘s butt.

Quick Henry, The Flit!

Quick Henry, The Flit!

By the 1990s, a new generation of public health officials was ready to take another run at the problem. Armed with a wider spectrum of antimalarial compounds, campaigns such as Roll Back Malaria seemed well prepared to deal with the problem of drug resistance by the parasite. Insecticide resistance was a different story. As before, the WHO-sponsored effort would rely heavily on a single chemical class to combat mosquitoes. This time, the effort favored pyrethroids.

The WHO’s enthusiasm for pyrethroids was understandable. As insecticides go, they’re pretty spectacular. These compounds are either mixtures or derivatives of a natural plant product called pyrethrum. Pyrethrum is only modestly effective by itself, but in the late 1940s chemists discovered that mixing it with another compound, piperonyl butoxide, boosts its killing power dramatically. Since then, researchers have synthesized several variants of pyrethrum, such as permethrin and deltamethrin, that are even more effective. What really makes these pesticides blockbusters, though, is that they’re highly specific for arthropods; their human and environmental toxicities are extremely low.

Because they’re so effective and nontoxic, pyrethroids are now the dominant over-the-counter insecticides worldwide. If you walk into the hardware store to buy some bug spray, you’ll see what appears to be a huge variety of products, but a close reading of the ingredient lists reveals that they’re almost all the same. Raid Ant Killer, Ortho Garden Insecticide, generic wasp killer, and most of the other colorful containers are just different package designs. What you’re really looking at is shelf upon shelf of pyrethroids.

We should know better. Bacteria, viruses, fungi, and protozoans have repeatedly taught us the same fundamental lesson about adaptation: if you keep throwing one chemical at a class of organisms long enough, they’ll eventually get used to it. Inevitably, the same has now happened with insects and pyrethroids.

In the tropics, particularly Africa, pyrethroid resistance has become a major public health problem. Because malaria control in poor, hot countries relies so heavily on pyrethroid-treated bed nets, resistant mosquitoes can now bypass the only real barrier between them and their victims.

Using these compounds willy-nilly has also spawned other problems. The treated bed nets, plus indoor spraying, have placed heavy selective pressure on all of the other insects that live in close association with people. Bedbugs, for example.

Indeed, bedbug populations have become highly resistant to pyrethroids, which is why homeowners’ DIY efforts to control them seldom work out. There’s been some debate about where that resistance came from, but recent results on US bedbug populations suggest that this resurgent pest is an import. It’s possible – even likely – that widespread pyrethroid use to combat mosquito-borne diseases in developing countries has spawned these new populations of superbugs.

Switching to other pesticides may help, at least sometimes with some insects. A study in Benin found that bendiocarb-treated bed nets were very effective against pyrethroid-resistant mosquitoes. Unfortunately, bendiocarb is highly toxic to birds and fish, and acutely toxic to humans in high doses. Treating a bed net with it is probably okay, but it’s not the kind of thing that should be sprayed around the house by amateur exterminators.

Nor is chemical-switching a panacea. Turning back to bedbugs, it appears their pyrethroid-resistance mechanisms are many and varied. Deep sequencing analysis revealed that the pesticide-resistant strains in a US infestation carry multiple changes in multiple genes, including increased expression of general detoxifying enzymes that could be useful against a broad spectrum of chemicals.

The solution, if there is one, will have to be twofold. First, we need a sustained research effort to understand the basic mechanisms of insecticide resistance and find new compounds that can overcome it. Second, both pesticide makers and public health officials need to take more responsibility for how these products are actually being used in the field, with a special focus on the problem of resistance. Our approach to distributing these powerful and important chemicals needs a thorough debugging.

Akogbeto, M., Padonou, G., Bankole, H., Gazard, D., & Gbedjissi, G. (2011). Dramatic Decrease in Malaria Transmission after Large-Scale Indoor Residual Spraying with Bendiocarb in Benin, an Area of High Resistance of Anopheles gambiae to Pyrethroids American Journal of Tropical Medicine and Hygiene, 85 (4), 586-593 DOI: 10.4269/ajtmh.2011.10-0668

Adelman, Z., Kilcullen, K., Koganemaru, R., Anderson, M., Anderson, T., & Miller, D. (2011). Deep Sequencing of Pyrethroid-Resistant Bed Bugs Reveals Multiple Mechanisms of Resistance within a Single Population PLoS ONE, 6 (10) DOI: 10.1371/journal.pone.0026228

So Does The Flu Vaccine Work Or Not?

