The
information in this column is intended for informational
purposes only, and does not constitute medical advice or
recommendations by the author. Please consult with your
physician before making any lifestyle or medication changes, or if you
have any other concerns regarding your health.
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.
The
percentage,
or prevalence, of children with asthma has been steadily rising in the United States.
According to data
from the Centers for Disease
Control (CDC), approximately 3% of children had asthma in 1980. In 1995, 15 years later,
an estimated 7.5% of
American children (or, approximately 5 million children) had asthma. Indeed, asthma is the
second most common
chronic illness among children, and results in an estimated 14 million
days of
school absences per year, according to the CDC.
While asthma affects adults as well, it is far more common
during
childhood. Asthma
also appears to affect
females more than males, at least according to more recent data. As with many aspects
regarding asthma, the reason,
or reasons, for this female predilection is currently unknown. Given the high prevalence
of asthma in our
population, it is not surprising that the public health costs related
to this
disease are substantial, with an estimated cost to society of more than
$14
billion per year, according to the CDC.
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.
Exposure
to certain
environmental allergens, especially during childhood, also appears to
be
associated with an increased risk of developing asthma, and with an
increased
risk of asthma attacks in patients who already have the disease,
according to
the Institute
of Medicine.
A particularly
common allergen in most homes
is dust mite allergen, and which has been shown to be a particularly
potent
inducer of asthma symptoms in susceptible children.
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.)
A
new clinical
research study in The Lancet adds
yet
another potential risk factor for the development of asthma in
children, and the
recent publication of this study has already added considerable fuel to
the
ongoing debate surrounding the potential causes of asthma and, in
particular,
those causes that are likely to be preventable.
This study was primarily conducted by researchers at the
Medical Research
Institute, the University
of Auckland,
and the University
of Wellington,
all in New Zealand. It must also be noted that
this research
study was funded, in part, by the drug manufacturers Astra Zeneca and
Glaxo
Wellcome, both of whom hold a major share of the market for asthma
medications
(I will have more to say about the potential significance of this
relationship
later).
In
this huge clinical
study, which enrolled more than 205,000 children from 31 countries, and
all between
the ages of 6 and 7, written questionnaires were obtained regarding the
presence
or absence of the symptoms of asthma, hay fever and eczema. Also included in the
questionnaire were
questions regarding exposure to known allergens associated with these
atopic
diseases, as well as exposure to acetaminophen use.
Acetaminophen, (also known as Tylenol® in the
United
States,
and paracetamol in many other countries), is one of the most commonly
used
medications for acute childhood (and adult) illnesses.
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.
First
of all,
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
medication
that has been in widespread use for more than 50 years is a primary or
very
frequent cause of asthma, at least by itself.
Furthermore, there is the question of cause-and-effect
versus mere
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
left with
only the suggestion of an apparent association between exposure to this
drug
and the development of asthma. At
the
same time, certain childhood febrile illnesses are, themselves, known
to be
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 U.S.
market, in 1955, as a medication for childhood fever and pain,
acetaminophen has
become the most commonly used drug for the symptoms of acute childhood
febrile
illnesses, including respiratory infections, in the United States
and around the world. This
raises the rather obvious question of
whether it the febrile illness, itself, that is the primary risk factor
for
asthma, or the drug that is so commonly used to treat the symptoms of
the
febrile illness in childhood (or both).
Unfortunately,
survey-based public health studies, such as this one, are unable to
distinguish
potential cause-and-effect mechanisms from mere (and often unrelated)
associations.
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.
Disclaimer:
As always, my advice to readers is to seek the advice of your physician
before making any significant changes in
medications, diet, or level of physical activity.
