First responses to DEVTA roll in

In my last post I highlighted the findings from the DEVTA trial of deworming in Vitamin A in India, noting that the Vitamin A results would be more controversial. I said I expected commentaries over the coming months, but we didn't have to wait that long after all. First is a BBC Health Check program features a discussion of DEVTA with Richard Peto, one of the study's authors. It's for a general audience so it doesn't get very technical, and because of that it really grated when they described this as a "clinical trial," as that has certain connotations of rigor that aren't reflected in the design of the study. If DEVTA is a clinical trial, then so was

Peto also says there were two reasons for the massive delay in publishing the trial, 1) time to check things and "get it straight," and 2) that they were " afraid of putting up a trial with a false negative." [An aside for those interested in publication bias issues: can you imagine an author with strong positive findings ever saying the same thing about avoiding false positives?!]

Peto ends by sounding fairly neutral re: Vitamin A (portraying himself in a middle position between advocates in favor and skeptics opposed) but acknowledges that with their meta-analysis results Vitamin A is still "cost-effective by many criteria."

Second is a commentary in The Lancet by Al Sommers, Keith West, and Reynaldo Martorell. A little history: Sommers ran the first big Vitamin A trials in Sumtra (published in 1986) and is the former dean of the Johns Hopkins School of Public Health.  (Sommers' long-term friendship with Michael Bloomberg, who went to Hopkins as an undergrad, is also one reason the latter is so big on public health.) For more background, here's a recent JHU story on Sommers' receiving a $1 million research prize in part for his work on Vitamin A.

Part of their commentary is excerpted below, with my highlights in bold:

But this was neither a rigorously conducted nor acceptably executed efficacy trial: children were not enumerated, consented, formally enrolled, or carefully followed up for vital events, which is the reason there is no CONSORT diagram. Coverage was ascertained from logbooks of overworked government community workers (anganwadi workers), and verified by a small number of supervisors who periodically visited randomly selected anganwadi workers to question and examine children who these workers gathered for them. Both anganwadi worker self-reports, and the validation procedures, are fraught with potential bias that would inflate the actual coverage.

To achieve 96% coverage in Uttar Pradesh in children found in the anganwadi workers' registries would have been an astonishing feat; covering 72% of children not found in the anganwadi workers' registries seems even more improbable. In 2005—06, shortly after DEVTA ended, only 6·1% of children aged 6—59 months in Uttar Pradesh were reported to have received a vitamin A supplement in the previous 6 months according to results from the National Family Health Survey, a national household survey representative at national and state level.... Thus, it is hard to understand how DEVTA ramped up coverage to extremely high levels (and if it did, why so little of this effort was sustained). DEVTA provided the anganwadi workers with less than half a day's training and minimal if any incentive.

They also note that the study funding was minimalist compared to more rigorous studies, which may be an indication of quality. And as an indication that there will almost certainly be alternative meta-analyses that weight the different studies differently:

We are also concerned that Awasthi and colleagues included the results from this study, which is really a programme evaluation, in a meta-analysis in which all of the positive studies were rigorously designed and conducted efficacy trials and thus represented a much higher level of evidence. Compounding the problem, Awasthi and colleagues used a fixed-effects analytical model, which dramatically overweights the results of their negative findings from a single population setting. The size of a study says nothing about the quality of its data or the generalisability of its findings.

I'm sure there will be more commentaries to follow. In my previous post I noted that I'm still trying to wrap my head around the findings, and I think that's still right. If I had time I'd dig into this a bit more, especially the relationship with the Indian National Family Health Survey. But for now I think it's safe to say that two parsimonious explanations for how to reconcile DEVTA with the prior research are emerging:

1. DEVTA wasn't all that rigorous and thus never achieved the high population coverage levels necessary to have a strong mortality impact; the mortality impact was attenuated by poor coverage, resulting in the lack of a statistically significant effect in line with prior results. Thus is shouldn't move our priors all that much. (Sommers et al. seem to be arguing for this.) Or,

2. There's some underlying change in the populations between the older studies and these newer studies that causes the effect of Vitamin A to decline -- this could be nutrition, vaccination status, shifting causes of mortality, etc. If you believe this, then you might discount studies because they're older.

(h/t to @karengrepin for the Lancet commentary.)

