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(Chest. 2005;127:604-612.)
© 2005 American College of Chest Physicians

Acetaminophen and the Risk of Asthma*

The Epidemiologic and Pathophysiologic Evidence

Ihuoma Eneli, MD, MS; Katayoun Sadri, MD; Carlos Camargo, Jr, MD, DrPH, FCCP and R. Graham Barr, MD, DrPH

* From the Sparrow Hospital Pediatric Residency Program (Dr. Sadri) and Department of Pediatrics and Human Development (Dr. Eneli), Michigan State University, Lansing, MI; Department of Emergency Medicine (Dr. Camargo), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Department of Medicine (Dr. Barr), College of Physicians & Surgeons, Mailman School of Public Health, Columbia University, New York, NY.

Correspondence to: Ihuoma Eneli, MD, MS, Department of Pediatrics and Human Development, Michigan State University, B220 Clinical Center Bldg, East Lansing, MI 48824-1313; e-mail: Eneli{at}msu.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
 References
 
The prevalence of asthma has increased worldwide. The reasons for this rise remain unclear. Various studies have reported an association between acetaminophen, a widely used analgesic, and diagnosed asthma. In a prospective cohort study, the rate of newly diagnosed asthma was 63% higher among frequent acetaminophen users than nonusers in multivariate analyses. Studies of patients with asthma suggest that acetaminophen challenge can precipitate a decline in FEV1 > 15% among sensitive individuals. Plausible mechanisms to explain this association include depletion of pulmonary glutathione and oxidative stress. This article reviews the existing literature and evaluates the epidemiologic and pathophysiologic evidence underlying a possible link between acetaminophen and asthma.

Key Words: acetaminophen • asthma • bronchoconstriction


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
 References
 
The prevalence of asthma in the United States has risen by 75% in the last 3 decades, with a particularly marked increase in children < 5 years of age (160%).1 This rise transcends age, gender, ethnicity, and geographic location, but affects minority groups, the socioeconomically disadvantaged, and inner-city populations disproportionately. The reason for the surge in prevalence is unclear. A number of hypotheses have been proposed, including increased environmental exposures to "synthetic" materials and indoor allergens, decreased exposure to bacteria and childhood illnesses (the "hygiene" hypothesis), the increasing prevalence of obesity, changes in diet and antioxidant intake, increased exposure to cockroaches, changing meteorological patterns, and decreased use of aspirin.23456789 In addition, cytokine imbalance or dysregulation occurring as a result of environmental exposures during infancy and early childhood is hypothesized to induce lifelong T-helper type 2 (allergic) dominance over T-helper type 1 (nonallergic) responses. T-helper type 2 dominance increases the risk for atopic diseases, including asthma.4610 While most studies467 have focused on the effects of these factors after birth, some610 have suggested sensitization in utero.

A link between acetaminophen and bronchoconstriction was originally suggested in a case report of an aspirin-intolerant patient as early as 1967 by Chafee and Settipane.11 Recently, with the rise in asthma prevalence, there has been renewed interest in the role of acetaminophen. Acetaminophen, found frequently in combination with other drugs such as opiates and cold/cough formulations, is the most common form of analgesia used in the United States, particularly in children.12 Kogan et al12 estimated that approximately two thirds of analgesia used over a 30-day period by US preschool-aged children was acetaminophen. Concurrent with the use of acetaminophen, a large increase in asthma, particularly in the pediatric population, has been reported.1 This review will summarize and evaluate the epidemiologic and pathophysiologic evidence underlying the hypothesis that acetaminophen is a risk factor for asthma and may have contributed to the recent increase in asthma prevalence.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
 References
 
