DOES TYLENOL® (ACETAMINOPHEN) CAUSE ASTHMA?
Asthma, also referred to as reactive airway disease, is an increasingly common disorder in our modern society. Asthma is a disease that affects the airways within the lungs. In the presence of allergens (substances that evoke an allergic reaction), patients with asthma can develop swelling, constriction and obstruction of the airways, cutting off the delivery of oxygen to the alveolar surfaces of the lungs that absorb oxygen into the blood. During an asthma attack, patients often experience varying degrees of wheezing, shortness of breath, and chest pain. Especially severe attacks of asthma can even be fatal, particularly in younger children.
or prevalence, of children with asthma has been steadily rising in the
Although the cause, or causes, of asthma remain unclear at this time, there are a number of risk factors that appear to be associated with this condition. Certain genetic factors appear to increase the risk of asthma, most notably in people who produce an excess of IgE, an antibody that is directly involved in the allergic response mechanism that underlies not only asthma, but also hay fever, contact dermatitis, eczema, food and drug allergies, and allergies to the stings of certain insects, among other forms of acute allergic reactions. In addition to having high levels of IgE in the blood, which is thought to be a genetic trait, having a close relative with asthma also significantly increases one’s risk of developing asthma too.
environmental allergens, especially during childhood, also appears to
associated with an increased risk of developing asthma, and with an
risk of asthma attacks in patients who already have the disease,
Tobacco smoke is another potent allergen that has been implicated not only in the development of asthma, but in causing repeated asthma attacks in children (and adults) with asthma. Moreover, it appears that prenatal exposure to secondhand smoke, through maternal smoking during pregnancy, also raises the risk of subsequent asthma development.
Other factors associated with an increased risk of asthma include exposure to cockroach allergen and infections with respiratory syncytial virus (RSV) in susceptible children.
In children who already have a diagnosis of asthma, exposures to several types of allergens are known to cause acute asthma attacks, and to worsen the chronic symptoms of asthma. These include exposures to cats, house mites, tobacco smoke, pollen and mold, and viral respiratory infections. Other possible culprits that may worsen asthma symptoms in both children and adults include exposures to dogs, pet birds, perfumes and other strong fragrances or fumes, cold weather, high levels of common air pollutants, emotional or physical stress, certain medications (e.g., aspirin and other anti-inflammatory medications, and beta-blockers), preservatives in dried foods and wine (e.g., sulfites), and gastroesophageal reflux disorder (GERD)
Another theory has recently been proposed to explain the rising prevalence of asthma in our modern society. With the advent of powerful disinfectants, and a growing obsession with maintaining a “germ-free” environment in both the home and the workplace, childhood exposure to many of the microbes that normally inhabit our world has been significantly reduced in many places, recently. Many immunologists believe that a child’s developing immune system “learns” to discriminate between potentially harmful bacteria or viruses, versus other nontoxic allergens in the environment, through regular exposure to all of these potential allergens during childhood. Indeed, there is some evidence that children who grow up in these “semi-sterile” environments may develop hyperactive immune systems, a condition referred to as atopy, and increased levels of IgE antibodies directed against common but otherwise nontoxic allergens in the surrounding environment. (Another public health concern related to our society’s recent “sterile environment” mania is the potential for a loss of immunity against the many bacteria that are, increasingly, becoming resistant to antibiotics.)
research study in The Lancet adds
another potential risk factor for the development of asthma in
children, and the
recent publication of this study has already added considerable fuel to
ongoing debate surrounding the potential causes of asthma and, in
those causes that are likely to be preventable.
This study was primarily conducted by researchers at the
this huge clinical
study, which enrolled more than 205,000 children from 31 countries, and
the ages of 6 and 7, written questionnaires were obtained regarding the
or absence of the symptoms of asthma, hay fever and eczema. Also included in the
questions regarding exposure to known allergens associated with these
diseases, as well as exposure to acetaminophen use.
Acetaminophen, (also known as Tylenol® in the
The researchers concluded that the use of acetaminophen for febrile illnesses during the first year of life was associated with a nearly 50% increased risk of asthma symptoms by age 6 or 7. The continued use of acetaminophen by 6 and 7 year-old children not only appeared to be associated with a greater incidence of asthma symptoms overall, but, importantly, the actual risk of developing asthma symptoms appeared to rise with increasing use of acetaminophen. When comparing 6 and 7 year-old children who used acetaminophen frequently with same-aged children who never used this medication, the risk of having asthma symptoms was more than 3 times higher among the children who had used acetaminophen most frequently. Not only was the risk of asthma symptoms increased with both current and prior use of acetaminophen, but heavy use of this over-the-counter medication was also associated with an increased risk of severe asthma-related symptoms as well. Finally, the use of acetaminophen during infancy and early childhood also appeared to increase the risk of hay fever symptoms and eczema as well.
