Those confounded links to the causes of asthma

We've blogged a number of times about asthma -- specifically, why has it increased in prevalence so dramatically over the last 30 years, and why hasn't epidemiology figured it out?  (Here's our most recent post on this, and here's one on the Hygiene Hypothesis.) A disease that goes from not so common to very common very quickly most likely has an environmental trigger.  It's unlikely to be some new genetic risk, because genes don't change that quickly, and it's likely to be an environmental cause with a major effect, since it's triggering the disease in a whole lot of people.  And, since epidemiology is best at figuring out major environmental effects -- smoking, infectious agents, um....  -- you'd think they'd have knocked this one long ago.  But no, the answer to why so many kids are getting asthma has been elusive.  Until maybe now.

But, let's back up.  Millions -- and millions -- of dollars have been spent on the genetics of asthma.  Numerous family studies, GWAS (genomewide association studies), admixture mapping studies, and so on, and nothing to explain any significant amount of variation in risk has yet been found.  The idea was -- we guess -- that while asthma was certainly increasing in prevalence, not everyone was getting it, and the explanation for that must be genetic.  Let's ignore the root cause, whatever had changed in the environment, and just explain why some people respond to whatever-it-is with asthma.  Beyond our current fetish with geneticizing everything that moves, the rationale was that druggable pathways would be identified this way, and so whether or not we understood the source of the epidemic, by golly, we would be able to sell a lot of drugs to treat it.

Ok, that's one approach.

But to be fair, environmental and observational epidemiologists did try their darndest to tease out the environmental cause, and all they got for their pains were confusing and contradictory results.  Breast feeding, bottle feeding; environments that were too clean or environments that were too dirty; lack of helminth infections, lack of air pollution (really -- this was based on observations such as that asthma was on the increase in the early days of the epidemic in places like West Germany, but not right over the wall in East Germany, where air pollution was high).  We got the Hygiene Hypothesis out of all this work, a still live conjecture about the importance of boosting our immune systems when we're young. Maybe true.

But now the asthma community has a new idea, and again to be fair, it's in part due to some good sleuthing by epidemiologists.  Actually, the idea isn't so new -- the first paper suggesting it was published in 1998 -- but the idea is just now getting legs.  It's probably the most likely possible solution to the question of what's causing this epidemic that has been offered to date.  (Though we're still disappointed that no one picked up on our suggestion in a 2006 paper that the use of plastic diapers grew right along with the asthma epidemic, a correlation that we thought might do with some looking into.) And if this current suggestion is true, it shows again the problem of correlation not proving causation.

A story in the New York Times reported on this recently. The idea is that acetaminophen causes asthma.  In the 1980's, when the epidemic began, doctors started recommending that parents treat their infants' pain and fever with acetaminophen rather than aspirin because aspirin had been found to cause Reyes' Syndrome.  So, Tylenol sales took off.  And, not too long after that, so did inhaler sales.  More than 20 studies that show this association have now been published, and it's starting to look strong, not only based on epidemiological measures such as the strength of the association (the strength of the association between air pollution and low risk was strong too, but more on that below), but with a fairly substantial understanding of the biological mechanism that could explain the risk.

Here's the abstract from a paper in the November issue of Pediatrics, by John McBride:

The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adults is well established. A variety of observations suggest that acetaminophen use has contributed to the recent increase in asthma prevalence in children: (1) the strength of the association; (2) the consistency of the association across age, geography, and culture; (3) the dose-response relationship; (4) the timing of increased acetaminophen use and the asthma epidemic; (5) the relationship between per-capita sales of acetaminophen and asthma prevalence across countries; (6) the results of a double-blind trial of ibuprofen and acetaminophen for treatment of fever in asthmatic children; and (7) the biologically plausible mechanism of glutathione depletion in airway mucosa. Until future studies document the safety of this drug, children with asthma or at risk for asthma should avoid the use of acetaminophen.

A somewhat more detailed description of the findings on JournalWatch is here.

So, some in the pediatric community are starting to take notice, and recommend that parents give their kids ibuprofen rather than acetaminophen or aspirin.  Though, some are still doubtful; parents give their children acetaminophen when they have fevers, often of viral origin, and it could be the virus that causes asthma, not the treatment, some say.  Others are dubious because many of the studies relied on parents recalling how much of the drug they gave their children sometimes years in the past.  Relying on recall is a common cause of iffy results in epidemiological studies.

In addition, according to the Times,

So far, only one randomized controlled trial has investigated the link. Researchers at Boston University School of Medicine randomly assigned 1,879 children with asthma to take either acetaminophen or ibuprofen if they developed a fever. The results, published in 2002, showed that children who took acetaminophen to treat a fever were more than twice as likely to seek a doctor’s care later for asthma symptoms as those who took ibuprofen.

Of course, these are children who already have asthma, which complicates the interpretation of causation, but it does suggest that the mechanism, glutathione depletion in airways, might indeed be involved (though see above).  What's really needed to confirm the role of acetaminophen is a prospective study of children from birth through childhood but the ethics of a study that involves giving acetaminophen to babies surely would be questionable at this stage.

So, what about these other associations that looked so strong not long ago?  The idea that helminth infections or air pollution might actually reduce risk of asthma?  They could still be true, it could be that asthma, which is as complex and variable a disease as almost any disease out there, could have many causes.  Or, if the acetaminophen link is true, then these other factors are either independent confounders or in some way actively interact with the acetaminophen-related mechanism.  In rural African villages where helminths are a common fact of life, or in cities where air pollution is high, acetaminophen use is not.  The Hygiene Hypothesis, even given that people have suggested possible biological explanations for it, may be on its way out.

If this association does explain the epidemic, there's still this question -- will geneticists stop looking for genes 'for' asthma?  We don't bet on it.  That's not to say that better treatment isn't needed, and that the triggers and responses need to be better understood because the biology is complex -- indeed, some say that every case is unique -- and asthma is often difficult to control.  But, continuing to search for genetic causation?  Bah, humbug.