American Journal of Respiratory and Critical Care Medicine

Am. J. Respir. Crit. Care Med., Volume 169, Number 7, April 2004, 836-841
A more recent version of this article appeared on April 1, 2004

Prospective Study of Acetaminophen Use and Newly Diagnosed Asthma among Women

R. Graham Barr^1*, Catherine C Wentowski², Gary C Curhan³, Samuel C Somers², Meir J Stampfer³, Joel Schwartz⁴, Frank E Speizer⁴, and Carlos A Camargo⁵

Acetaminophen decreases glutathione levels in the lung, which may predispose to oxidative injury and bronchospasm. Acetaminophen use has been associated with asthma in cross-sectional and birth-cohort studies. We hypothesized that acetaminophen use would be associated with newly diagnosed adult-onset asthma in the Nurses Health Study, a prospective cohort study of 121,700 women. Participants were first asked about frequency of acetaminophen use in 1990.Asthma cases were defined as new physician diagnosis of asthma between 1990 and 1996, plus reiteration of the diagnosis and controller medication use. Proportional hazard models included age, race, socioeconomic status, body mass index, smoking, other analgesic use and postmenopausal hormone use. During 352,719 person-years of follow-up, 346 participants reported a new physician diagnosis of asthma meeting diagnostic criteria. Increasing frequency of acetaminophen use was positively associated with newly diagnosed asthma (P-trend = 0.006). The multivariate rate ratio for asthma for participants who took acetaminophen for more than 14 days per month was 1.63 (95% CI 1.11-2.39)compared to non-users. It would be premature to recommend acetaminophen avoidance for patients with asthma, but further research on pulmonary responses to acetaminophen is necessary to confirm or refute these findings and to identify subgroups whose asthma may be modified by acetaminophen.

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Meta study, pooled risk increase 63%, children 60%.   Plausible mechanisms to explain this association include depletion of pulmonary glutathione and oxidative stress.

http://chestjournal.chestpubs.org/content/136/5/1316.short

Acetaminophen Use and the Risk of Asthma in Children and Adults

A Systematic Review and Metaanalysis

1.       Mahyar Etminan, PharmD, MSc, Mohsen Sadatsafavi, MD, MHSc, Siavash Jafari, MD, MHSc,  Mimi Doyle-Waters,  MSc, Kevin Aminzadeh, DDS and  J. Mark FitzGerald, MD, FCCP

Background: Epidemiologic studies have identified an increased risk of asthma with acetaminophen use, but the results have been conflicting. We sought to quantify the association between acetaminophen use and the risk of asthma in children and adults.

Methods: We searched all the major medical databases, including MEDLINE (from 1966 to 2008) and EMBASE (from 1980 to 2008) to identify pertinent articles. All clinical trials and observational studies were considered. For observational studies, we selected those that clearly defined acetaminophen use and asthma diagnosis. Study quality was assessed by two reviewers, and data were extracted into a spreadsheet. A random-effects model was used to combine studies with asthma and wheezing among both children and adults.

Results: Thirteen cross-sectional studies, four cohort studies, and two case-control studies comprising 425,140 subjects were included in the review. The pooled odds ratio (OR) for asthma among subjects using acetaminophen was 1.63 (95% CI, 1.46 to 1.77). The risk of asthma in children among users of acetaminophen in the year prior to asthma diagnosis and within the first year of life was elevated (OR: 1.60 [95% CI, 1.48 to 1.74] and 1.47 [95% CI, 1.36 to 1.56], respectively). Only one study reported the association between high acetaminophen dose and asthma in children (OR, 3.23; 95% CI, 2.9 to 3.6). There was an increase in the risk of asthma and wheezing with prenatal use of acetaminophen (OR: 1.28 [95% CI, 1.16 to 41] and 1.50 [95% CI, 1.10 to 2.05], respectively).

Conclusions: The results of our review are consistent with an increase in the risk of asthma and wheezing in both children and adults exposed to acetaminophen. Future studies are needed to confirm these results.