A computerized search of the English-language literature of PUBMED, the IOWA Databases, and the Cochrane Clinical Trial Database between 1966 and 2002 was conducted using the terms asthma, wheezing, cough, analgesia, acetaminophen, and paracetamol. Various combinations of the terms were used to maximize the results. Bibliographies of original research, commentaries, textbooks, and symposia were reviewed for additional relevant references. These publications were abstracted and compiled into tabular form under types of study design. An article was included if it fulfilled the following criteria: (1) clinical study design, (2) human subjects, (3) acetaminophen use, and (4) outcome involved respiratory symptoms (cough, dyspnea, wheezing, or lung function changes). Two of the authors (I.U.E., K.S.) reviewed each article independently. Twenty-two articles met the inclusion criteria and were selected for critical review. Disagreements regarding inclusion were resolved by consensus. Of the articles excluded, most were letters to the editors or case reports that described anaphylactic reactions such as angioedema and urticaria, but without respiratory symptoms.13141516171819202122232425262728


   Clinical Studies Examining the Relationship Between Acetaminophen and Asthma
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 Abstract
 Introduction
 Materials and Methods
 Clinical Studies Examining the...
Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
 References
 
Various epidemiologic and quasiexperimental stud-ies have suggested a link between both therapeutic and overdose ingestion of acetaminophen and bronchoconstriction in certain individuals. Table 1 lists these studies by research design.


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  		Table 1. Clinical and Epidemiologic Studies of Acetaminophen and Asthma

 
Across European countries, asthma rates have been ecologically associated with acetaminophen use.29 This study by Newson et al29 was the first large epidemiologic study to suggest a link between asthma and acetaminophen. Using data from the International Study of Asthma and Allergies in Childhood and the European Community Respiratory Health Survey (ECHRIS), the authors observed a positive correlation between acetaminophen sales and asthma symptoms, eczema, and allergic rhinoconjunctivitis at the country level. For each gram increase in per capita paracetamol sales in 1994/1995, the prevalence of wheeze increased by 0.52% among 13- to 14-year-old subjects in the International Study of Asthma and Allergies in Childhood study. Similarly, wheezing rose by 0.26% (p = 0.0005) per gram increase among young adults surveyed in ECHRIS. The results parallel comparative prevalence trends of asthma noted since acetaminophen became the primary over-the-counter analgesic. While ecologic findings such as these are helpful for the description of group-level (in this case, country-level) patterns of association, inferences about individuals (or patients) cannot be surmised.

The association between asthma and acetaminophen has also been seen at the individual level. In a large population-based, case-control study30 of young adults (n = 1,574), daily and weekly use of acetaminophen was strongly associated with asthma. Acetaminophen exposure was defined only by frequency of intake. There was a significant trend comparing acetaminophen users: never users, infrequent users (less than monthly), monthly users, weekly and daily users (p = 0.0002), and self-reported history of asthma. In a multivariate regression analysis controlling for sex, age, social class, type of accommodation, employment and parental status, other analgesic use, and smoking and passive smoke exposure, acetaminophen use was positively associated with asthma (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.21 to 2.65). The relationship was much stronger for severe asthma (OR, 8.2; 95% CI, 2.8 to 23). Aspirin avoidance did not appear to account for the positive results, as the association was found in those taking only acetaminophen as well as in those taking both analgesics. Limitations in the study included an overall response rate of 50%, with lower enrollment in younger persons, current smokers, and men, hence introducing selection bias, as acetaminophen use may differ among these groups. The study did not account for factors such as headaches and respiratory tract infections, which may lead to increased use of acetaminophen among asthmatic patients. Furthermore, given the cross-sectional design of the study, it is unclear if acetaminophen contributed to asthma or vice versa.

A recent report from the Nurses’ Health Study,31 a prospective cohort study of 121,700 women (age range, 30 to 55 years) in 1976, found that increased frequency of acetaminophen use in 1990 to 1992 was associated with a subsequent risk of physician diagnosis of new-onset asthma diagnosed between 1990 and 1996 (adjusted relative risk [RR], 1.63; 95% CI, 1.11 to 2.39; p = 0.006 for trend). The positive association remained unchanged whether the participants used or did not use aspirin. In multivariate analysis adjusting for a variety of potential confounders including body mass index, osteoarthritis, and frequency of physician visits, aspirin was inversely associated with newly diagnosed asthma (p = 0.03 for trend), but no association was seen with nonsteroidal antiinflammatory drugs (p = 0.12 for trend). The results, however, are difficult to generalize to other ethnic groups, ages, or gender as the study was carried out in an older, female, predominantly white population.