A paper that came out Wednesday on influenza vaccine efficacy has generated a new round of speculation about what is probably the hardest sell in the vaccine business. There’s a lot to complain about with our current flu vaccines: everyone needs a new shot every year, vaccine makers don’t always guess right about which strains of flu will be circulating that season, and plenty of people can tell stories about how they got the shot and still got sick.

Now, in the middle of flu vaccine season, we get a new peer-reviewed report – and of course an accompanying press release – that seems to bring more bad news:

“Evidence for consistent high-level protection is elusive for the present generation of vaccines, especially in individuals at risk of medical complications or those aged 65 years or older. The ongoing health burden caused by seasonal influenza and the potential global effect of a severe pandemic suggests an urgent need for a new generation of more highly effective and cross-protective vaccines that can be manufactured rapidly”, explains Michael Osterholm from the University of Minnesota, USA, lead author of the study.

The news coverage was a mixed bag, ranging from predictable rantings from the antivaccination nuts (no links – you can find them yourself) to balanced, nuanced explanations such as this. Most of it was somewhere in between, no doubt confusing plenty of regular folks.

While Mark Crislip provided a typically excellent and thorough overview of flu vaccine efficacy back in ’09, I’m just going to highlight a few important features of the new paper from Osterholm’s group.

First, there’s not really any news here. Yes, Osterholm and his colleagues did yeoman’s work mining the literature and compiling their data, but they could not escape the fundamental limitations of all meta-analyses. In a meta-analysis, researchers look at existing publications, pick the ones that meet a particular (and in this case extremely strict) set of criteria, and compile the results into a new paper. There’s no new experimentation involved.

Furthermore, the conclusion of this particular meta-analysis should surprise exactly nobody. We’ve known for a long time that flu vaccines are imperfect, and while Osterholm has now put specific numbers on that imperfection for particular age groups, those numbers are neither definitive nor shocking.

Osterholm’s latest results weren’t exactly secret, either. He presented them at the National Influenza Vaccine Summit in May, and the conference report I wrote for them went on the NIVS web site this summer. It may not be in the top of everyone’s news feed, but anyone who’s really tracked this issue closely already knew these results were coming.

These findings don’t alter the main conclusion of decades of public health advice, either. Flu vaccines aren’t 100% effective, but given their outstanding safety record, and the very real risks involved in catching the flu, they’re a whole lot better than nothing.

Finally, while the study’s headline conclusion was that vaccine efficacy averages only around 59% in healthy adults, the team also found that the H1N1 pandemic flu vaccine was a bit above average (69% effective), and discovered even better results for the live attenuated flu vaccine (LAIV, also known as FluMist) in one of the groups at highest risk of severe flu infection:

By contrast, LAIV showed significant protection against infection in young children, preventing influenza in 83% of children aged 7 years or younger. However, the Advisory Committee on Immunization Practices (ACIP) does not currently recommend LAIV over TIV in these children.

Besides its apparently higher efficacy, FluMist has another huge advantage: it’s inhaled rather than injected. My daughter used to scream her head off each Fall before, during, and after her flu shot. Now she can barely stop giggling through the procedure. With the new meta-analysis showing that this snorted vaccine is probably more effective for her than the shot, I can feel good about it as both a virologist and a father.

Shocking: Popular Music Mentions Booze, Sex

In a surprising new development, researchers at the University of Pittsburgh report that the modern “rock” and “rap” music popular with adolescents makes repeated references to alcohol, sex, and drugs. As this important new paper concludes:

One in five songs sampled from US popular music had explicit references to alcohol, and one-quarter of these mentioned a specific alcohol brand. These alcohol brand appearances are associated commonly with a luxury life-style characterized by wealth, sex, partying and other drugs.

