Clinical scenario

A 3-year-old is seen in Accident & Emergency with a rash and fever. On examination, there are vesicular lesions consistent with chicken pox. His parents are concerned about his fever and distress despite regular paracetamol, and ask you if they can give ibuprofen as well.

Structured clinical question

In children with varicella (population), does the use of non-steroidal anti-inflammatory drugs (NSAID) (exposure) increase the risk of infectious complications of varicella (outcome)?

Search strategy

Ovid Medline was searched using the search terms (Varicella (mapped to Chicken Pox)) AND (NSAID OR ibuprofen OR non-steroidal anti-inflammatory). The search resulted in 64 articles and all available abstracts were reviewed. Review articles, studies not addressing the question, case studies, letters and articles not published in English were excluded at this point. Ten articles were relevant. On review of the full text, five of these ten articles did not address the clinical question and were excluded, leaving a total of five studies. Each article was appraised using a structured approach (table 1).

Commentary

There have been a number of studies trying to determine whether exposure to NSAIDs in patients with varicella increases the risk of developing secondary infections. However, the studies differ in their exposures and outcomes: some looked at all NSAIDs and some just at ibuprofen. Two studies looked at any skin and soft tissue infection (SSTI) as the outcome,1 2 but Lesko et al3 was more specific looking for necrotising soft tissue infection (NSTI) or invasive group A streptococcal infection (iGAS). Zerr et al’s4 outcome of interest was only necrotising fasciitis (NF) and in fact used patients with other SSTIs postvaricella as their control group.

In every study, the results pointed towards an association with NSAID exposure and postvaricella complications, with all but one achieving statistical significance. This finding was confirmed in the most recent study, a 2008 publication looking at 159 children hospitalised in France. There was a statistically significant association between NSAID exposure and subsequent bacterial skin infection (OR 4.8, 95% CI 1.6 to 14.4).5 They did not, however, ask whether the NSAID exposure occurred before or after the onset of signs of a skin infection.

In fact, only two studies made an attempt to differentiate between exposure and causality.1 3 It could be that children with more severe chicken pox are more likely to need symptom relief and are also more likely to develop a secondary skin infection. It could also be that NSAIDs are being used to treat fever caused by an already-established skin infection, rather than contributing to its development. This is exemplified in Zerr et al’s paper,4 where seven of their nine cases were first exposed to ibuprofen after the development of symptoms of NF. Lesko et al3 also found that parents were likely to choose to use ibuprofen if their children had higher temperatures, chills, somnolence or seemed severely ill.

The paper that best addressed this potential confounder was Lesko et al,3 who developed a structured method for assessing the time of onset of skin or iGAS infection (index hour) and did not include NSAID exposure in the 12 hours before the index hour. Their primary outcome achieved statistical significance, with cases who had used an NSAID being more likely to develop the compound outcome of NSTI or iGAS (OR 3.9, 95% CI 1.3 to 12). However, they are hesitant to attribute causation. They note that when the results are broken down, this association is with iGAS rather than NSTI and is only observed in the group of patients who have used an NSAID in combination with paracetamol. They also note that the association does not strengthen with increasing doses of NSAID. This study benefited from industry sponsorship from manufacturers of children’s acetaminophen (paracetamol equivalent) and ibuprofen.

This series of studies demonstrates clearly that there is an association between NSAID exposure and the development of secondary infections in varicella. Lesko et al’s study,3 the only one to adequately look for a causative association, found a statistically significant association. They conclude that this is the result of unknown confounders and have not specifically recommended avoiding NSAIDs in patients with varicella. However, none of the studies have satisfactorily demonstrated that NSAIDs are safe to use in patients with varicella. In the absence of further information, it is difficult to endorse the use of NSAIDs in varicella.