Acetaminophen increase ASTHMA risk 63%

ASPIRIN prevents MI, Cancer, and Alzheimer's disease
Celebrex and COX-2 inhibitors--American Heart Association Warnings
American Heart Association warns NSAIDs cause MI
COX-2 Inhibitors, their deadly mechanism
AHA on COX inhibitors
NSAIDs & Myocardial Infraction Risk--only ASPIRIN is safe
How VIOXX kills--jk
COX-2 INHIBITORS not as good as Ibuprofen
Continued Risk after taking VIOXX
HYDROCODONE--Opiates work for pain management
Acetaminophen, causes asthma, liver failure, & male infertility,
Acetaminophen causes male infertility
Liver failure Acetaminophen
Acetaminophen leading drug cause of liver damage
Acetaminophen increase ASTHMA risk 63%
Asthma risk and acetaminophen
Warfarin Number 1 Causes of Hospital Emergencies--WP

ACETAMINOPHEN INCREASE ASTHMA RISK 60% IN CHILDREN--also increase risk for adults 74% (this is a robust finding)  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%).  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.  some610 have suggested sensitization in utero.

Article found at http://www.rxlist.com/script/main/art.asp?articlekey=107369

Nov. 5, 2009 -- The popular pain and fever reliever acetaminophen may be linked with an increased risk of asthma in children and adults, according to a new research review of previously published studies by Canadian researchers.

But the manufacturer of Tylenol® -- the brand-name version of acetaminophen -- says the painkiller has a well-established safety record.

Researchers pooled the results of 19 clinical studies, with a total of more than 425,000 participants, to see if the association between the pain reliever use and asthma (and wheezing in children) held up. It did.

What triggered the review? "Concern over the risk of acetaminophen and asthma highlighted by the 2008 ISAAC study, published in The Lancet," says the review's lead author Mahyar Etminan, PharmD, a scientist at the Vancouver Coastal Health Research Institute in British Columbia and an assistant professor of medicine at the University of British Columbia.

In the ISAAC (International Study of Asthma and Allergies in Childhood) study, researchers looked at more than 205,000 children, ages 6 to 7, in 31 countries and found that acetaminophen use for fever in the first year of life was linked to increased risk of asthma symptoms in children 6 to 7 years old. Current use of acetaminophen was also linked to increased risk of asthma symptoms.

Other studies, Etminan says, have produced conflicting results, so the Canadian team conducted the review.  {This has to be bull-shit by an industry representative, for the percentage increase is far too great for there to be fundamentally conflicting results.  Conflicting results probably mean other studies find a different percentage of increase--jk.}

Sales of acetaminophen products in the U.S. are about $1 billion annually, the researchers estimate.

Calculating Asthma Risk

Etminan's team searched the medical literature to find high-quality published studies, trying to quantify the risk of asthma and wheezing among acetaminophen users, as well as the effect of prenatal exposure to the medicine.

After eliminating studies that weren't scientifically sound enough, the researchers focused on 19 studies. Overall, they found that acetaminophen users were 63% more likely to have asthma than nonusers. Other findings:

  • The risk of asthma in children given acetaminophen in the year before their asthma diagnosis was increased by 60%.
  • The risk of asthma in children who used acetaminophen in the first year of life was 47% higher than in those who didn't use it.
  • The risk of asthma in adults who used acetaminophen was 74% higher than in those who did not.
  • Prenatal use of acetaminophen boosted the risk of wheezing by 50% and the risk of asthma by 28% in children.

The researchers concede that children with severe asthma may be more likely to get acetaminophen for viral or other infections that may actually be due to asthma or may precede an asthma diagnosis.

The finding of acetaminophen use and asthma is an association, they say, but not necessarily a cause and effect.

The researchers say other mechanisms may explain the link. Acetaminophen, they say, may boost an enzyme involved in the anti-inflammatory response in asthma.