I am frankly shocked. Clearly, we need to restrict our kids’ access to this corrosive new music. Instead, they should experience the wholesome, safe and healthy lifestyles promoted in the classic songs and music videos my generation grew up on. This one, for example:

Betty the Bat

I was out in the yard a few days ago, and noticed an object stuck to one of our second-story windows. Thinking it was a wasp nest, I made a mental note to look at it from inside. When I actually remembered to do that, here’s what I found:

Betty the Bat

Betty the Bat (Myotis lucifugus?)

It looks huge because I actually know how to use the “macro” feature on my camera, so this photo was taken a few inches from the bat’s face. Look at the screen mesh for a sense of scale. The bat, which my daughter promptly named “Betty,” is actually about two and a half inches (6cm) long from nose to tail. Even at close range it’s hard to photograph her, because she’s sandwiched between the screen and the slightly-open storm window, and I’m not about to open the inner window to reduce the glare.

I’m no chiropterist, but I think Betty is a little brown bat (Myotis lucifugus). Her current position precludes a detailed examination of all of the identifying marks, and when I asked her to move she ignored me.

Besides providing a handy natural history lesson for Sophie, Betty’s visit has given me some new insight on rabies transmission. People can catch this highly lethal virus through contact with bats. Now I see an obvious mechanism that doesn’t involve spelunking. Had I not noticed Betty from outside, I would have thought nothing of opening this particular window and putting the screen down to let some air into the house. If Betty had lodged herself on the other side of the screen, I’d have a very frightened bat flapping around the room.

Of course, contact with a bat doesn’t automatically produce a lethal human rabies infection. The bat has to be infected with the virus, and the human has to ignore the incident. Indeed, rabies is the only virus I know of where the vaccine actually works just fine when given after exposure. If you have contact with a bat, don’t panic – just go get a few shots.

An even better solution is the one I’m employing: keep the window closed. Betty seems to have taken a liking to her new roost, going out each night shortly after sunset and returning before we get up in the morning. If she keeps this up for a couple of weeks, I’ll probably wait until she’s out on her nightly rounds and then adjust the storm window so she can’t get back in. Much as I hate to evict a possibly-endangered animal, winter will be here soon enough, and I don’t think it would be healthy for Betty to hibernate on our warm window.

Leapfrogging Microfluidics?

“Microfluidics” is one of the hottest buzzwords in biotechnology and diagnostics research these days, with good reason: these lab-on-a-chip devices are about the coolest technology to come along since monoclonal antibodies. The designs vary widely, but the basic principle is to take traditional lab assays and miniaturize them onto silicone or plastic chips, often using manufacturing techniques developed by the semiconductor industry. I’ve blogged about these nifty devices once or twice (okay, maybe three times) before.

While I’ve found the technology fascinating to watch, it’s remained a bit of a laboratory curiosity. Everyone seems to agree that the “killer app” for microfluidics will be field-portable devices that that will let minimally-trained people diagnose diseases or detect specific compounds in the environment, especially in poor countries. That’s because chip-based labs can incorporate all of their equipment and reagents onto a disposable device no larger than a credit card. In principle, a technician could place a drop of fluid, such as blood, onto one end of the chip, and micrometer-size channels would siphon it around, mixing it and moving it to different chambers to perform assays that would normally require a fully-equipped lab. The volumes are so small that the reactions tend to occur very quickly, often shortening multi-hour tests to a few minutes. But that’s where the good news ends.

Because the reactions produce subtle chemical changes inside minuscule containers, detecting the result usually requires sophisticated analytical equipment, at which point we’re right back to building a full-size laboratory. No matter how cheap or portable the chips get, the assay readout has generally remained huge and pricey.

Until now. Two recent papers highlight what I think is a new stage in the development of microfluidics, where researchers are finally addressing the readout problem. In one effort, scientists at Columbia University report on a microfluidic clinical testing system that incorporates a whole slew of new ideas. More importantly, it actually seems to work in the field. As senior investigator Samuel Sia says in an accompanying press release:

“We have engineered a disposable credit card-sized device that can produce blood-based diagnostic results in minutes,” said Sia. “The idea is to make a large class of diagnostic tests accessible to patients in any setting in the world, rather than forcing them to go to a clinic to draw blood and then wait days for their results.”

