Acetaminophen and asthma: A review of evidence in the literature

Acetaminophen has been the topic of this column on many occasions in the past years. This commonly used medication can be useful for symptom relief for infants and children, from a wide variety of infectious diseases and other disorders.

Acetaminophen’s availability as an over-the-counter product may cause it to be used with little or no direction from a health care professional. This likely has contributed to its misuse, resulting in significant adverse effects. The recent change in the strengths and concentrations of the pediatric liquid formulations was done to limit inappropriate use and dosing of acetaminophen. Another potential difficulty facing this important therapeutic agent is gaining increasing attention in the medical and lay literature. Evidence has been accumulating that acetaminophen use may be an important risk factor for the development of asthma in infants and children. Although this evidence is largely based upon epidemiologic information and data from observational and cohort studies, the implication that this commonly used medication may contribute to the prevalence of asthma is significant.

Studies

The largest published study describing an association between acetaminophen and asthma is the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC is a cross-sectional study of randomly sampled children in two age groups (6 to 7 years and 13 to 14 years) that was conducted in more than 30 countries. Questionnaires were administered to caregivers and adolescents and designed to obtain prevalence data about asthma, rhinoconjunctivitis and eczema, and environmental data about risk factors for the development of asthma and allergic disorders.

These environmental data included questions about frequency of acetaminophen use within the past 12 months. The primary outcome measure was the association between acetaminophen use for fever in the first year of life and asthma symptoms at 6 to 7 years of age. The major strength of this study is the large sample size: 205,487 children 6 to 7 years of age from 73 centers in 31 countries. Analysis of data revealed that use of acetaminophen for fever in the first year of life was associated with an increased risk of asthma symptoms at age 6 to 7 years, with an OR of 1.46 (95% CI, 1.36-1.56).

Current acetaminophen use was also associated with a dose-dependent increased risk of asthma symptoms for medium and high use (OR=1.61 and 3.23, respectively, with neither including 1.0 for 95% CI) vs. no use. Medium and high use were defined as “at least once a year,” and “at least once per month,” respectively. Acetaminophen use was additionally associated with similar, significantly increased risks of symptoms of rhinoconjunctivitis and eczema.

Data obtained from the adolescent study group (13 to 14 years) in ISAAC were reported in a separate publication. Data from 322,959 adolescents in 115 centers in 50 countries were analyzed. The primary outcome measure was the association between current acetaminophen use and current asthma symptoms. Acetaminophen use and asthma symptoms (“wheezing or whistling in the chest”) were assessed within the past 12 months and included definitions of medium (“at least once a year”) and high (“at least once per month”) use of acetaminophen vs. no use. ORs demonstrated that recent use of acetaminophen was associated with increased risks of current asthma symptoms for medium and high use — 1.43 (95% CI, 1.33-1.53) and 2.51 (95% CI, 2.33-2.70), respectively, compared with no use of acetaminophen. Acetaminophen use was additionally associated with similar, significantly increased risks of symptoms of rhinoconjunctivitis and eczema.

A recently published meta-analysis of published studies on acetaminophen use and its associations with asthma evaluated 19 observational studies, with 425,140 participants (prenatal use and use by children and adults). The ISAAC study (6- to 7-year-old children) was included. Observational trials included in this analysis were required to have clearly defined acetaminophen use and asthma diagnosis. The pooled OR for asthma among users of acetaminophen was 1.63 (95% CI, 1.46-1.77). An increased risk for asthma was found in children born to mothers who used acetaminophen during pregnancy, with an OR of 1.28 (95% CI, 1.13-1.39).

The risk for asthma in children who used acetaminophen in the year before diagnosis and within the first year of life was increased (OR=1.60 and 1.47, respectively, with neither including 1.0 for 95% CI). A strength of this meta-analysis is the large sample size evaluated. However, these data are limited by the heterogeneous nature of data collection among the studies and inclusion of self-reporting of asthma diagnoses.

Acetaminophen vs. ibuprofen

A review of the literature and data on acetaminophen use and asthma includes a description of data obtained from only one randomized controlled trial. This randomized, double blind trial was conducted initially to evaluate the safety of ibuprofen suspension for the use of fever in children aged 6 months to 12 years (n=83,915). Two doses of ibuprofen (5 mg/kg and 10 mg/kg) were compared with acetaminophen (12 mg/kg). A placebo control group was not included.