A massive trial, a huge publication delay, and enormous questions

It's been called the "largest clinical* trial ever": DEVTA (Deworming and Enhanced ViTamin A supplementation), a study of Vitamin A supplementation and deworming in over 2 million children in India, just published its results. "DEVTA" may mean "deity" or "divine being" in Hindi but some global health experts and advocates will probably think these results come straight from the devil. Why? Because they call into question -- or at least attenuate -- our estimates of the effectiveness of some of the easiest, best "bang for the buck" interventions out there. Data collection was completed in 2006, but the results were just published in The Lancet. Why the massive delay? According to the accompany discussion paper, it sounds like the delay was rooted in very strong resistance to the results after preliminary outcomes were presented at a conference in 2007. If it weren't for the repeated and very public shaming by the authors of recent Cochrane Collaboration reviews, we might not have the results even today. (Bravo again, Cochrane.)

So, about DEVTA. In short, this was a randomized 2x2 factorial trial, like so:

The results were published as two separate papers, one on Vitamin A and one on deworming, with an additional commentary piece:

The controversy is going to be more about what this trial didn't find, rather than what they did: the confidence interval on the Vitamin A study's mortality estimate (mortality ratio 0.96, 95% confidence interval of 0.89 to 1.03) is consistent with a mortality reduction as large as 11%, or as much as a 3% increase. The consensus from previous Vitamin A studies was mortality reductions of 20-30%, so this is a big surprise. Here's the abstract to that paper:

Background

In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2–3% die at ages 1·0–6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality.

Methods

Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200 000 IU retinyl acetate in oil, to be cut and dripped into the child’s mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs36 clusters).

The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6–72 months.  Annually, one centre per block was randomly selected and visited by a study team 1–5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100 000 visits, 25 000 deaths at ages 1·0–6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547.

Findings

Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6% vs13%, decrease 7% [SE 1%]), as was that of Bitot’s spots (1·4% vs3·5%, decrease 2·1% [SE 0·7%]).

Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89–1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected.

Interpretation

DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20–30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5–16, p=0·00015), reliably contradicting the hypothesis of no effect.

Note that instead of just publishing these no-effect results and leaving the meta-analysis to a separate publication, the authors go ahead and do their own meta-analysis of DEVTA plus previous studies and report that -- much attenuated, but still positive -- effect in their conclusion. I think that's a fair approach, but also reveals that the study's authors very much believe there are large Vitamin A mortality effects despite the outcome of their own study!

[The only media coverage I've seen of these results so far comes from the Times of India, which includes quotes from the authors and Abhijit Banerjee.]

To be honest, I don't know what to make of the inconsistency between these findings and previous studies, and am writing this post in part to see what discussion it generates. I imagine there will be more commentaries on these findings over the coming months, with some decrying the results and methodologies and others seeing vindication in them. In my view the best possible outcome is an ongoing concern for issues of external validity in biomedical trials.

What do I mean? Epidemiologists tend to think that external validity is less of an issue in randomized trials of biomedical interventions -- as opposed to behavioral, social, or organizational trials -- but this isn't necessarily the case. Trials of vaccine efficacy have shown quite different efficacy for the same vaccine (see BCG and rotavirus) in different locations, possibly due to differing underlying nutritional status or disease burdens. Our ability to interpret discrepant findings can only be as sophisticated as the available data allows, or as sophisticated as allowed by our understanding of the biological and epidemiologic mechanisms that matter on the pathway from intervention to outcome. We can't go back in time and collect additional information (think nutrition, immune response, baseline mortality, and so forth) on studies far in the past, but we can keep such issues in mind when designing trials moving forward.

All that to say, these results are confusing, and I look forward to seeing the global health community sort through them. Also, while the outcomes here (health outcomes) are different from those in the Kremer deworming study (education outcomes), I've argued before that lack of effect or small effects on the health side should certainly influence our judgment of the potential education outcomes of deworming.

*I think given the design it's not that helpful to call this a 'clinical' trial at all - but that's another story.

Outbreak control

The latest MMWR (Morbidity and Mortality Weekly Report) from the CDC  has a summary of a meningitis outbreak in Oklahoma and how public health authorities responded: "Outbreak of Meningococcal Disease Associated with an Elementary School - Oklahoma, March 2010." MMWR reports have a consistent style that I think is helpful for this sort of notice: they're short with tight editing and little superfluous information. They also often present harrying situations that are made more disturbing by the clinical detachment. In this case:

Five cases of meningococcal disease (including one probable case) were identified among four elementary school students and one high school student. Two students died; two recovered fully, and one survivor required amputation of all four limbs and facial reconstruction.

