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In responding to Meharban Singh, J Lawrence and colleagues, and Adrian Lowe and colleagues, we reiterate that causality cannot be established from the ISAAC study, owing to several potential biases that might confound the association, including, but not limited to recall bias, misclassification bias, and confounding by indication, as discussed in detail in the paper. X 1 Beasley, R, Clayton, T, Crane, J., and the ISAAC Phase Three Study Group. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. 2008; 372: 1039–1048 In particular, respiratory-tract illnesses in infancy such as respiratory syncytial virus and rhinovirus infections are associated with an increased risk of wheezing in later childhood, and paracetamol use for such episodes could lead to confounding in our study. However, many of these biases are less likely to influence the dose-dependent association between current paracetamol use and asthma symptoms seen in the 6–7-year-old children or the association between paracetamol use and eczema, independent of asthma. Furthermore, the association was present worldwide in communities with different types of childhood febrile illness, different medical practices, and different over-the-counter medication use. There is also evidence that the use of paracetamol for febrile illness in the first year of life might have been expected to reduce rather than enhance the size of any association between paracetamol use in infancy and asthma in later childhood.

This idea is based on the finding that an episode of fever of 383°C or greater in the first year of life is associated with a reduced risk of atopic asthma at age 6–7 years. X 2 Williams, LK, Peterson, EL, Ownby, DR, and Johnson, CC. The relationship between early fever and allergic sensitization at age 6 to 7 years. J Allergy Clin Immunol. 2004; 113: 291–296 Thus the extent to which confounding might have contributed to the association between paracetamol and asthma in the ISAAC study is uncertain, and the presence of confounding does not exclude the possibility of a coexisting causal relation. The classification of paracetamol use was arbitrary but appropriate, allowing classification into broad categories of use.

The category “medium” includes children who received paracetamol at least once per year, up to “at least once per month” which represented “high” current use. In our view, a physician-based diagnosis of asthma is not preferable to current wheeze, owing to the major diagnostic differences related to access to medical care, language, and medical practice in populations worldwide. However, it is relevant to note that the use of a doctor diagnosis of asthma resulted in similar estimates of risk as did current wheezing, and consequently a similar population attributable risk. We propose that the ISAAC findings should be considered together with those from other studies that indicate that the use of paracetamol might represent a risk factor for asthma, as summarised in the panel.

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Meharban Singh Pediatrics Drug Dosage Pdf EditorMeharban Singh Pediatrics Drug Dosage Pdf Editor

Importantly, the sole randomised controlled trial x 3 Lesko, SM, Louik, C, Vezina, RM, and Mitchell, AA. Asthma morbidity after the short-term use of ibuprofen in children. 2002; 109: e20 showed that, in children with asthma, paracetamol use for febrile illness was associated with a two-fold higher risk of hospital outpatient visits for asthma than ibuprofen. As outlined by Graham Barr in the Comment x 4 Barr, RG. Does paracetamol cause asthma in children? Time to remove the guesswork. 2008; 372: 1011–1012 accompanying our paper, this finding, together with other evidence, raises the important issue of whether non-steroidal anti-inflammatory drugs might have some protective effect.

It is difficult to interpret the findings of Lowe and colleagues fully, since they are published in abstract form only; however, we do note their conclusions that the frequent use of paracetamol in infancy might be associated with increased risk of childhood asthma, and that unnecessary use should be avoided. What is agreed is the urgent need for further research, including randomised controlled trials into the long-term effects of repeated use of paracetamol, to enable the development of evidence-based guidelines for paracetamol use in childhood. X 1 Beasley, R, Clayton, T, Crane, J., and the ISAAC Phase Three Study Group.

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Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. 2008; 372: 1039–1048 , x 4 Barr, RG. Does paracetamol cause asthma in children? Time to remove the guesswork. 2008; 372: 1011–1012 , x 5 Russell, FM, Shann, F, Curtis, N, and Mulholland, K. Evidence on the use of paracetamol in febrile children.

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Bull World Health Organ. 2008; 81: 367–372 We declare that we have no conflict of interest. References. 1 Beasley, R, Clayton, T, Crane, J., and the ISAAC Phase Three Study Group.

Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. 2008; 372: 1039–1048. 2 Williams, LK, Peterson, EL, Ownby, DR, and Johnson, CC. The relationship between early fever and allergic sensitization at age 6 to 7 years.

J Allergy Clin Immunol. Sp 100 pill. 2004; 113: 291–296. 3 Lesko, SM, Louik, C, Vezina, RM, and Mitchell, AA.

Asthma morbidity after the short-term use of ibuprofen in children. 2002; 109: e20. 4 Barr, RG.

Does paracetamol cause asthma in children? Time to remove the guesswork. 2008; 372: 1011–1012.

5 Russell, FM, Shann, F, Curtis, N, and Mulholland, K. Evidence on the use of paracetamol in febrile children.

Bull World Health Organ. 2008; 81: 367–372.

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