Data from this study were used in part to gain approval for ibuprofen suspension availability as an OTC pediatric product. Of the total sample size, 1,879 children were described as receiving treatment for asthma (receiving a beta-agonist, theophylline or inhaled corticosteroid). The objective of this additional data analysis was to evaluate the hypothesis that short-term use of ibuprofen increases asthma morbidity. Thus, the initial study producing these data was not designed to investigate an association between asthma and acetaminophen.

The data demonstrate that children receiving ibuprofen had a lower risk of requiring an outpatient visit for asthma, with an RR of 0.56 (95% CI, 0.34-0.95) vs. children receiving acetaminophen. Rates of hospitalization for asthma did not differ among children receiving ibuprofen or acetaminophen. The study researchers concluded that a difference in risk for asthma symptoms cannot be attributed to an increased risk from acetaminophen as compared with a decreased risk from ibuprofen.

It is important to consider the strengths and weaknesses of the data obtained from these studies. Strengths of these data include the large sample sizes evaluated in the ISAAC studies; similar data from other observational studies; statistically significant associations; an association of asthma and acetaminophen use across various countries and cultures; an association across age groups (prenatal, children, adults); and an associated dose-response relationship.

Proposed biologic and pharmacologic mechanisms underlying an acetaminophen-asthma relationship are additionally plausible. A significant weakness of these data includes their source from observational studies. These observational studies are limited by recall bias (retrospective data collection), reporting bias and reporting of asthma diagnosis or symptoms by caregivers or self. Observational studies are subject to confounding variables, and although the ISAAC and other studies attempted to control for many potentially confounding variables, other variables not assessed (such as hygiene practices or use of ibuprofen or other nonsteroidal anti-inflammatory drugs) may be important. Thus, association does not imply causation.

Several researchers have additionally reported on some data that suggest that increased respiratory tract infection morbidity is more likely to be associated with later development of asthma, and not use of acetaminophen. Although data from a randomized controlled trial are described in the literature, as discussed, this study did not include a placebo control and was not initially designed to address a potential relationship between acetaminophen use and asthma. An important question raised by this controlled trial is the potential for a protective effect of NSAIDs vs. a deleterious effect of acetaminophen on asthma. Randomized trials in adults have additionally shown that aspirin (an NSAID) can have a protective effect against asthma.

Mechanisms

Proposed biologic and pharmacologic mechanisms underlying a potential association between acetaminophen use and asthma include an acetaminophen-induced reduction in pulmonary glutathione. Glutathione acts as an antioxidant, and reduced levels may contribute to pulmonary tissue damage, inflammation and the development of asthma. Reduced glutathione may also alter differential cytokine production, potentially increasing risk of development of allergic disorders.

Conclusions

The findings from these studies are interesting and certainly cannot be ignored. Studies with large sample sizes have identified an association between acetaminophen use in children and asthma. Most study and editorial authors do not believe we should change our current practices of this commonly used medication in infants and children at this time.

One author of a recently published discussion on this topic, however, does believe that acetaminophen should not be used by children with asthma or those at risk for asthma. Until stronger data are available from additional studies, it seems premature to alter our current practice patterns. Although ibuprofen is an alternative antipyretic and analgesic agent that is additionally available for infants and children, it is not labeled for use in children aged younger than 6 months, and there are children with specific underlying disorders that can be at increased risk of adverse effects (eg, renal disorders) from its use. A prospective, controlled trial is urgently needed to address this potential problem, with perhaps the most commonly used medication in the pediatric population.

For more information:

• Barr RG. Lancet. 2008;372:1011-1012.
• Beasley R. Am J Respir Crit Care Med. 2011;183:171-178.
• Beasley R. Lancet. 2008;372:1039-1047.
• Etminan M. Chest. 2009;136:1316-1323.
• Farquhar H. J Allergy Clin Immunol. 2009;124:649-651.
• Holgate ST. Am J Respir Crit Care Med. 2011;183:147-151.
• Lesko SM. Pediatrics. 2002;109:E20.
• McBride JT. Pediatrics. 2011;128:1181-1185.
• Schnabel E. J Allergy Clin Immunol. 2010;126:1071-1073.

Edward A. Bell, PharmD, BCPS, is professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. Disclosure: Dr. Bell reports no relevant financial disclosures.