They also often include a helpful summary answering three questions: 1) What is already known on this topic? 2) What is added by this report? and 3) What are the implications for public health practice? I think some other publications (especially in the social sciences) would benefit from this helpful little formatting addition.

Before you get all excited about male birth control

When you're a public health grad student and something related to health hits the news, your friends make sure you see it. Since there's a lot of bad science writing on the internet this can be rather frustrating. In the last few hours I've seen several people post this  to Facebook, and another emailed me with the subject line "Woh" and asked if this was too good to be true.... So what's the story? Techcitement has a breathless article titled "The Best Birth Control In The World Is For Men" by Jon Clinkenbeard, which he followed up with "Could This Male Contraceptive Pill Make a Vas Deferens in the Fight Against HIV?" The first article starts with this hook:

If I were going to describe the perfect contraceptive, it would go something like this: no babies, no latex, no daily pill to remember, no hormones to interfere with mood or sex drive, no negative health effects whatsoever, and 100 percent effectiveness. The funny thing is, something like that currently exists.

Clinkenbeard is describing RISUG, or "Reversible inhibition of sperm under guidance." Wikipedia explains:

RISUG is similar to vasectomy in that a local anesthetic is administered, an incision is made in the scrotum, and the vas deferens is tugged out with a small pair of forceps. Rather than being cut and cauterized, as it is in a vasectomy, the vas deferens is injected with [a] polymer gel and pushed back into the scrotum.

Sounds awesome? Why don't we have it already? Clinkenbeard continues:

The trouble is, most people don’t even know this exists. And if men only need one super-cheap shot every 10 years or more, that’s not something that gets big pharmaceutical companies all fired up, because they’ll make zero money on it (even if it might have the side benefit of, you know, destroying HIV).

Before you go injecting something in your scrotum... not so fast! Yes, in one sense it exists. But on the other hand we don't really know how well it works, and we don't really know how safe it is. Clinkenbeard makes it sound like it's a done deal, and claiming that Big Pharma is standing between you and the cure for babies (not to mention HIV!) certainly helped the article go viral. He then links to a bunch or articles and a few petitions.

While pharmaceutical companies do all sorts of things to manipulate data (start here if you don't believe that), I think they could actually make TONS of money on this if it worked. The price of medicines isn't usually based on how much they cost to manufacture but on how much they can be sold for, and I think there's clearly a market for male contraception: just think how much men would pay for the insurance to both avoid pregnancy and not have to use condoms. A drug company could conceivably make a lot of money off this product by getting it to market first.

Guha's initial studies were very small. A Phase II clinical trial published by Guha et al in 1997 featured a grand total of 12 men (PDF). (It also contains this humorous understatement: "Objective data on posttreatment frequency of intercourse could not be obtained.") In another study 20 men received an injection, but one man's partner still got pregnant.

Before a drug can (or should) go to market, it needs to be tested for both efficacy and safety, and everything needs to be done up to certain standards. Guha's original work wasn't. From a Wired article on RISUG by Bill Gifford, published this time last year:

In its report, the WHO team agreed that the concept of RISUG was intriguing. But they found fault with the homegrown production methods: Guha and his staff made the concoction themselves in his lab, and the WHO delegation found his facilities wanting by modern pharmaceutical manufacturing standards. Furthermore, they found that Guha’s studies did not meet “international regulatory requirements” for new drug approval—certain data was missing. The final recommendation: WHO should pass on RISUG.

These barriers can be overcome, if the researchers can get the investment necessary to make high quality product and run clinical trials. The Wired article describes how they've made progress and are now running clinical trials in India -- but the results are still a few years out. In the same article we get this:

"Pharmaceutical companies are not interested in one-offs," Weiss says. "They’re interested in things they can sell repeatedly, like the birth control pill or Viagra."

But that's not as true as it used to be. These arguments used to explain why pharmaceutical companies didn't invest in developing vaccines, but then they realized they could charge obscene amounts for individual doses -- orders of magnitude higher than what they charged before. They've managed these high prices because 1) there are always new cohorts of kids needing the vaccine (as there would be with men needing RISUG) and 2) because the health benefits are so large that even at the higher prices the vaccines are cost effective.

