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Three Part Question

In [children with chickenpox], are [non-steroidal anti inflammatories (NSAIDs)] [safe to prescribe]?

Clinical Scenario

A 4 year old girl is brought to the Emergency Department with a rash that is obviously chicken pox and she is very distressed. The triage nurse comes to ask what analgesia can be given as paracetamol was given at home 30 minutes ago and they have heard that ibuprofen is contra-indicated in chicken pox.

Search Strategy

Medline, Embase and CINAHL were searched via Healthcare Databases Advanced Search (HDAS).18/07/17
No limits except for articles published in English were used in the search.
Cochrane was also searched although the one article found was also on HDAS.


"(("non steroidal anti inflammator*").ti,ab OR ("NSAIDs").ti,ab OR ("ibuprofen").ti,ab) AND (("chicken pox").ti,ab OR ("varicella").ti,ab)"

Search Outcome

From the initial results: Embase 66, Medline 31 and Cinahl 3, duplicated items were
deleted. Once Non-English papers, case series with fewer than 5 patients, and conference abstracts were excluded, this reduced further to 6 papers

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Dubos F et al 2008 France	21 patients with severe bacterial skin infection as complication of varicella within 4 weeks of primary varicella infection compared to 138 patients admitted with varicella but no severe skin infection.	secondary case-control series performed within a larger prospective case control series of all children admitted with Varicella (Level 3b)	Determine incidence rate of hospitalization for patients with secondary bacterial skin complications related to varicella and to identify potential risk factors	After multivariate analysis, only NSAID use (adjusted Odds Ratio =4.8; 95%CI: 1.6–14.4) was independently associated with the onset of severe bacterial skin complications	Study design constructed retrospectively from a prospective cohort- potential confounding factors may have affected analysis. Small numbers in the subanalysis
Mikaeloff Y et al 2008 United Kingdom	386 of 140111 patients with primary varicella diagnosed with severe skin or soft tissue complications during 2 month follow up period. These cases then matched with 2402 controls to look at risk factors including NSAID use	Nested-case control study (level 3b)	Determine rate of severe skin or soft tissue complications associated with NSAID or paracetamol use, adjusting for potential confounding factors	386 cases of severe skin or soft tissue complications. Rate of complications associated with exposure to NSAIDs was increased (rate ratio 4.9, 95% CI 2.1-11.4)	Study design allows confounding by indication to potentially occur, as well as a degree of random misclassification of exposure history as a proportion of persons may have taken NSAIDs without GP’s knowledge as prescription data came from GP research database
Grimprel E et al 2007 France	1575 patients hospitalised with varicella, 792 with bacterial superinfection as complication assessed for risk factors	Series of case reports from over 165 paediatric wards across France identified by French national network (level 4)	Descriptive analysis of results of surveillance for 2 years including analysis of contributing factors related to superinfection	Risk of superinfection increased by NSAIDs OR 2.65 (95%CI 1.8-3.4)	Series of case reports. No indication as to how many cases from each ward
Zerr D.M et al 1999 USA	19 patients with necrotising fasciitis as complication of varicella, occurring within 3 weeks of primary varicella were compared to 29 controls consisting of patients hospitalized with severe soft tissue infections other than necrotising fasciitis again within 3 weeks of primary varicella.	Retrospective Case-control study (level 3b)	Determine if ibuprofen use or other identifiable risk factors were associated with the development of necrotising fasciitis in the setting of primary varicella	After adjusting for gender, age and group A streptococcus isolation, cases were more likely than controls to have used ibuprofen (OR, 10.2; 95% CI 1.3-79.5)	Limited sample size, retrospective.
Choo P.W et al 1997 USA	7013 cases of varicella screened, 89 patients developed a superinfection within 30 days of primary varicella, 169 patients with varicella received ibuprofen during the preceding 180 days	Retrospective case-control study (level 3b)	To investigate the possible association between ibuprofen use and dermatologic superinfections among children with recent varicella infection	No statistically significant association found. 4 of 169 children receiving ibuprofen within 180 days of varicella developed a superinfection. Compared to control group without prior ibuprofen use, children with ibuprofen were 3.1 times more likely to be diagnosed with a superinfection (95% CI 0.1-19.7, P-value 0.31)	Information gathered retrospectively from automated hospital records Timing of ibuprofen exposure was classified according to the most recent dispensing of ibuprofen during the 180 days before the diagnosis of varicella.
Lesko S.M et al 2001 USA	52 cases meeting criteria of children <19years of age hospitalised with group A streptococcus or necrotising soft tissue infection within 2 weeks of varicella infection compared to 172 controls	Prospective multicentre case control study (level 3b)	To test hypothesis that NSAID use increases the risk of invasive GAS infection, with a primary interest in necrotising infections, in children with varicella	No increased risk of necrotising infection with ibuprofen. (OR 1.3 95% CI 0.33-5.3)	Large number of exclusions – 97 cases identified, 52 analysed, 226 controls identified, 172 analysed. Risk of potential uncontrolled confounding factors.

Comment(s)

No firm conclusions can be made as no good quality RCTs exist on this topic and in the studies that do exist the results are mixed. The majority of the papers included show an increased risk of complications secondary to NSAID use. However, in many cases it is noted that NSAID use occurred after the onset of symptoms of secondary infection. This suggests a potential indication bias whereby NSAIDs are given as a response to infection in patients with severe disease rather than being a cause of the severity of the illness. One theory, based on animal studies suggests that the greater severity of soft tissue infection in those treated with an NSAID may be due to the delay in treatment induced by the masking effects of NSAIDs rather than to the alteration of bacterial defences. The number of reports suggesting that NSAIDs may play a causative role in severe invasive bacterial infections demonstrates the need for additional research. Until this work is performed it is advisable to avoid NSAID use in cases of primary varicella. These conclusions are echoed in the recommendations by the NICE Clinical Knowledge Summaries. This body states that they do not recommend the use of NSAIDS because of concerns based on a number of cohort and case-control studies, supported by expert opinion in review articles that the use of NSAIDs in children with varicella is associated with an increased risk of severe skin and soft tissue infections.

Editor Comment

KMJ

Clinical Bottom Line

Until further research is performed it is advisable to avoid NSAID use in cases of primary varicella due to the potential increased risk of increased severe bacterial infections. Paracetamol should be given instead.

References

1. Dubos F et al Bacterial skin infections in children hospitalized with varicella: A possible negative impact of non-steroidal anti-inflammatory drugs? Acta Dermato-Venereologica 2008; vol. 88 (no. 1); p. 26-30
2. Mikaeloff Y et al Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease British Journal of Clinical Pharmacology Feb 2008; vol. 65 (no. 2); p. 203-209
3. Grimprel E et al Paediatric varicella hospitalisations in France: A nationwide survey Clinical Microbiology and Infection May 2007; vol. 13 (no. 5); p. 546-549
4. Zerr D.M et al A case-control study of necrotizing fasciitis during primary varicella Pediatrics Apr 1999; vol. 103 (no. 4); p. 783-790
5. Choo P. W et al Ibuprofen and skin and soft tissue superinfections in children with varicella nals of Epidemiology Oct 1997; vol. 7 (no. 7); p. 440-445
6. Lesko S.M et al Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella Pediatrics 2001 May;107(5):1108-15.