The only published study32 to examine acetaminophen use during pregnancy and the risk of wheezing in offspring was conducted in Great Britain. Analgesic intake (aspirin and acetaminophen) was ascertained using questionnaires at 18 to 20 weeks and 32 weeks of gestation among 9,400 women participating in the Avon Longitudinal Study of Parents and Children. The study population represented 64% of the original cohort. Following adjustment for potential confounders such as family history of atopy, family size, antibiotic use, daycare attendance, environmental tobacco exposure, and anthropometric measures, the risk of wheezing was increased twofold in 30-to 42-month-old children whose mothers frequently used acetaminophen prenatally during weeks 20 to 32 of gestation. This association was stronger if the child had wheezed before 6 months (OR, 2.34; 95% CI, 1.24 to 4.40). Excluding infants with a maternal history of asthma did not change the results. Mothers who used aspirin frequently (most days/daily) were also more likely to have infants who wheezed within the first 6 months of life (OR, 2.73; 95% CI, 1.57 to 4.76), suggesting either a nonspecific effect or that important confounders may not have been considered. Since the prevalence of acetaminophen use in this study was only approximately 1.5%, the population-attributable risk fraction for acetaminophen use during pregnancy and wheeze in the offspring is only 0.9%. The low population-attributable risk fraction negates any recommendations to change acetaminophen as the analgesia of choice during pregnancy.

Lesko and Mitchell33 conducted a double-blinded randomized clinical trial to determine the safety of ibuprofen in children. The trial compared ibuprofen with acetaminophen for treatment of pediatric febrile illness among 84,000 children, but did not have a placebo study arm. Among 1,879 children with a physician diagnosis of asthma who received daily asthma medication, the risk of having an outpatient visit for asthma was significantly lower in children assigned to the ibuprofen group compared with the acetaminophen group (RR, 0.56; 95% CI, 0.34 to 0.95).81 Children who received ibuprofen also had lower rates of hospitalization than those who received acetaminophen, although it was not statistically significant (RR, 0.63; 95% CI, 0.25 to 1.6). With the lack of a placebo group in this study, it is unclear whether ibuprofen reduced the risk of asthma, acetaminophen increased the risk, or a combination of both occurred. Although this study did not primarily seek to examine the association between asthma and acetaminophen, the size and rigor of the study design (randomized clinical trial) provides a measure of confidence for validity of the results.

Multiple case reports, case series, and oral challenge tests34353637383940414243444546474849 have described respiratory symptoms and acute declines in respiratory function indexes following ingestion of acetaminophen among both aspirin-sensitive and aspirin-tolerant patients. While studies summarized in Table 2 do not support the premise that increased acetaminophen use has led to the rise in asthma prevalence, they provide evidence of potentially deleterious effects of acetaminophen on respiratory function among selected individuals. Schwarz and Ham Pong37 reported a > 20% fall in FEV1 and FVC in a 13-year-old, aspirin-sensitive patient challenged with 325 mg of acetaminophen, while an Australian study43 reported bronchoconstriction and anaphylaxis in five aspirin-tolerant patients with doses ranging from 500 to 1,000 mg. In sequential challenge tests with 1,000 mg and 1500 mg of acetaminophen among 50 aspirin-sensitive patients, 34% of the patients had at least a 15% decline in FEV1 compared with none of the non–aspirin-sensitive control subjects (p = 0.0013).39 Cross-reactivity with acetaminophen is estimated in 20 to 30% of aspirin-sensitive asthmatics.40 The severity of asthma at the time of drug ingestion, rather than the dose ingested, appears to be a better indicator of likelihood of a reaction to acetaminophen.383940 Reports of respiratory reactions have also been found in reviews of drug registries.42 Of 68 adverse reaction reports that could be causally linked to acetaminophen in the Australian Drug registry,41 15 patients presented with bronchoconstriction. However, since registries rely on passive reporting mechanisms, these numbers may severely underestimate the incidence of adverse drug reactions.50 Furthermore, estimates may be particularly low for established, commonly used, or over-the-counter drugs.