So are pharma companies just disinterested in male contraception? No. For quick and dirty evidence check ClinicalTrials.gov, where US clinical trials must be registered. I find 436 studies on contraception, of which 84 are specifically about male contraception. There's a disparity there, but it's explained in part by the fact that many of the non-male contraception studies are about delivery methods (like this one involving text message reminders) and you can't even start do this sort of research on male birth control before we have effective methods. Maybe they're under-investing a bit -- drug R&D is risky, as firms spend an average of $1.3 billion on research for every one drug  brought to market -- but it's not being ignored.

In closing, that Wired article from last year has some of the same breathless new-techthusiasm as the new Techcitement piece, but it's a lot better at explaining where things stand today. Clinical trials in India are ongoing, but it will be another year or so before we hear any results. If those are considered high quality and they're successful, it might spur the drug behemoths to up the massive amounts required for clinical trials in the US.

Generally, getting your science news from the coauthor of "The Pirate Treasure of the Himalaya" does't seem like the best idea. Drugs and treatments fail at every stage of the clinical trials pipeline, and that's a good thing because it means consumers will be less likely to spend money on ineffective or unsafe drugs. If everything works out with RISUG, it could be an incredible success story and a great public health tool. There might well be hope on the horizon, but contrary to Clinkenbeard's assertions we don't yet know very well if this works, and we don't yet know if it's safe. For that, we need good ole clinical trials, not petitions.

Coincidence or consequence?

Imagine there's a pandemic flu virus on the loose, and a vaccine has just been introduced. Then come reports of dozens of cases of Guillain-Barré syndrome (GBS), a rare type of paralysis. Did the new vaccine cause it? How would you even begin to know? One first step (though certainly not the only one) is to think about the background rate of disease:

Inappropriate assessment of vaccine safety data could severely undermine the eff ectiveness of mass campaigns against pandemic H1N1 2009 influenza. Guillain-Barré syndrome is a good example to consider. Since the 1976–77 swine influenza vaccination campaign was associated with an increased number of cases of Guillain-Barré syndrome, assessment of such cases after vaccination will be a high priority. Therefore, it is important to know the background rates of this syndrome and how this rate might vary with regard to population demographics. The background rate of the syndrome in the USA is about 1–2 cases per 1 million person-months of observation. During a pandemic H1N1 vaccine campaign in the USA, 100 million individuals could be vaccinated. For a 6-week follow-up period for each dose, this corresponds to 150 million person-months of observation time during which a predicted 200 or more new cases of Guillain-Barré syndrome would occur as background coincident cases. The reporting of even a fraction of such a large number of cases as adverse events after immunisation, with attendant media coverage, would probably give rise to intense public concern, even though the occurrence of such cases was completely predictable and would have happened in the absence of a mass campaign.

That's from a paper by Steven Black et al. in 2009, "Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 infl uenza vaccines". They also calculate background rates for spontaneous abortion, preterm delivery, and spontaneous death among other things.

Polio and confidence

Maryn McKenna writes about a new report (PDF) on polio eradication at Wired's SuperBug blog. The report comes from the Independent Monitoring Board (IMB) of the Global Polio Eradication Initiative (GPEI). The GPEI has existed for 23 years now, and while they've made much progress (polio cases are down 99% since the campaign started) the campaign has repeatedly missed the deadlines it sets for itself for eradication. The latest goal is to interrupt polio transmission worldwide by 2012, and despite a recent infusion of funding and enthusiasm the campaign is -- according to the IMB -- likely to miss yet another of its own goals. McKenna writes, "Possibly the biggest problem, the board concludes, is a get-it-done optimism so ingrained in the 23-year effort that it cannot acknowledge when things are not working." She quotes the report to the same effect:

The Programme has an established narrative of positivity – a pervading sense of "nearly there". The danger comes in how the Programme deals with information that does not sit well with this narrative. We have observed that the Programme:

  • Is not wholly open to critical voices, perceiving them as too negative – despite the fact that they may be reporting important information from which the Programme could benefit.
  • Tends to believe that observed dysfunctions are confined to the particular geography in which they occur, rather than being indicative of broader systemic problems.
  • Displays nervousness in openly discussing difficult or negative items.

