The Association Between Acetaminophen and Asthma

Should Its Pediatric Use Be Banned?

Antonio Martinez-Gimeno; Luis García-Marcos

Expert Rev Resp Med. 2013;7(2):113-122.

The Question of Acetaminophen & Wheezing Disorders in the Light of Evidence-based Medicine

To properly address the question of acetaminophen and wheezing disorders in the light of evidence-based medicine, one must analyze the different statements pertaining at different levels of knowledge that we have already discussed which, although related, do not need the same sort of supporting evidence.

The authors can classify these statements in epidemiological statements and clinical intervention statements. While the former have a large body of evidence in their support, the latter are less well supported.

The first epidemiological statement, acetaminophen exposure is associated with an increase in wheezing disorders prevalence, can be ranked in the top level of evidence-based medicine grading systems, being supported by a good number of well-designed, large epidemiological studies of every nature and confirmed by well-designed systematic reviews and meta-analyses. This statement is valid for in utero, childhood and adult life exposure. The only drawback of this body of evidence is the possibility of a huge source of bias confounding the whole association, as already discussed.

The second epidemiological statement, acetaminophen exposure is associated with an increase in asthma morbidity, can also be ranked in the top level of evidence-based medicine grading systems, being also supported by a good number of well-designed large epidemiological studies and confirmed by well-designed systematic reviews and meta-analyses. Importantly, this statement is also supported by a randomized double-blind clinical trial in children, which shows that avoiding acetaminophen in febrile conditions reduces asthma outpatient visits in the following month, as already discussed.^[15] So, it must be ranked in the top level of evidence-based medicine grading systems.

The clinical intervention statements derive from the epidemiological statements and seem quite logical. However, clinical and physiopathological reasoning is the humblest level of evidence and has proved to be unreliable in many clinical situations. Therefore, these clinical intervention statements must be directly and carefully studied.

The first clinical intervention statement can be analyzed as follows: avoiding acetaminophen exposure (intervention) in pregnant women, children and adults (object population) reduces wheezing disorders prevalence (clinical outcome). This statement has never been directly studied by means of a clinical trial, as previously discussed. Therefore, it must be ranked low in the evidence-based medicine grading systems. Its supporting evidence comes from clinical and epidemiological reasoning and experts' opinion. It is clearly a statement, which deserves further appropriate studies.

The second clinical intervention statement is: avoiding (or limiting) acetaminophen exposure (intervention) in asthmatic children and adults (object population) reduces asthma morbidity (clinical outcome). This statement is supported, in children, by the well-designed, large randomized clinical trial already discussed.^[15] Therefore, it can be ranked highly, but not top, in evidence-based medicine grading systems.

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Next Section

Abstract and Introduction
The Case Against Acetaminophen as a Wheezing Disorders Promoter
Epidemiological Evidence
Evidence From Randomized Clinical Trials
Biological Plausibility
Review of the Bradford Hill Criteria
Weakness of the Case Against Acetaminophen as a Wheezing Disorders Promoter
The Question of Acetaminophen & Wheezing Disorders in the Light of Evidence-based Medicine
Should the Pediatric Use of Acetaminophen Be Banned?
Theoretical Effect Size of Limiting Acetaminophen Exposure
Experts' Opinion & Attitudes to the Acetaminophen as a Wheezing Disorders Promoter Hypothesis
Conclusion
Expert Commentary
Five-year View
References
Sidebar

Table 1. Bradford Hill criteria applied to the hypothesis of acetaminophen as wheezing diseases promoter.
Criteria	Evidence
Strength of effect	Increased risk after acetaminophen exposure ≥1.5
Dose response	Present for acetaminophen exposure in utero, childhood and adult life
Consistency/coherence	Consistency among studies, age groups, sex, geography and culture
Exposure before response	Observed in prospective studies of acetaminophen exposure in utero, infancy and adult life Observed in the only prospective double-blind randomized clinical trial in children
Biological plausibility	Increased oxidant-induced airway inflammation Enhanced Th2 response Decreased immune response to rhinovirus infection
Removal of exposure prevents disease	Partially examined in the only double-blind randomized clinical trial on the subject published to date: using ibuprofen instead of acetaminophen in febrile children with concomitant use of anti-asthma drugs reduced the risk for an outpatient visit for asthma in the following month Effect of removal of exposure on prevalence to be determined
Specificity	No increased risk of asthma associated with aspirin or other NSAID
Analogy	Weak, protective effects of antioxidant diet in asthma

Adapted with permission from [17].

Table 2. Overview of arguments in the case against acetaminophen as a promoter of wheezing disorders in children.
Arguments that support a detrimental effect of acetaminophen in asthma	Arguments against a detrimental effect of acetaminophen in asthma
Epidemiologic association between acetaminophen exposure and asthma
Strength of the association Consistency of the association across geography, culture, age and studies Dose dependency of the epidemiologic association Coincidence in time of increase in asthma prevalence and increase in acetaminophen use Ecologic relationship among asthma prevalence and per-capita sales of acetaminophen Uniqueness of this association, more consistent than any other environmental factor	The whole epidemiologic association may be spurious, acetaminophen being an innocent bystander falsely accused due to several bias or confounding factors: Confounding by indication (real culprit, respiratory virus infections producing fever) Confounding by reverse causation (real culprit, asthma itself which induces acetaminophen use) Confounding by preferential use of acetaminophen by children at higher risk of asthma or already asthmatics
Clinical trials
A randomized clinical trial with 1879 children 6 months to 12 years old with asthma exacerbation and fever, showing a lower incidence of outpatient visits for asthma in those randomly assigned to ibuprofen compared with acetaminophen (adjusted relative risk: 0.56 [95% CI: 0.34–0.95] compared with those receiving acetaminophen)	No placebo group included. The lower relative risk for children who received ibuprofen could be due to a protective effect of ibuprofen instead of a detrimental effect of acetaminophen No clinical trials have been performed on the effect of acetaminophen on the prevalence of asthma
Biological plausibility
Acetaminophen depletes glutathione from the airways Acetaminophen reduces immune response to, and prolongs, rhinovirus infection