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  		Table 2. Acetaminophen and Acute Respiratory Reactions

 
Although most published studies report a positive association between asthma and acetaminophen, the credibility of the relationship hinges on biological plausibility of the association. Recently, several hypotheses have been proposed to explain the association, some more advanced than others. Figure 1 summarizes these hypotheses.



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  		Figure 1. Proposed mechanisms for acetaminophen-induced lung injury. **Unlikely to explain the rise in asthma prevalence.

 

   Acetaminophen, Glutathione, and Lung Inflammation
TOP
 Abstract
 Introduction
 Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
Limitations of Available Studies
 Conclusions and Clinical...
 References
 
Glutathione (L-gamma-glutamyl-L-cysteinyl glycine) is found in respiratory tract lining fluid, of which > 95% is present in the reduced form as an antioxidant.51 Glutathione has been implicated in lung inflammation in a number of studies.535764 Compared with healthy children, glutathione has been detected at lower levels in the exhaled breath condensate of asthmatic children during exacerbations.52 Some studies report reduced glutathione peroxidase activity in platelets and whole blood in asthmatic and atopic patients, suggesting impairment of the glutathione redox system in handling reactive oxygen species; others have found no relationship.53545556 Genetic polymorphisms of glutathione-S-transferase enzyme systems, which counteract products of oxidant stress, have also been detected in asthmatic patients.5758 Asthmatic children who are homozygous for specific allele variants have significantly lower values for FVC, FEV1, and maximal mid-expiratory flow than children without asthma.58

Acetaminophen decreases glutathione levels, principally in the liver and kidneys, but also in the lungs.5960 These decreases are dose dependent: overdose levels of acetaminophen are cytotoxic to pneumocytes and cause acute lung injury,61 whereas nontoxic, therapeutic doses produce smaller, but significant reductions in glutathione levels in type II pneumocytes and alveolar macrophages.62 Among healthy young volunteers, significantly lower serum antioxidant capacity has been seen within 2 weeks of ingestion of 1 gm of acetaminophen.63 By depleting glutathione levels, acetaminophen weakens the ability of the host to mitigate oxidative stress produced by reactive oxygen species (ROS) such as superoxide anions (O2-), hydroxyl (•OH), and peroxyl (ROO–) radicals.515364 ROS are formed either by loss or gain of a single electron from a nonradical produced by inflammatory cells. They then trigger a cascade of epithelial desquamation, edema, release of leukotrienes, bronchoconstriction, and stimulation of additional inflammatory cells.

ROS and their metabolites oxidize phospholipids within the cell membrane through a sequence of initiation, propagation, and termination, a process termed lipid peroxidation. Arachidonic acid, a major building block for prostaglandins and leukotrienes, two key inflammatory mediators in asthma, is released from membrane phospholipids through lipid peroxidation. This process damages the integrity of the cell membrane or the nucleus, ultimately resulting in cell death. Generation of ROS products have been correlated with airway inflammation and nocturnal asthma,6566 and oxygen radicals have also been implicated in bronchial smooth-muscle contraction in dogs, cows, and guinea pigs.6768

Eosinophils, also inflammatory mediators in asthma, not only generate oxygen radicals but release an enzyme, eosinophil peroxidase, which potentiates cytotoxic effects on type II pneumocytes.69 Wu et al70 identified a new oxidant-mediated pathway for lung injury through bromination of tyrosine residues by the eosinophil peroxidase-H2O2 system in the presence of plasma levels of halides.