This report is likely to ruffle some feathers as the public discussion regarding polio eradication often suffers from the same dearth of criticism. One reason for that -- and likely for GPEI's own "get-it-done optimism" -- seems to be that polio eradication is an epic high-stakes gamble. If we can do it the benefits are huge: no more polio, and less need for continued vaccination (though much of the projected cost-savings are predicated on the idea that the US and other countries will stop polio vaccination, which is highly unlikely given fears of vaccine-derived strains or bioterrorism). But if we can't do it then it might be better to spend resources on some other priority in global health; spend some lesser amount on polio, allow a bit of resurgence (but not too much), and focus resources on other vital needs. Thus the real battle is over the general donor consensus around whether polio eradication will be achieved soon. As soon as the global health donor community decides that eradication isn't actually possible, that belief will become a self-fulfilling prophecy.

Avoid immunization, go to jail. Eek.

Via Foreign Policy:

In Nigeria, avoiding a shot could mean going to jail

As Bill Gates unveiled his plan this week to rid the world of polio, health officials in the northern Nigerian state of Kano announced their own assault on the disease. "The government will henceforth arrest and prosecute any parent that refuses to allow health workers to vaccinate his child against child-killer diseases, particularly polio," said a health ministry official.

This news, which was announced at the outset of the government's four-day vaccination campaign targeting six million children, marks a shift in government policy toward immunization programs in the north of the country. Nigeria's polio vaccination program stalled for more than a year after Muslim leaders raised doubts over the inoculations' safety in the summer of 2003 -- resulting in bans issued by some northern state governments....

I'm not familiar with every vaccination law in the world, but this seems like a first to me. If not a first, at least an exception to the norm. I don't like this more coercive approach. If you have enough resistance to a policy that you feel you need to threaten jail time, then actually making that threat -- and following through on it -- seems likely to breed more resistance.

I think governments can and should both incentivize vaccination and make it difficult to avoid without a really good reason. Any government policy should make it easier to get vaccinated against childhood diseases than avoid vaccination, because having a fully-vaccinated population is a classic public good. I like the fact that most states in the US have opt-out provisions for religious objections to vaccination, but I also think that states should not design a policy such that getting that exemption is simpler -- in terms of time and money -- than getting a child vaccinated, as is the case in many states.

But threatening to throw parents in jail? Way too heavy-handed to me, and too likely to backfire.

Happy Hep Day

Today is the first ever WHO-sponsored World Hepatitis Day:

These successes and challenges are amplified because viral hepatitis is not a single disease. Hepatitis is caused by at least five viruses—including two spread by water or food contaminated with feces(hepatitis A and E) and three transmitted by blood and body fluids (hepatitis B, D, and C) during childbirth (from infected mother to child); through injecting drug use, needle sticks, or transfusions; or through sexual contact. Hepatitis B and C infections can cause cirrhosis of the liver and lead to liver cancer.

Today, more than 500 million persons worldwide are living with viral hepatitis and do not have adequate access to care—increasing their risk for premature death from liver cirrhosis and liver cancer. Each year, more than 1 million people die from viral hepatitis and millions of new infections add to this global burden of disease and death.

It is not, however, the first ever World Hepatitis Day – it’s just the first one recognized by WHO. Many of these international attention-raising events grow out of smaller things which pick up steam and eventually get official recognition from international organizations. It turns out that World Hepatitis Day has been going on for several years.

On a related note, did you know that Hep B is a cause of discrimination in China, and that there is a burgeoning carriers’ rights movement? I didn’t either until I started browsing the impressively worked out Wikipedia Hepatitis B page (some epidemiologist had a field day) and found that there’s an entire page for Hep B in China. An excerpt:

Discrimination

Hepatitis B sufferers in China frequently face discrimination in all aspects of life and work. For example, many Chinese employers and universities refuse to accept anyone who tests positive. Some kindergartens refuse admission to children who are carriers of the virus. The hepatitis problem is a reflection of the vast developmental gap between China's rural and urban areas. The largest problem facing Chinese people infected with HBV is that illegal blood testing is required by most employers in China.[17] Following an incident involving a Hepatitis B carrier's killing of an employer and other calls against discriminatory employment practices, China's ministries of health and personnel announced that Hepatitis B carriers must not be discriminated against when seeking employment and education.[18] While the laws exist to protect the privacy of employees and job seekers, many believe that they are not enforced.

