By Aric Carroll, PharmD Student
A young child is very susceptible to getting sick, and with that sickness often comes fever. How do most parents treat their child’s fever? The answer for the past few decades has been acetaminophen. In many countries around the world, the first line drug approved for treating fever in children is acetaminophen.1 It has been estimated from one study that up to 75% of all children in Western countries are at some time treated with fever reducing drugs such as acetaminophen.2,3 In the United States acetaminophen use without a physician visit is approved for children as young as 2 years old.4,5 In the past decade, a lot of research has looked at a connection between the rise of acetaminophen use and the rise of asthma in young children.6
A recent study from the Journal of Korean Medical Science (JKMS)9 investigated the relationship between acetaminophen use and asthma prevalence, but took it a step further to try to see why acetaminophen use could be associated with the condition of asthma. The study particularly looked at a specific gene for a receptor in the body called toll-like receptor 4 (TLR4). This is one of the first studies to focus on the combination of TLR4 modification and acetaminophen use and the risk of asthma associated with that combination. In past studies, modification of the gene for TLR4 has been associated with a higher prevalence rate of asthma.7 It has been suggested that modification at this particular gene affects how the TLR4 functions. Modifications may cause the body to work harder at dealing with fine particles that are inhaled leading to physical symptoms associated with asthma.8 The authors of the recent JKMS study acknowledge that TLR4 facilitates the symptoms of asthma by contributing to the release of reactive oxygen species, which are molecules that cause excess stress on the body. This excess stress can then lead to the release of cells that cause inflammation, cause the airways to be inflamed, and cause bronchial hyperresponsiveness (BHR) or tightening of the airways. The study suggests that modification of the TLR4 gene could cause the receptor to be more abundant and lead to greater asthma symptoms.9
The study examined 2, 428 children aged between 8 and 13. The parents of each child were asked to fill out a questionnaire, which included questions about whether the child had used acetaminophen, and whether the child had been diagnosed with asthma. Tests were run on each child to determine a forced expiratory volume after a methocholine challenge, which is an indicator of BHR. Methocholine causes constriction of the airways. BHR to methocholine was defined as a PC20 (the concentration of methocholine re-quired to provoke a 20% reduction in FEV1) ≤ 16 mg/mL. Genetic tests were run on each child to determine modification of the TLR4 gene. The results showed that the use of acetaminophen was associated with risk of BHR; however, it was not associated with actual asthma diagnosis. Modification of the TLR4 receptor was not associated with asthma diagnosis or risk of BHR. A combination of acetaminophen use and TLR4 modification was significantly associated with asthma diagnosis as well as risk for BHR. The study concluded TLR4 gene modification may increase the risk of asthma in children who have used acetaminophen.9
While the study had a very large sample size of children, it had limitations that could have affected the study’s results. The study only looked at acetaminophen use in the past 12 months, but did not take into account whether children had used acetaminophen in earlier years. Also, the study looked at patients with a recall of an actual diagnosis of asthma in the children instead of asking about certain symptoms of asthma such as shortness of breath during physical exercise, wheezing, or increased coughing. Many children may have had symptoms of asthma but had never been diagnosed by a physician. The study also did not in any way establish a relationship between dose or duration of acetaminophen use. Acetaminophen use was defined as if they took acetaminophen longer than 3 days in the last 12 months. This was also solely based on patient recall. These limitations are significant and reduced the generalizability of the study. This type of observational study cannot determine a causative relationship. Thus, this kind of research can only suggest potential risks associated with exposure.
While this study, along with others, have evidence to support a relationship between TLR4 modification and asthma, other similar studies have not found this relationship.10 The conflicting evidence on this specific mechanism makes it hard to conclude one way or another whether TLR4 modification is directly linked to asthma symptoms. Also, at this time there seems to be a lack of sufficient evidence to directly link acetaminophen use to asthma symptoms. More prospective research needs to be done looking at acetaminophen use and its relationship with asthma symptoms specifically in combination with TLR4 gene modification. It may be possible that acetaminophen has a greater adverse effect on children who have a TLR4 gene modification which would increase the risk of asthma specifically in those children. With what evidence is available at this time, it is difficult to say that treating a child with acetaminophen will cause them to develop asthma symptoms.
So, what are your thoughts? Even with this possibility of acetaminophen use in children leading to asthma symptoms, do you think it’s still reasonable for acetaminophen to be used to treat a child’s fever?
- Gonzalez-Barcala F, Pertega S, Silvarrey A, et al. Exposure to paracetamol and asthma symptoms. European Journal Of Public Health [serial online]. August 2013;23(4):706-710. Available from: Food Science Source, Ipswich, MA. Accessed October 15, 2014.
- Jensen J, Tønnesen L, Söderström M, Thorsen H, Siersma V. Paracetamol for feverish children: parental motives and experiences. Scandinavian Journal Of Primary Health Care [serial online]. June 2010;28(2):115-120. Available from: CINAHL Plus with Full Text, Ipswich, MA. Accessed October 16, 2014.
- Sullivan J, Farrar H. Fever and antipyretic use in children. Pediatrics [serial online]. March 2011;127(3):580-587. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed October 16, 2014.
- Reducing fever in children: safe use of acetaminophen. FDA Consumer Health Information. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm263989.htm. Published July 21, 2011. Updated June 6, 2014. Accessed October 15, 2014.
- Krinsky, D. L., Berardi, R. R., & Ferreri, S. P. (2011). Handbook of nonprescription drugs: An interactive approach to self-care (17th ed.). Washington, D.C: American Pharmacists Association.
- Farquhar H, Stewart A, Beasley R, et al. The role of paracetamol in the pathogenesis of asthma. Clinical & Experimental Allergy [serial online]. January 2010;40(1):32-41. Available from: Academic Search Complete, Ipswich, MA. Accessed October 15, 2014.
- Fagerås Böttcher M, Hmani-Aifa M, Vaarala O, et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. The Journal Of Allergy And Clinical Immunology. September 2004;114(3):561-567. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed October 16, 2014.
- Kerkhof M, Postma D, Koppelman G, et al. Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax [serial online]. August 2010;65(8):690-697. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed October 18, 2014.
- Lee S, Kang M, Hong S, et al. Association between Recent Acetaminophen Use and Asthma: Modification by Polymorphism at TLR4. Journal Of Korean Medical Science. March 2014;29(5):662-668. Available from: Science Citation Index, Ipswich, MA. Accessed October 10, 2014.
- Hussein Y, Awad H, Shalaby S, Ali A, Alzahrani S. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: A case-control analysis. Cellular Immunology [serial online]. 2012;274(1-2):34-38. Available from: Science Citation Index, Ipswich, MA. Accessed October 18, 2014.