Sia’s lab at Columbia Engineering has developed the mChip devices in collaboration with Claros Diagnostics Inc., a venture capital-backed startup that Sia co-founded in 2004. The microchip inside the device is formed through injection molding and holds miniature forms of test tubes and chemicals; the cost of the chip is about $1 and the entire instrument about $100.

The injection-molding process is a departure from most microfluidic construction methods. Instead of engraving the device onto a silicon chip, the researchers made a mold and cast duplicates in a mass-production system. Injection molding gives us plastic cups and soda bottles, so it’s clearly a mature technology that can be scaled way, way up. That’s what drives the per-chip cost down so low.

The investigators used this cheap chip to build a miniaturized ELISA, or enzyme-linked immunosorbent assay, platform. If you’ve ever been tested for any infectious disease, you’ve probably had an ELISA; it’s one of the most common and important assays in clinical diagnosis. To perform it, one needs to incubate a sample with a reagent that will bind some analyte – let’s say an antigen that will bind antibodies against HIV in a patient’s blood. Once the analyte binds, a series of washes and secondary reagents clears up background reactions and causes some kind of easily-detected chemical change. It typically takes a skilled lab technician a few hours to perform an ELISA, and it requires careful attention to detail through the various washing and incubation steps.

On the new chips, a simple channel meanders through the plastic. The binding reagent is stuck to one section of the channel, and Sia and his colleauges feed the blood sample, wash solutions, and other reagents through the tube sequentially. To separate the reagents, they simply added tiny bubbles between them, like you might see in a very small straw that’s reached the bottom of the glass. A common medical syringe provides the vacuum force to draw the whole train of reagents through the system.

Completing this tour de force of clever ideas, the team used a nanoparticle-based detection system that deposits visible quantities of silver in the channel if there’s been a reaction. A cheap absorbance meter quantifies the amount of silver, and determines whether a test is positive or negative. The researchers walk through the system’s advantages in a nicely-produced video interview Nature Medicine released to accompany the piece:

As you’ll see in the video, the researchers also put their system to the ultimate test, hauling it to Rwanda and testing actual patient samples in an underfunded, overworked clinic. The results were impressive: the new assay is about as accurate as traditional ELISA tests for detecting HIV and syphilis, but much faster and cheaper.

This makes me wonder whether we’re about to see another example of leapfrogging in poor countries. The most popular (and really only) current example of this phenomenon is cellular phones. There are virtually no landline connections in most poor countries, but nearly everyone has a phone. By missing the first telecommunication revolution, these countries have “leapfrogged” to the second, gaining all of the advantages of instant communication without going through the intermediate stages of rural electrification, Ma Bell, party lines, and rotary dials. If microfluidic devices can bring modern medical tests to the bedside in Rwanda, will we see them and other poor countries catapulting into 21st century medicine without having to establish 20th (or even 19th) century medical infrastructure first? Maybe.

What makes me optimistic about this is that Sia and his colleagues aren’t the only ones working on this problem. Indeed, around the time their paper came out, a less-noticed but equally interesting bit of work came out in the journal Analytical Chemistry. In that paper, Aydogan Ozcan and his colleagues at UCLA and elsewhere describe a system for performing flow cytometry on a microfluidic device. Flow cytometry, or cell sorting, is a sort of ELISA on speed. Rather than incubate the bulk sample with the reagent, cell sorters separate individual cells into a stream of droplets, like one would get by shaking a running garden hose. The droplets pass through a detector that measures specific parameters of the cell, such as its light diffraction characteristics or whether it bound a fluorescently labeled antibody. Researchers can then quantify exactly how many cells of each type were in a sample.

It’s a tremendously powerful technique for immunological research, and can also be used to perform a variety of blood-counting assays, but it requires even more skill and money than an ELISA. Research-grade cell sorters are massive machines that usually occupy a small room of their own and employ a dedicated technician.