"In the Hepatitis B Camp"

"In the Hepatitis B Camp" is a popular website for hepatitis B carriers' human rights in China. Its online forum is the world's biggest such forum with over 300,000 members. The website was first shut down by the Chinese government in November 2007. Lu Jun, the head of the rights group, managed to reopen the website by moving it to an overseas server, but the authorities in May 2008 began blocking access to the website within China, only 10 days after government officials participated in an event for World Hepatitis Day at the Great Wall of China. An official had told the head of the rights group, Lu Jun, at the time that the closure was due to the Beijing Olympic Games.[19]

(h/t to Tom)

CIA's despicable Pakistan vaccination ploy

Via Conflict Health, The Guardian reports that the "CIA organised fake vaccination drive to get Osama bin Laden's family DNA":

In March health workers administered the vaccine in a poor neighborhood on the edge of Abbottabad called Nawa Sher. The hepatitis B vaccine is usually given in three doses, the second a month after the first. But in April, instead of administering the second dose in Nawa Sher, the doctor returned to Abbottabad and moved the nurses on to Bilal Town, the suburb where Bin Laden lived.

Christopher Albon of Conflict Health writes:

If true, the CIA’s actions are irresponsible and utterly reprehensible. The quote above implies that the patients never received their second or third doses of the hepatitis B vaccine. And even if they did, there is absolutely no guarantee that the vaccines were real. The simple fact is that the health of the children of Abbottabad has been put at risk through a deceptive medical operations by the Central Intelligence Agency. Furthermore, the operation undermines future vaccination campaigns and Pakistani health workers by fueling conspiracy theories about their true purpose.

Albon notes that the Guardian's source is Pakistan's ISI... but this McClatchy story seems to confirm it via US sources:

The doctor's role was to help American officials know with certainty that bin Laden was in the compound, according to security officials and residents here, all of whom spoke only on the condition of anonymity because they feared government retribution. U.S. officials in Washington confirmed the general outlines of the effort. They asked not to be identified because of the sensitivity of the topic.

The sensitivity of the topic? No kidding. This is absolutely terrible, and not just because the kids originally involved might not have gotten the second round of vaccine (which is bad) or because it will make the work of legitimate public health officials in Pakistan even harder (which is very bad). Vaccines are amazing innovations that save millions of lives, and they are so widely respected that combatants have gone to extraordinary lengths to allow vaccination campaigns to proceed in the midst of war. For instance, UNICEF has brokered ceasefires in Afghanistan and Pakistan for polio vaccine campaigns which are essential since those are two of the four countries where polio transmission has never been interrupted.
I hope I'm not overreacting, but I'm afraid this news may be bad for the kids of Pakistan, Afghanistan, and the rest of the world. Assuming the early reports are confirmed, this plot should be condemned by everyone. If US officials who support global vaccination efforts are going to control the damage as much as possible -- though it's likely much of it has already been done -- then there need to be some very public repercussions for whoever authorized this or had any foreknowledge. What tragic stupidity: a few branches of the US government are spending millions and millions to promote vaccines, while another branch is doing this. The CIA is out of control. Sadly, I'm not optimistic that there will be any accountability, and I'm fuming that my own country breached this critical, neutral tool of peace and health. How incredibly short-sighted.


Update: In addition to the Guardian story, Conflict Health, and McClatchy stories linked above, this NYTimes article offers further confirmation and the CNN piece has some additional details. Tom Paulson at Humanosphere, Mark Leon Goldberg of UN Dispatch, Charles Kenny of CGD, and Seth Mnookin all offer commentary.


Measles is big this year

The CDC just put out a Health Advisory describing measles' big comeback. Though endemic transmission is the US has been interrupted, but importations keep happening when the unvaccinated population travels or come into contact with travelers:

The United States is experiencing a high number of reported measles cases in 2011, many of which were acquired during international travel. From January 1 through June 17 this year, 156 confirmed cases of measles were reported to CDC. This is the highest reported number since 1996. Most cases (136) were associated with importations from measles-endemic countries or countries where large outbreaks are occurring. The imported cases involved unvaccinated U.S. residents who recently traveled abroad, unvaccinated visitors to the United States, and people linked to these imported cases. To date, 12 outbreaks (3 or more linked cases) have occurred, accounting for 47% of the 156 cases. Of the total case-patients, 133 (85%) were unvaccinated or had undocumented vaccination status. Of the 139 case-patients who were U.S. residents, 86 (62%) were unvaccinated, 30 (22%) had undocumented vaccination status, 11 (8%) had received 1 dose of measles-mumps-rubella (MMR) vaccine, 11 (8%) had received 2 doses, and 1 (1%) had received 3 (documented) doses.