There are other possible mechanisms. ''There isn't enough evidence to favor one over the other," Etminan says. He says more studies are needed to fully understand the association.

Drugmaker's Perspective

In a prepared statement, McNeil Consumer Healthcare, which makes Tylenol®, says:

TYLENOL® (acetaminophen) has over 50 years of clinical history to support its safety and efficacy and, when used as labeled, TYLENOL® has a superior safety profile compared with many other over-the-counter (OTC) pain relievers. The well-documented safety profile for acetaminophen makes it the preferred pain reliever for asthma sufferers."  {This more bull shit, for acetaminophen is the leading cause of drug induced liver failure, and is why some medications with it have been pulled in other countries such as Britain--jk.}

The statement continues: "There are no prospective, randomized controlled studies that show a causal link between acetaminophen and asthma. The systematic review and meta-analysis published in Chest does not establish a definitive casual relationship between the therapeutic use of acetaminophen and an increased risk of asthma and wheezing in both children and adults. In fact, the study investigators admit that their systematic review is subject to several limitations, one of which is that diagnosis of asthma in most of the studies was through self-reporting and the possibility of misclassification of asthma with other respiratory conditions can't be excluded. The authors also stated that additional studies would be needed in order to verify their findings.''  {Would you want your child to be in a study to see if acetaminophen causes asthma--jk?}

Second Opinion

Another expert said the review is strong. "This is clearly synthesizing the studies that have been conducted over the past 10 years and is showing the emerging evidence that acetaminophen seems to be associated with the development of asthma and asthma-like symptoms in children and adults," says Matt Perzanowski, PhD, assistant professor of environmental health sciences at the Mailman School of Public Health at Columbia University in New York.

With his colleagues at Columbia, Perzanowski recently found that prenatal acetaminophen exposure boosts the risk of wheezing in inner city, minority children (who have high rates of asthma) at age 5.

They believe that children with a genetic mutation affecting an antioxidant that helps ''detox'' the body may be the ones at risk, Perzanowski tells WebMD.

A practicing allergist, Rebecca G. Piltch, MD, who cares for patients with asthma and allergies in Marin County, Calif., says the association is interesting but points out it does not prove cause and effect.  {Neither does the statistics which show that 85% of lung cancer is with those who smoke--jk}

Perzanowski agrees, saying: "There is still a possibility the association is due to some other mechanism besides the acetaminophen."  {Not with cigarette-like percentage of increase--jk.}

Until more research is done, what's a parent or adult to do? "The American Academy of Pediatrics recommends acetaminophen as the drug of choice for controlling fever," Etminan says. "Parents should still follow these guidelines until the recommendations change."

"For adults, ibuprofen is an alternative drug that can be used," he says. "Unlike acetaminophen, ibuprofen has not been shown to be associated with asthma."

Following the recommended dose is important, he says. The question of whether a specific dose is linked with the risk of asthma needs to be studied, Etminan says.

Patients already diagnosed with asthma should check with their own doctor about acetaminophen use, Piltch says. Those who don't have asthma ''but have concerns about acetaminophen should discuss them with their primary care provider."

Mahyar Etminan, PharmD, scientist, Center for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research Institute; assistant professor of medicine, University of British Columbia, Canada.
Etminan, M. Chest, November, 2009; vol 135: pp 1316-1323.
Beasley, R. The Lancet, Sept. 20, 2008; vol 372: pp 1039-1048.
Perzanowski, M. Thorax, published online Oct. 22, 2009.
Matt Perzanowski, PhD, assistant professor of environmental health sciences, Mailman School of Public Health, Columbia University.
Rebecca G. Piltch, MD, allergist and immunologist, Marin County, Calif.
Marc Boston, McNeil Consumer Healthcare.
© 2009 WebMD, LLC. All rights reserved.


Asthma increased 63% for 14 times a day or more

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 Barr1*, 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.


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


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.



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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Materials and Methods

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.

Acetaminophen, Glutathione, and Lung Inflammation

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.




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