An unlikely mechanism in the glutathione depletion theory is through the hepatic P450 cytochrome pathway, a system that metabolizes acetaminophen. The end product of this metabolic pathway, N-acetyl-p-benzoquinonemine, is conjugated by glutathione into a harmless substance. When glutathione is depleted, N-acetyl-p-benzoquinonemine accumulates and arylates cellular macromolecules, resulting in cell death. The ability of the liver to remove these toxic intermediates is exceeded when an overdose occurs; however, occasional toxicity has been reported with therapeutic doses in certain circumstances, eg, alcoholics.7172 The critical period of injury occurs during the glutathione resynthesis process when levels remain low.51 Dimova et al62 demonstrated damage to rodent type II pneumocytes and alveolar macrophages following exposure to doses comparable to human therapeutic levels of acetaminophen. These effects were more pronounced in type II pneumocytes, which are particularly vulnerable because of their P450 cytochrome and prostaglandin synthase systems, which are involved in the metabolism of acetaminophen.

Finally, when glutathione levels are low, defective processing of disulfide bonds that are key in antigen presentation has been hypothesized.7374 It is conceivable that decreased levels of glutathione guide the expression of T-helper cell pathways by altering antigen presentation and recognition, thereby favoring the T2 allergic dominant pathway. Clearly, glutathione is a versatile molecule, assuming different roles in multiple metabolic pathways; however, this characteristic highlights gaps in our understanding of the glutathione depletion hypothesis and the lack of a single mechanism of action.

Contradictory results from studies using nebulized glutathione (granted there are only two studies) illustrate the difficulty with this hypothesis. A double-blind, cross-over study of eight patients with mild asthma receiving nebulized glutathione and saline solution as a placebo, found glutathione induced a decline of 19% in FEV1 and increased total pulmonary resistance by 61%. Bagnato et al75 found the contrary, reporting a protective effect of glutathione on FEV1 following a "fog" challenge using nebulized distilled water in 12 patients with mild-to-moderate asthma. Glutathione is not only a scavenger for ROS, but has also been implicated in the formation of leukotriene C4 and D4, both potent bronchoconstrictors. Furthermore, the period of glutathione resynthesis in the lungs is very short, making it unlikely that significant oxidative stress likely to cause asthma can occur within such a short window of time. The role of ROS in lung injury, counteracting systems, particularly glutathione, has generated significant interest and may present a plausible mechanism. However, ROS have been implicated in a wide range of disorders, thereby weakening the specificity of this mechanism for true causality.

Cyclooxygenase Pathway
Another hypothesized mechanism unrelated to glutathione involves the cyclooxygenase-2 receptors and other yet-to-be defined cyclooxygenase receptors. Acetaminophen may well exert an effect on the lungs mediated by the lack of suppression of cyclooxygenase, an inflammatory pathway. Cyclooxygenase-2 promotes the production of prostaglandin E2. Prostaglandin E2 tilts the immunologic process in favor of a T-helper type 2 response, while inhibiting T-helper type 1 lymphocytes, thus establishing an allergic tendency in the immune response to various antigenic stimuli.976

IgE-Mediated Pathway
The least developed of the hypotheses involves an IgE-mediated mechanism with acetaminophen as the antigenic agent.1548 Using four aspirin and nonsteroidal antiinflammatory drug-tolerant patients and 30 matched control subjects, de Paramo et al15 conducted skin-prick tests and measured acetaminophen-specific serum IgE levels following an oral challenge of 250 mg and 500 mg of acetaminophen. Both the control subjects and patients tolerated oral challenges with 250 and 500 mg aspirin. Following ingestion of acetaminophen, elevated IgE levels and positive skin-prick test findings were noted in two of the four patients, but not in the control subjects. Only one patient had both high IgE levels and positive skin-prick test results. In addition, two studies1649 have shown elevated levels of histamine, a key chemical mediator in the IgE-triggered cascade of inflammation seen in asthma. While this may be an intuitively appealing hypothesis, our understanding of the pathogenesis of other analgesia-induced asthma does not lend credence to this mechanism. For example, the ASA triad (aspirin sensitivity, asthma, and nasal polyps) is thought to arise not from an IgE-mediated pathway, but rather hypersensitivity to inhibition of the cyclooxygenase pathway.76 Finally, it is possible, but unlikely, that an excipient in the acetaminophen formulations is responsible for these reactions.


