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Review

Asthma: epidemiology, etiology and risk factors

Padmaja Subbarao, Piush J. Mandhane and Malcolm R. Sears
CMAJ October 27, 2009 181 (9) E181-E190; DOI: https://doi.org/10.1503/cmaj.080612
Padmaja Subbarao
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Piush J. Mandhane
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Malcolm R. Sears
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  • Authors' response to Dr. Singh
    Padmaja Subbarao
    Posted on: 28 September 2009
  • Acetaminophen -an important etiological agent for asthma
    Akashdeep Singh
    Posted on: 24 September 2009
  • Posted on: (28 September 2009)
    Authors' response to Dr. Singh
    • Padmaja Subbarao, Hospital for Sick Children

    We would like to thank Dr. Singh for his comments and his in-depth review of the acetaminophen and asthma literature. As in any review,it is difficult to address all possible risk factors and we attempted to link data that was causally linked in multiple studies with incident asthma. The meta-analysis by Etminan et al1, published earlier this year provides a comprehensive overview of the studies associating acetaminophe...

    Show More

    We would like to thank Dr. Singh for his comments and his in-depth review of the acetaminophen and asthma literature. As in any review,it is difficult to address all possible risk factors and we attempted to link data that was causally linked in multiple studies with incident asthma. The meta-analysis by Etminan et al1, published earlier this year provides a comprehensive overview of the studies associating acetaminophen and asthma risk. As per the overview, the evidence is mounting that acetaminophen use is linked to increased rates of asthma but to date little evidence is available to suggest that acetaminophen is actually causing asthma. Of particular note is the absence of a consistent data between prenatal acetaminophen use and asthma development. As mentioned in the Etminam article, at this point there are many potential confounders such as viral infection which may in part explain this finding. Careful further study may help to elucidate the role of acetaminophen in the development of incident asthma.

    1. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, Fitzgerald JM. Acetaminophen Use and the Risk of Asthma in Children and Adults: A Systematic Review and Metaanalysis. Chest. 2009 Aug 20.

    Padmaja Subbarao MD, MSc, Piush J Mandhane MD, PhD and Malcolm R Sears MB, ChB

    Show Less
    Competing Interests: None declared.
  • Posted on: (24 September 2009)
    Acetaminophen -an important etiological agent for asthma
    • Akashdeep Singh

    I must congratulate Padmaja Subbarao et al for their elegant review on Asthma: epidemiology, etiology and risk factors. They have missed to cover acetaminophen as an etiological cause of asthma both in adults and children. Several studies have shown a relationship between acetaminophen consumption and presence of asthma.

    Newson et al (1) found that acetaminophen sales correlated positively with the prevalence o...

    Show More

    I must congratulate Padmaja Subbarao et al for their elegant review on Asthma: epidemiology, etiology and risk factors. They have missed to cover acetaminophen as an etiological cause of asthma both in adults and children. Several studies have shown a relationship between acetaminophen consumption and presence of asthma.

    Newson et al (1) found that acetaminophen sales correlated positively with the prevalence of asthma, rhinitis, atopic eczema, and wheezing in children who participated in ISAAC. Cohet et al(2) studied the association between infections in children aged 0 to 4 years and medications used (antibiotics and acetaminophen) and the subsequent presentation of asthma at age 6 to 7; the authors observed that the use of acetaminophen in the first year of life was weakly associated with wheezing, asthma, rhinitis, and eczema. Shaheen et al(3) conducted a study showing that the increasing use of acetaminophen was strongly associated with presence of asthma and its severity-, before and after adjusting for confounders. In their prospective study, Barr et al(4) found that acetaminophen use was associated with the presence of newly diagnosed asthma among women. In a cohort study of pregnant women, Shaheen et al(5) observed an association between daily or almost-daily use of acetaminophen during late pregnancy (20-32 weeks) and presence of wheezing in their children at age 3. Later, following the same cohort, Shaheen et al(6) reported that the use of acetaminophen during pregnancy was associated with a higher frequency of asthma and wheezing when the children reached 6 to 7 years.