Ozcan’s team decided to use a cell phone instead. With about $5 worth of parts, they cobbled together an adapter that connects an inexpensive microfluidic cell sorter to the camera on a Sony-Ericsson phone. As they explain in an accompanying press release:

The microfluidic assembly is placed just above a separate, inexpensive lens that is put in contact with the cell phone’s existing camera unit. This way, the entire cross-section of the microfluidic device can be mapped onto the phone’s CMOS sensor-chip. The sample fluid is delivered continuously through a disposable microfluidic channel via a syringe pump.

The device is illuminated from the side by the LEDs using a simple butt-coupling technique. The excitation light is then guided within the cross-section of the device, uniformly exciting the specimens in the imaging fluid. The optofluidic pumping scheme also allows for the use of an inexpensive plastic absorption filter to create the dark-field background needed for fluorescent imaging. In addition, video post-processing and contour-detection and tracking algorithms are used to count and label the cells or particles passing through the microfluidic chip.

While they haven’t taken it into a poor country’s clinics yet, the investigators did put the system through its paces in the lab. So far, they’ve demonstrated that it can measure white blood cell density as a cell sorter, and also operate as a mid-power fluorescent microscope. The former capability could provide tests for leukemia and AIDS progression, while the latter could be useful for a variety of analyses, including detecting pathogens in drinking water.

It’s going to take more than a couple of new testing systems to fix the health problems of poor countries, but papers like these – and I suspect others will follow shortly – show at least part of the solution. Perhaps these technologies will even make their way back to the developed world, as we seem to have some of our own issues with medical costs these days.

References:

ResearchBlogging.org

Chin, C., Laksanasopin, T., Cheung, Y., Steinmiller, D., Linder, V., Parsa, H., Wang, J., Moore, H., Rouse, R., Umviligihozo, G., Karita, E., Mwambarangwe, L., Braunstein, S., van de Wijgert, J., Sahabo, R., Justman, J., El-Sadr, W., & Sia, S. (2011). Microfluidics-based diagnostics of infectious diseases in the developing world Nature Medicine DOI: 10.1038/nm.2408

Seo, S., Isikman, S., Sencan, I., Mudanyali, O., Su, T., Bishara, W., Erlinger, A., & Ozcan, A. (2010). High-Throughput Lens-Free Blood Analysis on a Chip Analytical Chemistry, 82 (11), 4621-4627 DOI: 10.1021/ac1007915

From Designer Drugs to … Bath Salts?

The ever-enlightening Morbidity and Mortality Weekly Reports has a new paper on the latest recreational drug craze: bath salts. Yes, bath salts. As MMWR explains:

From November 2010 to January 2011, the Marquette County [Michigan] ED treated seven patients who arrived at the ED with hypertension, tachycardia, tremors, motor automatisms, mydriasis, delusions, and paranoia. Some patients were violent, placing increased demand on ED staff members. Responding to the cluster also placed additional demands on local law enforcement and foster care, because many patients had young children who needed care while their parents were incapacitated. The patients reported using “bath salts” purchased at a local store for about $20 a package and labeled “not intended for human consumption.”

Way to set a good example, Ma and Pa. Apparently these weren’t just any bath salts – only a few, um, provocatively-named brands:

Efforts by the local ED, law enforcement, and prosecuting attorney’s office led to the execution of an emergency public health order on February 4 by the Marquette County Health Department. The proprietor of the store was ordered to immediately remove from sale and turn over to government authorities any and all products known as White Rush, Cloud Nine, Ivory Wave, Ocean Snow, Charge Plus, White Lightning, Scarface, Hurricane Charlie, Red Dove, White Dove, and Sextasy. The Michigan Department of State Police laboratory tested the White Rush seized from the store and detected the presence of MDPV.

MDPV is 3,4-methylenedioxypyrovalerone, which has apparently been a designer street drug since 2004. But how bad could a product called White Rush really be?

