The Journal of Allergy and Clinical Immunology
Volume 124, Issue 4 , Pages 649-651, October 2009

The acetaminophen and asthma hypothesis 10 years on: A case to answer

  • Hamish Farquhar

      Affiliations

    • Medical Research Institute of New Zealand, Wellington, New Zealand
    • ,
  • Julian Crane, MBBS

      Affiliations

    • Department of Medicine, University of Otago, Wellington, New Zealand
    • ,
  • Edwin A. Mitchell, DSc

      Affiliations

    • Faculty of Medical & Health Sciences, the University of Auckland, Auckland, New Zealand
    • ,
  • Sally Eyers, MBChB

      Affiliations

    • Medical Research Institute of New Zealand, Wellington, New Zealand
    • Capital & Coast District Health Board, Wellington, New Zealand
    • ,
  • Richard Beasley, DSc

      Affiliations

    • Medical Research Institute of New Zealand, Wellington, New Zealand
    • Capital & Coast District Health Board, Wellington, New Zealand
    • Corresponding Author InformationReprint requests: Richard Beasley, DSc, Medical Research Institute of New Zealand, PO Box 10055, Wellington 6143, New Zealand.

Received 25 January 2009; received in revised form 24 June 2009; accepted 23 July 2009. published online 22 September 2009.

Article Outline

Key words: Asthma, acetaminophen, epidemiologic studies, risk factor

 

It is now just over 10 years since the hypothesis was first proposed that acetaminophen might increase the risk of asthma and that the change from aspirin to acetaminophen use in the United States in the 1980s might have contributed to the increasing prevalence of childhood asthma during this period.1 Since then, there has been evidence presented that the risk of asthma might be increased with exposure to acetaminophen in the intrauterine environment,2, 3, 4, 5, 6, 7, 8 infancy,2, 9 later childhood,9 and adult life10, 11, 12, 13, 14, 15 and that this risk might also extend to rhinoconjunctivitis and eczema. Furthermore, the patterns of acetaminophen use might explain to some extent the worldwide variations in the prevalence of asthma and related allergic conditions.9 It is important for allergists and clinical immunologists to be aware of this evidence and for randomized controlled trials to be undertaken to determine the nature of the associations between acetaminophen use and the development of asthma and its severity.

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Intrauterine exposure 

There are now 6 studies that have reported that the use of acetaminophen in pregnancy is associated with an increased risk of childhood asthma.2, 3, 4, 5, 6, 7, 8 This association is present for persistent wheezing rather than transient infant wheezing, extends to asthma at the age of 7 years, and is observed with hospital admissions for asthma in childhood, suggesting an effect on both the occurrence and severity of asthma. The observation that the association between the frequent use of acetaminophen in pregnancy and wheeze in preschool children is restricted to nonasthmatic mothers6 indicates that this association cannot be due to mothers with asthma using acetaminophen in preference to aspirin or other nonsteroidal anti-inflammatory drugs. In 3 studies2, 7, 8 data suggest that the effects might depend on the timing of prenatal exposure to acetaminophen; however, there are also data to suggest that the risk of childhood asthma might be present with acetaminophen use at any time during pregnancy.4

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Acetaminophen use in infancy and childhood 

The main evidence for an association between the use of acetaminophen in infancy and the risk of childhood asthma comes from the International Study of Asthma and Allergies in Childhood, which included data from 72 centers in 31 countries worldwide.9 After adjustment for potential confounding variables, the administration of acetaminophen to infants was associated with a 46% increased risk of current asthma symptoms at the age of 6 to 7 years. Similar increased risks were observed with rhinoconjunctivitis and eczema, suggesting that the association extends to these related allergic conditions. It was notable that the association was present in countries throughout the world with different patterns of childhood febrile illnesses and differences in medical practice and over-the-counter medication use. There were a number of potential biases relevant to the interpretation of these findings, including but not limited to confounding by indication.16, 17, 18, 19 This can occur if paracetamol is given for lower respiratory tract infections, such as respiratory syncytial virus and rhinovirus, which are associated with an increased risk of asthma in later childhood.20, 21 It is evident that the extent to which confounding by indication might have contributed to the association between acetaminophen and asthma in the International Study of Asthma and Allergies in Childhood is uncertain and that the presence of confounding does not exclude the possibility of a coexisting causal relationship.19

The International Study of Asthma and Allergies in Childhood also reported an association between acetaminophen use in the 6- to 7-year-old children and current symptoms of asthma, rhinoconjunctivitis, and eczema.9 Importantly, in the 6- to 7-year-old-children there was a dose-dependent increased risk of current asthma symptoms, with a 1.6- and 3.2-fold increased risk for moderate and high versus no use, respectively. There was also a dose-dependent increased risk of severe asthma, suggesting that acetaminophen use might influence both the occurrence and severity of asthma. It was considered that reverse causation was unlikely to explain the findings because there was also an association between acetaminophen use and eczema independent of asthma, with the symptoms and complications of eczema not typically associated with acetaminophen use.

The only randomized controlled trial investigating the effect of acetaminophen use for fever and asthma outcomes was undertaken in asthmatic children who were not known to be sensitive to nonsteroidal anti-inflammatory drugs.22 Compared with asthmatic children who received acetaminophen treatment for a febrile illness in the community, those who received ibuprofen had a reduced risk of an outpatient visit for asthma. The increased risk with acetaminophen was dose dependent and related to respiratory febrile illnesses rather than other causes of fever. It was not possible to determine whether the effect was due to an increased risk with acetaminophen or a reduced risk with ibuprofen, for which evidence of a protective effect exists.23

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Acetaminophen use in adults 

The initial evidence of an association between acetaminophen use and asthma in adults came from a United Kingdom–based case-control study.10 This study reported both a dose-dependent association between acetaminophen use and asthma and a progressively greater risk in those with more severe disease, with an 8-fold risk in those with severe asthma, suggesting once again an effect on both the causation and severity of disease. The association was present in both users and nonusers of aspirin and could not be attributed to aspirin avoidance by patients with asthma. These findings have now been extended with the Global Allergy and Asthma European Network case-control study in 12 centers in Europe,11 in which weekly acetaminophen use was positively associated with asthma. Compared with less frequent use, there was a 2.9-fold increased risk, with no significant heterogeneity observed between the centers.