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Chest:  10.1378/chest.127.2.604CHEST February 2005 vol. 127 no. 2 604-612 http://chestjournal.chestpubs.org/content/127/2/604.full

Acetaminophen and the Risk of Asthma^*

The Epidemiologic and Pathophysiologic Evidence

1.       Ihuoma Eneli, MD, MS, 

2.       Katayoun Sadri, MD, 

3.       Carlos Camargo Jr, MD, DrPH, FCCP and 

4.       R. Graham Barr, MD, DrPH

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%).¹This 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.

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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 tests^{34353637383940414243444546474849} 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.

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.⁵¹Glutathione 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,⁶¹whereas 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 termedlipid 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 al⁷⁵found 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 E₂tilts 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.

1.       ↵ 

Mannino, DM, Homa, DM, Pertowski, CA, et al (1998) Surveillance for asthma: United States, 1960–1995. MMWR CDC Surveill Summ 47,1-27

Medline

2.       ↵ 

Camargo, CA, Jr, Weiss, JT, Zhang, S, et al Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159,2582-2588

Abstract/FREE Full Text

3.       ↵ 

Platts-Mills, TA The role of allergens in the induction of asthma. Curr Allergy Asthma Rep 2002;2,175-180

Medline

4.       ↵ 

Platts-Mills, T, Vaughan, J, Squillace, S, et al Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357,752-756

CrossRefMedlineWeb of Science

5.       ↵ 

Soutar, A, Seaton, A, Brown, K Bronchial reactivity and dietary antioxidants. Thorax 1997;52,166-170

Abstract

6.       ↵ 

Sporik, R, Platts-Mills, TA Allergen exposure and the development of asthma. Thorax 2001;56(suppl),ii58-ii63

7.       ↵ 

Sporik, R, Squillace, SP, Ingram, JM, et al Mite, cat, and cockroach exposure, allergen sensitization, and asthma in children: a case-control study of three schools. Thorax 1999;54,675-680

Abstract/FREE Full Text

8.       ↵ 

Goldsmith, JR, Friger, MD, Abramson, M Associations between health and air pollution in time-series analyses. Arch Environ Health 1996;51,359-367

MedlineWeb of Science

9.       ↵ 

Varner, AE, Busse, WW, Lemanske, RF, Jr Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol 1998;81,347-351

MedlineWeb of Science

10.    ↵ 

Devereux, G, Barker, RN, Seaton, A Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002;32,43-50

CrossRefMedlineWeb of Science

11.    ↵ 

Chafee, FH, Settipane, GA Asthma caused by FD&C approved dyes. J Allergy 1967;40,65-72

CrossRefMedlineWeb of Science

12.    ↵ 

Kogan, MD, Pappas, G, Yu, SM, et al Over-the-counter medication use among US preschool-age children. JAMA 1994;272,1025-1030

Abstract/FREE Full Text

13.    ↵ 

Karakaya, G, Kalyoncu, AF Paracetamol and asthma. Expert Opin Pharmacother 2003;4,13-21

CrossRefMedlineWeb of Science

14.    ↵ 

Bachmeyer, C, Vermeulen, C, Habki, R, et al Acetaminophen (paracetamol)-induced anaphylactic shock. South Med J 2002;95,759-760

MedlineWeb of Science

15.    ↵ 

de Paramo, BJ, Gancedo, SQ, Cuevas, M, et al Paracetamol (acetaminophen) hypersensitivity. Ann Allergy Asthma Immunol 2000;85,508-511

MedlineWeb of Science

16.    ↵ 

Doan, T, Greenberger, PA Nearly fatal episodes of hypotension, flushing, and dyspnea in a 47-year-old woman. Ann Allergy 1993;70,439-444

MedlineWeb of Science

17.    ↵ 

Furness, J, Macdonald, F Paracetamol and asthma [letter]. Thorax2000;55,882

CrossRefMedlineWeb of Science

18.    ↵ 

Ho, SW, Beilin, LJ Asthma associated with N-acetylcysteine infusion and paracetamol poisoning: report of two cases. BMJ (Clin Res Ed)1983;287,876-877

FREE Full Text

19.    ↵ 

Kalyoncu, AF, Kisacik, G, Sahin, AA, et al Prevalence of cross-sensitivity with acetaminophen and other nonsteroidal antiinflammatory drugs in asthmatic patients. J Allergy Clin Immunol 1996;98,713-714