Measles was declared eliminated in the United States in 2000 due to our high 2-dose measles vaccine coverage, but it is still endemic or large outbreaks are occurring in countries in Europe (including France, the United Kingdom, Spain, and Switzerland), Africa, and Asia (including India). The increase in measles cases and outbreaks in the United States this year underscores the ongoing risk of importations, the need for high measles vaccine coverage, and the importance of prompt and appropriate public health response to measles cases and outbreaks.

Measles is a highly contagious, acute viral illness that is transmitted by contact with an infected person through coughing and sneezing. After an infected person leaves a location, the virus remains contagious for up to 2 hours on surfaces and in the air. Measles can cause severe health complications, including pneumonia, encephalitis, and death.

The message is simple: parents should vaccinate their children because not doing so has serious health effects not only on those children, but also on those who are unable to be vaccinated because they are either too young or have medical contraindications. If everyone who believed (wrongly) that vaccines are unsafe would move to one country (let's call it Unvaccinstan) then the choice would have fewer ethical pitfalls: you make a bad choice, and your kids might get sick. But as it is there are many people who simply can't get vaccinated -- kids with cancer for example, or kids in the window between when your maternal antibodies aren't that effective against measles but still interfere with the vaccine -- so the choice has much broader societal impact. I imagine that many of the parents who choose not to vaccinate -- who are often of higher educational status and more liberal politics -- view themselves  as virtuous; the reality is sadly the opposite.

Progress on Polio in Africa?

From the latest CDC Morbidity and Mortality Weekly Report: "Progress Toward Interrupting Wild Poliovirus Circulation in Countries with Reestablished Transmission -- Africa, 2009-2010" There are only four countries where polio is still "endemic" -- Afghanistan, Pakistan, India, and Nigeria. Combined the four endemic countries have about 23% of the world's population, though to be fair polio is only endemic in some portion of each country.

But the actual definition of "endemic" may not match with lay assumptions about that term. For polio, endemic countries are defined as those where transmission has never been broken. So a country where polio has been reintroduced -- and is now spreading on its own, without the need for additional introductions -- is by definition still not endemic. Thus, there's essentially a three-tiered system: a) endemic countries, b) countries with reestablished transmission, and c) countries without established transmission, which may have sporadic outbreaks from imported cases or from vaccine-derived polio.

The CDC report linked above provides an overview of polio in African countries. Between 2002 and 2009 several dozen previously polio-free countries had outbreaks of polio from strains imported from India or Nigeria. (The strain of polio in each outbreak is genetically typed, which means we can determine which known strain the new one is closest too, and thus from whence the outbreak came.) Of those countries, four--Angola, Chad, Democratic Republic of the Congo (DRC), and Sudan--had persistent transmission (more than one year) after re-importation of polio that occurred before 2009. One of the milestone of the Global Polio Eradication Initiative (GPEI) was that polio transmission would be interrupted in those four countries by the end of 2010. The conclusion of the MMWR report is that it has been stopped in Sudan, but not Angola, Chad, or DRC.

Review: "The Panic Virus"

Review of The Panic Virus, by Seth Mnookin. Simon & Schuster Jan 2011 (Available at Amazon) [Disclosure: I got a free copy of the Panic Virus from a friend who has a friend that works at the publisher -- I wasn't given the copy specifically to write a review, but it's still probably better to disclose I didn't pay for the book.]

Seth Mnookin's The Panic Virus starts and ends with two stories of parents whose seemingly normal children come down with a serious illness. He describes their children before the episodes, and then their dread as they go downhill, are hospitalized, and fight for their lives. These stories intentionally parallel the narrative of the vaccines-cause-autism movement -- "our child was normal, then he got the vaccine, and then he got autism, so it must have been the vaccine." However, Mnookin's carefully chosen stories don't support the anti-vaccine movement; they do just the opposite and make you feel heartsick for the children affected by vaccine-preventable diseases.

Mnookin knows how to tug on heart strings, and how to get his readers riled up, so it's a good thing that he comes down strongly pro-vaccine. His case studies are selected for emotional value, and they illustrate how a thoughtfully written narrative can humanize statistics about disease outbreaks and the danger of the anti-vaccine movement. But I approve of Mnookin's tactics ultimately because his stories are true -- vaccines save lives, and much harm has been done by the spread of unfounded fear.