Complementing these studies are 2 population-based surveys from Ethiopia12 and the United States13 in which dose-dependent associations between acetaminophen use and asthma were observed. The Ethiopian study reported similar associations with rhinitis and eczema, whereas the United States–based study also reported positive associations with chronic obstructive pulmonary disease and an inverse correlation with lung function. In both studies there was no evidence to suggest that the association could be attributed to aspirin avoidance or reverse causation. There are also 2 cohort studies from the United States14 and Denmark15 in which frequent acetaminophen use was positively associated with newly diagnosed (adult-onset) asthma over a 7- and 8-year period, respectively. These studies provide evidence that exposure to acetaminophen might precede the development of asthma, as has been observed with intrauterine exposure and use in infancy.

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Ecologic associations 

At the population level, positive associations have also been reported between per capita consumption of acetaminophen and the prevalence of asthma in both children and adults.24 The key finding of this analysis was the very high per capita use of acetaminophen in English-speaking countries, which had among the highest prevalence rates of asthma worldwide. This provides a possible reason for the previously unexplained higher prevalence of asthma and related allergic disorders in many English-speaking countries. Completing this epidemiologic evidence is the observation that the prevalence of asthma has increased worldwide over the last 40 to 50 years,25 a trend that has occurred contemporaneously with the increasing use of acetaminophen, such that it is now probably the most commonly prescribed medicine in children.26

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Potential mechanisms 

There are a number of potential mechanisms whereby the frequent use of acetaminophen might increase the risk of asthma and related allergic disorders and their severity.27 First, acetaminophen might decrease the amount of reduced glutathione in the lung, thereby impairing respiratory antioxidant defenses.28, 29 Reactive oxygen species might contribute to epithelial damage and mucus secretion, cause smooth muscle contraction and increase bronchial responsiveness, and impair β-adrenergic function, all effects that could potentially contribute to the pathogenesis of asthma.30 Decreased glutathione levels might also cause a shift away from TH1 to TH2 cytokine production, thereby predisposing to atopic disorders, such as asthma.29, 31 Acetaminophen might also influence COX-2 activity and the production of prostaglandin E2.1 Another potential mechanism for which there is conflicting evidence32, 33 is that by suppressing fever, acetaminophen might reduce the predominant TH1 cytokine storm that occurs as part of the febrile response.

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Summary 

As summarized in Table I,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 19, 22, 25, 26, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39 there is evidence to suggest that acetaminophen use might be an important risk factor for the development of asthma and might have contributed to the increasing prevalence of asthma and allergic disorders over recent decades. Although further epidemiologic and laboratory-based studies will undoubtedly be informative, the priority is to undertake randomized controlled trials to explore the association of acetaminophen with both the development and maintenance of asthma. Indeed, it is a concern that no randomized controlled trials have been undertaken of the long-term use of acetaminophen and the development of asthma and its severity. We propose that there is a case to answer and that such randomized controlled trials should now be a high priority for the research community. Only then will it be possible to determine the role of acetaminophen in the pathogenesis of asthma and related disorders and for evidence-based guidelines for the recommended use of acetaminophen to be made.

Table I. Summary of the evidence linking paracetamol use and asthma based on Bradford Hill criteria of causation34
Strength of effectIncreased asthma risk of up to 2.1 (paracetamol exposure in utero),2, 3, 4, 5, 6, 7, 8 1.5 to 3.2 (paracetamol use in infancy or childhood),2, 9 and up to 2.9 (paracetamol use in adults)10, 11, 12, 13, 14, 15
Dose responsePresent for paracetamol exposure in utero,2, 3 in childhood,9 and in adults10, 12, 13, 14
Consistency/coherenceConsistency between different studies in different age groups in different populations worldwide2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 22
Exposure before responseObserved in studies of paracetamol exposure in the intrauterine environment,2, 3, 4, 5, 6, 7, 8 in infancy,9 and in adult life14, 15
Biologic plausibilityThrough increased oxidant-induced inflammation and potentially enhanced TH2 response27, 28, 29, 30, 31
Removal of exposure prevents diseaseNot yet examined
SpecificityNo increased risk of asthma associated with aspirin or other nonsteroidal anti-inflammatory drugs35, 36
Temporal associationInternational trends of increasing paracetamol use and increasing prevalence of asthma1, 25, 26
AnalogyOxidant-induced airway inflammation in asthma (eg, ozone)37; protective effects of antioxidant diet in asthma38, 39

Derived with modification from Beasley et al.19

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References 

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 Disclosure of potential conflict of interest: J. Crane has received research support from the Health Research Council of New Zealand, the National Institute of Environmental Health Sciences, Fonterra, and Rex Medical. E. A. Mitchell has received research support from the Health Research Council of New Zealand, the Child Health Research Foundation, the Auckland Medical Research Foundation, and Fonterra. S. Eyers has received research support from the Health Research Council of New Zealand and the Wellington Medical Research Foundation. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(09)01146-4

doi:10.1016/j.jaci.2009.07.037

The Journal of Allergy and Clinical Immunology
Volume 124, Issue 4 , Pages 649-651, October 2009

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