    A recent systematic review and meta-analysis by Etminan et al had similar results.The OR for asthma among users of acetaminophen (adult and children) was 1.63 (95% CI, 1.46-1.77). The risk of asthma in children among users of acetaminophen in the year prior to asthma diagnosis and first year of life was elevated by similar magnitude (1.60 [95% CI, 1.48- 1.74], 1.47[95% CI, 1.36-1.56] respectively). There was an increase in the risk of asthma and wheezing with prenatal acetaminophen use (1.28 [95%CI, 1.13-1.39], 1.50 [95% CI, 1.10-2.05] respectively).(7)

    Several mechanisms have been postulated that may explain the possible risk of asthma with acetaminophen use. The main mechanism involves glutathione which is a potent antioxidant found in lung tissue(8). Acetaminophen has shown to lower serum glutathione levels in healthy volunteers(9). Glutathione is a potent scavenger of free radicals(10) which are in turn responsible for lung injury and initiation of an inflammatory response leading to bronchoconstriction and asthmatic symptoms.

    A second possible mechanism is thought to beacetaminophen’s lack of inhibition of the enzyme cyclooxygeanse (COX)(11). COX is the key enzyme involved in the production of prostaglandins playing a major role in the inflammatory cascade in asthma. Finally, a new emerging hypothesis involves the possible antigenic effect of acetaminophen and subsequent rise in IgE and histamine levels with exposure to acetaminophen(12,13).

    References

    1. Newson RB, Shaheen SO, Chinn S, Burney PG. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J. 2000;16:817-23.

    2. Cohet C, Cheng S, MacDonald C, Baker M, Foliaki S, Huntington N, Douwes J, Pearce N. Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood. J Epidemiol Community Health. 2004;58:852-7.

    3. Shaheen SO, Sterne JA, Songhurst CE, Burney PG. Frequent paracetamol use and asthma in adults. Thorax. 2000;55:266-70.

    4. Barr RG, Wentowski CC, Curhan GC, Somers SC, Stampfer MJ, Schwartz J, Speizer FE, Camargo CA Jr. Prospective study of acetaminophen use and newly diagnosed asthma among women. Am J Respir Crit Care Med. 2004;169:836-41.

    5. Shaheen SO, Newson RB, Sherriff A, Henderson AJ, Heron JE, Burney PG, Golding J; ALSPAC Study Team. Paracetamol use in pregnancy and wheezing in early childhood. Thorax. 2002;57:958-63.

    6. Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton FD, Jones RW, Strachan DP; ALSPAC Study Team. Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood. Clin Exp Allergy. 2005;35:18- 25.

    7. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, Fitzgerald JM. Acetaminophen Use and the Risk of Asthma in Children and Adults: A Systematic Review and Metaanalysis. Chest. 2009 Aug 20.

    8. Kelly FJ. Glutathione: in defense of the lung. Food Chem Toxicol 1999;37:963–966.

    9. Nuttall SL, Khan, JN, Thorpe, GH, et al The impact of therapeutic doses of acetaminophen on serum total antioxidant capacity. J Clin Pharm Ther 2003;28,289-294.

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

    11. 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.

    12. De Paramo, BJ, Gancedo, SQ, Cuevas, M, et al Acetaminophen (acetaminophen) hypersensitivity. Ann Allergy Asthma Immunol 2000;85:508

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

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
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Canadian Medical Association Journal: 181 (9)
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Vol. 181, Issue 9
27 Oct 2009
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Asthma: epidemiology, etiology and risk factors
Padmaja Subbarao, Piush J. Mandhane, Malcolm R. Sears
CMAJ Oct 2009, 181 (9) E181-E190; DOI: 10.1503/cmaj.080612

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Asthma: epidemiology, etiology and risk factors
Padmaja Subbarao, Piush J. Mandhane, Malcolm R. Sears
CMAJ Oct 2009, 181 (9) E181-E190; DOI: 10.1503/cmaj.080612
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