MedlineWeb of Science

20.    ↵ 

Karakaya, G, Demir, AU, Kalyoncu, AF Paracetamol and asthma [letter].Thorax 2001;56,586

CrossRefMedlineWeb of Science

21.    ↵ 

Kumar, RK, Byard, I Paracetamol as a cause of anaphylaxis. Hosp Med1999;60,66-67

MedlineWeb of Science

22.    ↵ 

Martin, JA, Lazaro, M, Cuevas, M, et al Paracetamol anaphylaxis [letter].Clin Exp Allergy 1993;23,534

CrossRefMedlineWeb of Science

23.    ↵ 

Mendizabal, SL, Diez Gomez, ML Paracetamol sensitivity without aspirin intolerance. Allergy 1998;53,457-458

MedlineWeb of Science

24.    ↵ 

Shin, GY, Dargan, P, Jones, AL Paracetamol and asthma [letter]. Thorax2000;55,882

CrossRefMedlineWeb of Science

25.    ↵ 

Vidal, C, Perez-Carral, C, Gonzalez-Quintela, A Paracetamol (acetaminophen) hypersensitivity. Ann Allergy Asthma Immunol1997;79,320-321

MedlineWeb of Science

26.    ↵ 

Vale, JA, Buckley, BM Asthma associated with N-acetylcysteine infusion and paracetamol poisoning [letter]. BMJ (Clin Res Ed) 1983;287,1223

FREE Full Text

27.    ↵ 

Ownby, DR Acetaminophen-induced urticaria and tolerance of ibuprofen in an eight-year-old child. J Allergy Clin Immunol 1997;99,151-152

CrossRefMedlineWeb of Science

28.    ↵ 

Ibanez, MD, Alonso, E, Munoz, MC, et al Delayed hypersensitivity reaction to paracetamol (acetaminophen). Allergy 1996;51,121-123

MedlineWeb of Science

29.    ↵ 

Newson, RB, Shaheen, SO, Chinn, S, et al Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J2000;16,817-823

Abstract/FREE Full Text

30.    ↵ 

Shaheen, SO, Sterne, JA, Songhurst, CE, et al Frequent paracetamol use and asthma in adults. Thorax 2000;55,266-270

Abstract/FREE Full Text

31.    ↵ 

Barr, RG, Wentowski, CC, Curhan, GC, et al Prospective study of acetaminophen use and newly diagnosed asthma among women. Am J Respir Crit Care Med 2004;169,836-841

Abstract/FREE Full Text

32.    ↵ 

Shaheen, SO, Newson, RB, Sherriff, A, et al Paracetamol use in pregnancy and wheezing in early childhood. Thorax 2002;57,958-963

Abstract/FREE Full Text

33.    ↵ 

Lesko, SM, Mitchell, AA The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 1999;104,e39

Abstract/FREE Full Text

34.    ↵ 

Kivity, S, Pawlik, I, Katz, Y Acetaminophen hypersensitivity. Allergy1999;54,187-188

CrossRefMedlineWeb of Science

35.    ↵ 

Szczeklik, A, Gryglewski, RJ, Czerniawska-Mysik, G Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. BMJ 1975;1,67-69

Abstract/FREE Full Text

36.    ↵ 

Szczeklik, A, Gryglewski, RJ, Czerniawska-Mysik, G Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis. J Allergy Clin Immunol 1977;60,276-284

CrossRefMedlineWeb of Science

37.    ↵ 

Schwarz, N, Ham Pong, A Acetaminophen anaphylaxis with aspirin and sodium salicylate sensitivity: a case report. Ann Allergy Asthma Immunol1996;77,473-474

MedlineWeb of Science

38.    ↵ 

Falliers, CJ Acetaminophen and aspirin challenges in subgroups of asthmatics. J Asthma 1983;20(Suppl 1),39-49

Medline

39.    ↵ 

Settipane, RA, Schrank, PJ, Simon, RA, et al Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995;96,480-485

CrossRefMedlineWeb of Science

40.    ↵ 

Settipane, RA, Stevenson, DD Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. J Allergy Clin Immunol 1989;84,26-33