Given the many different risk factors associated with the onset of asthma to date, and in the absence of a clear understanding of how this disease actually develops, the publication of this study has caused quite a stir in both the medical and lay communities. Taken at face value, the results of this study strongly suggest that the use of acetaminophen during infancy and early childhood is associated with a significant risk of asthma symptoms and other atopic disorders. Although a clear mechanism is not apparent from this epidemiological, survey-based study, the presumption is that acetaminophen exposure is somehow related to causing the immune hypersensitivity that is know to underlie the symptoms of asthma. At the same time, however, the results of this study would appear to raise as many questions as it purports to answer.
acetaminophen has been in wide use since the 1950s.
In view of the steadily rising incidence of
asthma over the past 15 years, it is unlikely that an over-the-counter
that has been in widespread use for more than 50 years is a primary or
frequent cause of asthma, at least by itself.
Furthermore, there is the question of cause-and-effect
association that must be answered in this case. Since
this study cannot address the issue of
the mechanism whereby acetaminophen exposure might cause asthma, one is
only the suggestion of an apparent association between exposure to this
and the development of asthma. At
same time, certain childhood febrile illnesses are, themselves, known
associated with an increased risk of asthma.
Chief among these are viral respiratory infections, which
are among the
most common of acute childhood illnesses.
Since its entry into the
Another limitation of survey-based clinical studies is their risk of bias at several levels. Biases can be introduced into the design and distribution of the study’s questionnaire, into the environment in which the questionnaire is completed, and in the interpretation of the survey’s results. When compared to the “gold standard” of clinical research, which is the prospective, randomized, blinded study, survey-based studies provide a weaker standard of clinical evidence, although they allow for a very large population to be studied within a relatively short time, and are relatively inexpensive to conduct, unlike prospective, randomized, blinded studies.
My final critique of this very important study relates to its funding sources. It is becoming increasingly common for academic researchers to supplement their research funding via “industry” sources. Because of the intense competition from increasingly scarce government and philanthropic funding sources, scientists who wish to conduct clinical research often turn to industry sponsors. These sponsors are, for the most part, manufacturers of drugs and medical devices, and they tend to have very deep pockets. However, and not surprisingly, they are generally willing to open up those deep pockets only to those researchers who are conducting studies that involve their companies’ products.
There have been several interesting research studies that have recently looked into the impact of industry funding of clinical research studies, and virtually all of them find that some degree of bias tends to be introduced into such studies. The most common bias which arises revolves around which studies actually make it to publication, especially in the more prestigious medical journals. This “publishing bias” appears to operate at two different levels. First, researchers who depend upon industry funding tend to arrive at conclusions favoring their industry sponsors’ products more frequently than researchers who study the same issues without using funding from industry sponsors. Secondly, there is also a well-recognized publishing bias at the editorial level in many, if not most, medical journals. At this level of publishing bias is the tendency to preferentially accept those manuscripts with “positive conclusions.” Put another way, if presented with manuscripts from two very similar studies, medical journal editors will often select for publication the study that reveals a drug or a treatment to be effective rather than the study that finds little or no therapeutic effect from such treatments. These two forms of publishing bias cause the world’s body of published medical literature to be swayed, or biased, in favor of “positive studies” and, increasingly, in favor of industry-sponsored studies with favorable findings and conclusions.
For all of these reasons, the results of this study, in my view, should be viewed with considerable caution. At the same time, this study’s finding that the extent of acetaminophen use was proportionally associated with the prevalence and severity of asthma symptoms is a compelling epidemiological “red flag,” and suggests that there could be something more than a mere association going on here (there have been a few laboratory studies that have reported a toxic effect of acetaminophen on the lungs of animals). Ultimately, however, as I have often stated before with regards to other studies that offer relatively low levels of clinical evidence for their conclusions, a highly-controlled, prospective, randomized, double-blinded (placebo-controlled) study will need to be performed before we can be certain that acetaminophen does or does not, by itself, increase the risk of developing asthma. Until such a study is performed, however, it is wise to rely upon common sense, and to avoid, altogether, the use of medications that are unnecessary, particularly in children.
Dr. Wascher is an oncologic surgeon, professor of surgery, a widely published author, and the Director of the Division of Surgical Oncology at Newark Beth Israel Medical Center
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Copyright 2008. Robert A. Wascher, MD, FACS. All rights reserved.
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