That said, Mnookin's book isn't at all a fearmongering tale of what will happen if you don't vaccinate your child -- the bookend stories are just that, and he could probably have included a few more narratives throughout without stretching it. For the most part his book is a sober narrative of a social movement that goes back to the earliest vaccines, but has only come to nationwide fruition with the rise of the Internet.

Mnookin chronicles the development of early vaccines, and, to his credit, spends a good deal of time on what was done badly by the scientists and advocates. The Cutter Incident is there,  along with the 1976 swine flu vaccine. Mnookin doesn't mince words in describing injuries that have been caused by vaccines, and at many times I found myself cringing and thinking "why weren't better systems in place earlier?" and "they really should have done more".

This willingness to confront unpleasant truths is a strong point for the Panic Virus, and it also gives Mnookin an opportunity to introduce the safety innovations that stemmed from each incident, all while setting the stage for the anti-vaccine movement. Another strength is that The Panic Virus also offers compelling humanizations of many of the parents of autistic children who have been involved in the anti-vaccine movement. Their despair at seeing their children suffer, their ostracization in a society where autism is not accepted, their occasionally callous treatment by physicians who have no easy answers to offer -- all of this makes it impossible not to sympathize with them.

For the most part, Mnookin doesn't present parents as the villains of his story. That role is reserved for shoddy physicians, scientists and pseuodoscientists, and most of all for journalists. Andrew Wakefield, Mark and David Geier, and journalist/author David Kirby all come in for harsh reckonings, along with many other "expert witnesses" for anti-vaccine lawsuits. This book left me quite depressed regarding the role of journalists and TV personalities in the whole fiasco. There has been so much bad reporting, and so little good.

While reading The Panic Virus, I kept thinking that its major shortcoming is a lingering uncertainty about its target audience. Is Mnookin writing for the uninitiated who want an introduction to where the anti-vaccine movement? Or is he writing a broadside for those already staunchly in the pro-vaccine community? There are sections where the rhetoric made me think it was the latter, while the majority of the book seems to be for those with little outside knowledge of vaccine science. Since Mnookin cautions so much against being led astray by charlatans who peddle fear with a thin veneer of scientific-sounding verbiage, I wish he had done a bit more to explain the science done in recent years on vaccine safety, thiomersal, MMR, and autism. I understand why an author writing a popular narrative would avoid trying to describe these subjects: they are incredibly complicated and divert the reader from the narrative. [Note that I haven't read Paul Offit's Autism's False Prophets, which I understand might have a bit more of that.] And it's not like good science writing is entirely missing from The Panic Virus. Some things are explained well, but overall there's just a bit too much deference to the authority of  science and scientists for my tastes, especially for a book intended for lay audiences. It's a good book, but not a great book.

I also wish Mnookin had provided a better counter-narrative in the second half of the book. Broadly speaking, the first half follows the development of vaccines and early vaccine injury scares (founded and unfounded), and the second half explores the rise of the anti-vaccine social movement. The second half is missing strong pro-vaccine characters, such as one or two scientists or policymakers who have been working to combat the anti-vaccine crowd. A lot of good research has been done to disprove fallacious claims, and to look for policy solutions aimed at decreasing opt-out rates on a state level, but none of that is here.

To date the anti-vaccine crowd has really won the narrative war: their message is simpler, and scarier, and has the added perk of being anti-establishment in appealing ways. The Panic Virus didn't give me much hope that that would change soon -- although the book itself is mostly a step in the right direction, combining a pro-science view with a few emotional narratives about vaccine-preventable diseases.

Our best hope is that eventually our scientific explanations of autism etiology will solidify a bit more, and coupled with much more demonstrably effective treatments, the snake oil appeal of the "cures" sold by the anti-vaccine movement will lose their charm. One theme of the Panic Virus is that the anti-vaccine movement arose because parents of autistic children weren't getting the sympathy, explanations, and help they needed. Many factors including a lack of understanding by doctors and communities, isolation, weak scientific explanations, and a lack of viable treatments all created a situation like a field of dry grass. When a powerful idea -- "vaccines cause autism" -- arose and was amplified by the echo chambers of Internet communities, it ripped through the dry field like a wildfire, sowing panic and fear. And the fire still hasn't been put out.