   Limitations of Available Studies
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 Abstract
 Introduction
 Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
Conclusions and Clinical...
 References
 
A majority of epidemiologic studies examining the acetaminophen/asthma link have found a positive association. Lack of a rigorous case definition for asthma, cross-sectional nature of the study design, and inability to control for confounders limit the interpretation of the results.172477 Most of the studies address the relationship between acetaminophen, lung function, and asthma exacerbations. While this is an important research question with significant clinical and public health implications, it does not provide evidence of causation. A history of asthma or wheezing, which these studies ascertained, measures asthma prevalence and not incidence, thus muddling issues of temporality. Of the studies reviewed, only the Nurses Health Study31 and the Avon studies32 used an inception cohort (ie, population with no known history of asthma or wheezing).

The use of acetaminophen among patients with an asthma diagnosis may be explained by a general increase in medicalization or may represent physician analgesic preference for acetaminophen, rather than indicating a causal association. Confounding factors such as headaches and viral respiratory tract illnesses in asthmatic patients can also lead to an increase in acetaminophen use. In a large case-control study (64,678 matched pairs), Davey et al78 found modestly increased RR of 1.59 (95% CI, 1.54 to 1.65) for asthma in patients with migraines, while Chen and Leviton79 reported an increased risk for asthma in the first 7 years of life among offspring of mothers with migraines. However, the association cannot entirely be explained by confounding. Some of the associations for asthma have been larger than those reported for potential confounders.293031 The randomized clinical trial by Lesko et al,81 which, by study design, minimizes the potential for confounding, also found a significant association between increased outpatient visits for asthma and acetaminophen use.


   Conclusions and Clinical Implications
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 Abstract
 Introduction
 Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
References
 
Acetaminophen is one of the most widely used analgesic and antipyretic medications for patients of all ages. However, it is not entirely without adverse effects. Recently, the US Food and Drug Administration issued an advisory suggesting limiting its use, particularly in patients with liver diseases.80 A growing body of multidisciplinary evidence backed by biochemical explanations suggests that frequent acetaminophen use may also have a negative impact on lung function. The plausibility of each pathophysiologic mechanism is still questionable, as much of the supporting evidence for causality is preliminary or indirect. The heterogenous nature of asthma and its multiple etiologic factors, as well as individual variation in glutathione stores or drug metabolism, further complicates our understanding of this relationship. Furthermore, the role of ROS and asthma, a basic building block for the glutathione theory itself, is still evolving and needs to be better understood. In future epidemiologic studies addressing the acetaminophen-asthma link, case ascertainment needs to be more rigorous.

In summary, physicians need to be cognizant of analgesia intolerance in some asthmatic patients. However, it will be premature to recommend any change in current analgesic-prescribing patterns for adults and children with asthma. Further epidemiologic and biological research is warranted. The result of these studies will be of interest: either the association will be found to be spurious, or the studies will shed new light on potential acetaminophen toxicity on lung tissue and the rise in asthma prevalence and severity.


   Footnotes
 
Abbreviations: CI = confidence interval; ECHRIS = European Community Respiratory Health Survey; OR = odds ratio; ROS = reactive oxygen species; RR = relative risk

Received for publication November 17, 2003. Accepted for publication August 4, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Clinical Studies Examining the...
 Acetaminophen, Glutathione, and...
 Limitations of Available Studies
 Conclusions and Clinical...
 References
 

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