CrossRefMedlineWeb of Science

41.    ↵ 

Ayonrinde, OT, Saker, BM Anaphylactoid reactions to paracetamol.Postgrad Med J 2000;76,501-502

Abstract/FREE Full Text

42.    ↵ 

Stricker, BH, Meyboom, RH, Lindquist, M Acute hypersensitivity reactions to paracetamol. BMJ (Clin Res Ed) 1985;291,938-939

FREE Full Text

43.    ↵ 

Leung, R, Plomley, R, Czarny, D Paracetamol anaphylaxis. Clin Exp Allergy1992;22,831-833

CrossRefMedlineWeb of Science

44.    ↵ 

Grant, JA, Weiler, JM A report of a rare immediate reaction after ingestion of acetaminophen. Ann Allergy Asthma Immunol 2001;87,227-229

MedlineWeb of Science

45.    ↵ 

Spector, SL, Wangaard, CH, Farr, RS Aspirin and concomitant idiosyncrasies in adult asthmatic patients. J Allergy Clin Immunol1979;64,500-506

CrossRefMedlineWeb of Science

46.    ↵ 

Ellis, M, Haydik, I, Gillman, S, et al Immediate adverse reactions to acetaminophen in children: evaluation of histamine release and spirometry. J Pediatr 1989;114,654-656

CrossRefMedlineWeb of Science

47.    ↵ 

Fischer, TJ, Guilfoile, TD, Kesarwala, HH, et al Adverse pulmonary responses to aspirin and acetaminophen in chronic childhood asthma.Pediatrics 1983;71,313-318

Abstract/FREE Full Text

48.    ↵ 

Galindo, PA, Borja, J, Mur, P, et al Anaphylaxis to paracetamol. Allergol Immunopathol (Madr) 1998;26,199-200

Medline

49.    ↵ 

Van Diem, L, Grilliat, JP Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol 1990;38,389-390

CrossRefMedlineWeb of Science

50.    ↵ 

Talbot, JC, Nilsson, BS Pharmacovigilance in the pharmaceutical industry.Br J Clin Pharmacol 1998;45,427-431

CrossRefMedlineWeb of Science

51.    ↵ 

Kelly, FJ Glutathione: in defense of the lung. Food Chem Toxicol1999;37,963-966

CrossRefMedlineWeb of Science

52.    ↵ 

Corradi, M, Folesani, G, Andreoli, R, et al Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation. Am J Respir Crit Care Med 2003;167,395-399

Abstract/FREE Full Text

53.    ↵ 

Rahman, I, MacNee, W Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16,534-554

Abstract/FREE Full Text

54.    ↵ 

Powell, CV, Nash, AA, Powers, HJ, et al Antioxidant status in asthma.Pediatr Pulmonol 1994;18,34-38

MedlineWeb of Science

55.    ↵ 

Plaza, V, Prat, J, Rosello, J, et al In vitro release of arachidonic acid metabolites, glutathione peroxidase, and oxygen-free radicals from platelets of asthmatic patients with and without aspirin intolerance. Thorax1995;50,490-496

Abstract/FREE Full Text

56.    ↵ 

Misso, NL, Powers, KA, Gillon, RL, et al Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients. Clin Exp Allergy 1996;26,838-847

CrossRefMedlineWeb of Science

57.    ↵ 

Fryer, AA, Bianco, A, Hepple, M, et al Polymorphism at the glutathione S-transferase GSTP1 locus: a new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med 2000;161,1437-1442

Abstract/FREE Full Text

58.    ↵ 

Gilliland, FD, Gauderman, WJ, Vora, H, et al Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth. Am J Respir Crit Care Med 2002;166,710-716

Abstract/FREE Full Text

59.    ↵ 

Chen, TS, Richie, JP, Jr, Lang, CA Life span profiles of glutathione and acetaminophen detoxification. Drug Metab Dispos 1990;18,882-887

Abstract

60.    ↵ 

Micheli, L, Cerretani, D, Fiaschi, AI, et al Effect of acetaminophen on glutathione levels in rat testis and lung. Environ Health Perspect1994;102(Suppl 9),63-64