Of the 17 hospitalized persons, nine were admitted to the intensive care unit (ICU), five were admitted to a general floor, and three were admitted directly to a psychiatric unit. Four persons who were first hospitalized in the ICU or a general floor later were transferred to a psychiatric unit. Treatment generally included a benzodiazepine such as lorazepam to control signs of toxicity; low or moderate doses usually were sufficient. Antipsychotics were used as secondary agents when benzodiazepine sedation was ineffective. Of three patients who revisited the ED, one had rhabdomyolysis, chest pain, and dizziness but left against medical advice. Two months later, the patient was admitted to the ICU, moved to a psychiatric floor for 12 days, and then transferred to a different hospital for liver failure. The second patient was admitted to the hospital, discharged, and revisited the ED the same day of discharge after again using “bath salts.” The third patient was treated in the ED twice, with the visits 1 month apart.

Apparently, the drug also carries a high risk of ending up in an embarassing news story:

CHARLESTON, W.Va. — Police say an Alum Creek man high on bath salts killed his neighbor’s pygmy goat and that neighbors found him in his bedroom, dressed in a bra and panties, next to the dead animal, said Lt. Bryan Stover of the Kanawha County Sheriff’s Department.

Now if you’ll excuse me, I think I need to go take a bath.

The Epidemic That Still Isn’t: Autism Rates and Case Definitions

A paper that came out yesterday in the American Journal of Psychiatry has generated a lot of press coverage of the “autism epidemic,” as it purportedly shows that one in every 38 South Korean children is autistic. That’s more than double the incidence previous epidemiological studies have found. I have no doubt that this result, completely devoid of its larger context, will now be picked up by all manner of woo-woo peddlers as indisputable proof of whatever nonsense they’re selling. What the paper really shows, though, is how slightly different interpretations of case definitions can produce radically different results.

First, let’s dispense with the most obvious flaw in much of the news coverage of autism: there is no “epidemic.” As numerous epidemiologists have found every time they’ve looked at this issue, the apparent rise in the rate of autism spectrum disorder (ASD) tracks perfectly with changes in the diagnostic and special education criteria for the disease. It’s not rising, just being identified more often.

One particularly telling point is that the supposed increase in ASD doesn’t age well. Autism appears in childhood, but many folks seem to forget that children grow up, and the disease doesn’t go away when they do. That means that if ASD rates are genuinely increasing, there should be more autistic kids than autistic adults. But as a paper last week in Archives of General Psychiatry showed, there aren’t.

A Reuters story on that paper explained the key finding nicely:

Researchers found nearly one percent of Britons older than 16 years have autism, a rate that is similar to that seen in children. Younger people were no more likely to be affected than older ones, however, which would have been expected if the condition were truly on the increase.

“It was surprising to all of us,” said Dr. Traolach Brugha, a psychiatrist at the University of Leicester, who worked on the study. “If this study is correct, it does put a big question mark over the autism epidemic.”

Not so much a question mark as a stake through the heart. Brugha’s team found that the adults with ASD were less likely to have been diagnosed previously than kids with it, pretty much proving that the rising rates are due to increased diagnosis and awareness. Nor is Brugha’s report the first in this genre. For example, Orac at Respectful Insolence has an excellent post about a 2006 study that essentially proved the same point using a different method.

So case rates aren’t rising. But are they really only 1%? That’s what Kim et al. wanted to determine in the new South Korean study. I encourage everyone to read the whole paper, which Am J Psych has made available for free. It’s an impressive piece of work.

First, the researchers identified a South Korean community that was demographically diverse, and set out to sample all 7- to 12-year-old kids in that region. There were 55,266 of them. Before I start my criticism of this study, I have to congratulate the authors on the dedication, organization, and plain hard work that they put in to tackle such a huge job. As I said, it’s an impressive paper.

Kim’s team broke their sample into two groups: those who received special education or other psychiatric help (the “high-probability group”), and those who were in the general school population. That ensured that their sample wouldn’t be skewed by accidentally pulling too many kids from special ed. Between the two groups, they found a whopping 2.64% prevalence for ASD, or about 1 in 38 kids. That’s the conclusion that’s been plastered all over the headlines, and the one that I predict will launch a thousand quacks.