Medline

61.    ↵ 

Baudouin, SV, Howdle, P, O’Grady, JG, et al Acute lung injury in fulminant hepatic failure following paracetamol poisoning. Thorax 1995;50,399-402

Abstract/FREE Full Text

62.    ↵ 

Dimova, S, Hoet, PH, Nemery, B Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro. Biochem Pharmacol 2000;59,1467-1475

CrossRefMedlineWeb of Science

63.    ↵ 

Nuttall, SL, Khan, JN, Thorpe, GH, et al The impact of therapeutic doses of paracetamol on serum total antioxidant capacity. J Clin Pharm Ther2003;28,289-294

CrossRefMedlineWeb of Science

64.    ↵ 

Smith, LJ, Anderson, J, Shamsuddin, M, et al Effect of fasting on hyperoxic lung injury in mice: the role of glutathione. Am Rev Respir Dis1990;141,141-149

MedlineWeb of Science

65.    ↵ 

Jarjour, NN, Calhoun, WJ Enhanced production of oxygen radicals in asthma. J Lab Clin Med 1994;123,131-136

MedlineWeb of Science

66.    ↵ 

Dohlman, AW, Black, HR, Royall, JA Expired breath hydrogen peroxide is a marker of acute airway inflammation in pediatric patients with asthma. Am Rev Respir Dis 1993;148,955-960

MedlineWeb of Science

67.    ↵ 

Stewart, RM, Weir, EK, Montgomery, MR, et al Hydrogen peroxide contracts airway smooth muscle: a possible endogenous mechanism. Respir Physiol1981;45,333-342

CrossRefMedlineWeb of Science

68.    ↵ 

Nishida, Y, Suzuki, S, Miyamoto, T Biphasic contraction of isolated guinea pig tracheal chains by superoxide radical. Inflammation 1985;9,333-337

CrossRefMedlineWeb of Science

69.    ↵ 

Barnes, PJ Reactive oxygen species and airway inflammation. Free Radic Biol Med 1990;9,235-243

CrossRefMedlineWeb of Science

70.    ↵ 

Wu, W, Samoszuk, MK, Comhair, SA, et al Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest2000;105,1455-1463

MedlineWeb of Science

71.    ↵ 

Day, RO, Graham, GG, Whelton, A The position of paracetamol in the world of analgesics. Am J Ther 2000;7,51-54

Medline

72.    ↵ 

Zimmerman, HJ, Maddrey, WC Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22,767-773

CrossRefMedlineWeb of Science

73.    ↵ 

Peterson, JD, Herzenberg, LA, Vasquez, K, et al Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci U S A 1998;95,3071-3076

Abstract/FREE Full Text

74.    ↵ 

Droge, W, Breitkreutz, R Glutathione and immune function. Proc Nutr Soc2000;59,595-600

MedlineWeb of Science

75.    ↵ 

Bagnato, GF, Gulli, S, De Pasquale, R, et al Effect of inhaled glutathione on airway response to “Fog” challenge in asthmatic patients. Respiration1999;66,518-521

CrossRefMedlineWeb of Science

76.    ↵ 

Varner, A Paracetamol and asthma [letter]. Thorax 2000;55,882-883

CrossRefMedlineWeb of Science

77.    ↵ 

Probst, L, Stoney, P, Jeney, E, et al Nasal polyps, bronchial asthma and aspirin sensitivity. J Otolaryngol 1992;21,60-65

MedlineWeb of Science

78.    ↵ 

Mudge, D Paracetamol and asthma. Thorax 2000;55,883-884

MedlineWeb of Science

79.    ↵ 

Davey, G, Sedgwick, P, Maier, W, et al Association between migraine and asthma: matched case-control study. Br J Gen Pract 2002;52,723-727

MedlineWeb of Science

80.    ↵ 

Chen, TC, Leviton, A Asthma and eczema in children born to women with migraine. Arch Neurol 1990;47,1227-1230

Abstract/FREE Full Text

81.    ↵ 

USDA Food and Drug Administration. Use caution with pain relievers, January-February 2003. Available at: http://www.fda.gov/fdac/features/2003/103_pain.html. Accessed January 20, 2005

82.    Lesko, SM, Louik, C, Vezina, RM, et al Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics 2002;109,E20

CrossRefMedline