As often happens, though, the Abstract giveth while the Results taketh away. Let’s start with the autism rates in the high-probability group, which were, unsurprisingly, very high:

In the high-probability group (those in the Disability Register, those in special education schools, and those in regular schools who had psychiatric or psychological service use) 97 of 114 children were confirmed to have autistic disorder (N=74) or other ASDs (N=23). The high- probability group contributes 0.18% for any ASD to the total population prevalence (autistic disorder=0.13% and other ASDs=0.05%; the ratio of autistic disorder to other ASDs was 2.6:1).

I’ll parse that. In ASD, the middle letter is critical: autism occurs on a spectrum. Contrary to popular belief, not everyone with ASD is Rain Man. In fact, the cases depicted in movies are generally the extreme end of the spectrum, people with the biggest problems. Milder cases extend from there all the way through (according to many researchers) Asperger Syndrome. There are no bright lines dividing these folks. Indeed, there’s no reason to believe that there’s even a clear boundary between “sick” and “well” here. Extremely autistic individuals clearly need help, but what about high-functioning folks with Asperger’s? At what point does one divide someone with very mild ASD from someone who’s just socially awkward? Like most psychiatric case definitions, it’s murky at the edge.

What Kim et al. found in the special ed group was a lot of ASD, with the majority of diagnoses in the “autistic” category rather than in milder categories. These are the sickest kids. Presumably that’s why they’ve been singled out for special help. So far, so good.

The general population data get more problematic:

For 104 children with ASDs in the general-population sample, among the 172 assessed, the crude prevalence for any ASD was similar to that in the high-probability group (0.19%). However, the ratio of autistic disorder to other ASDs was reversed, with prevalences of 0.05% and 0.14%, respectively (ratio, 1:2.6) (Table 2). Other differences between the high-probability and general-population groups included the ratio of boys to girls, which was 5.1:1 in the high-probability group and 2.5:1 in the general-population sample (p=0.037) (Table 2). Mean performance IQ for individuals with any ASD was 75 (SD=28) in the high-probability group and 98 (SD=19) in the general-population sample (p<0.001)

Now we’re seeing a majority who are on the mild end of the spectrum. How mild? In some cases, quite. The surveys the researchers used to assess ASD, while standard in the field, suffer from the usual drawbacks of any psychiatric survey tool. Does your child have only a few friends? Prefer playing alone? Is he or she easily overwhelmed by extraneous stimuli? There’s lots of wiggle room on questions like these, and the closer you look the more likely you are to start pathologizing mere eccentricity.

Finally, there’s an extrapolation problem. As the numbers in the paragraphs above indicate, the researchers didn’t manage to get detailed diagnostic information on all 55,266 kids in the district. A lot of parents responded to the initial questionnaire, but many didn’t. Of the ones who did, many declined subsequent followups. By the time we get to the most detailed tests, the investigators are down to hundreds rather than thousands of data points. Nonetheless, they extrapolate from this self-selected group to the entire population. If we assume that parents who had some concerns about their children were more likely to follow up with the study – a reasonable assumption – then the extrapolation fails.

I’m not saying the results are completely bogus. The researchers are aware of their tools’ limitations, and they take efforts to control for some of them. Still, we have to ask whether a child who’s enrolled in regular school programs, hasn’t been identified as sick by any of his or her teachers, and seems to be progressing just fine in life needs to be given a diagnosis. Maybe there are a lot of children who aren’t truly “normal,” but who are acting the part well enough to pass. On some level, doesn’t that describe us all?

Brugha, T., McManus, S., Bankart, J., Scott, F., Purdon, S., Smith, J., Bebbington, P., Jenkins, R., & Meltzer, H. (2011). Epidemiology of Autism Spectrum Disorders in Adults in the Community in England Archives of General Psychiatry, 68 (5), 459-465 DOI: 10.1001/archgenpsychiatry.2011.38

Kim, Y., Leventhal, B., Koh, Y., Fombonne, E., Laska, E., Lim, E., Cheon, K., Kim, S., Kim, Y., Lee, H., Song, D., & Grinker, R. (2011). Prevalence of Autism Spectrum Disorders in a Total Population Sample American Journal of Psychiatry DOI: 10.1176/appi.ajp.2011.10101532