Varicella and NSAIDs – are you too chicken to prescribe?

Jaxon is a 3-year-old boy brought to the ED by his mother with chickenpox because of decreased oral intake. On examination, he has a rash consistent with chickenpox but no red flags.

He is febrile and looks uncomfortable, and you note his heart rate is high. You go to prescribe paracetamol, but his mum has given him four doses in the past 24 hours already.

You wonder if you can prescribe ibuprofen instead, but your colleague warns against it.

Where did this controversy arise?

There is a long history of anecdotal evidence associating invasive group A Strep (GAS) complications or severe skin and soft tissue infections (SSTIs) with exposure to NSAIDs. The chickenpox story started with a series of case reports linking ibuprofen with invasive GAS, prompting an attempt to investigate the association more rigorously.

There are currently 5 papers, published between 1997 and 2008, that attempt to answer this question. I will not take these individual studies apart here, but feel free to delve deeper into each one using this fantastic resource from the UK Medicines Information Agency on this topic.

How did they answer the question?

Almost all studies used a case-control design to address this question.

What does that mean? They took a group of children who had varicella and the outcome of interest (invasive GAS infection, severe SSTI). They compared them with a group of children who had varicella and did not experience these outcomes, to determine which groups were more likely to have received ibuprofen.

What did they find?

The studies are pretty heterogeneous, so unsurprisingly, the results varied. One study found no association. Most found an association between ibuprofen exposure and severe GAS/SSTI, with an odds ratio between 2 and 5 (one study reported an OR of 10, but the sample size was too small to trust).

So, what’s the controversy?

These studies all found an association, but they generally all suffer from the same big problem, which is confounding by indication.

What does that mean? Basically, if you have more severe varicella or are developing complications, you’re more likely to need ibuprofen. It might not be that ibuprofen causes complications, but rather that bad varicella needs ibuprofen and is also more likely to get complications anyway. As the famous saying goes, “Correlation does not equal causation”.

There have also been suggestions that easing symptoms with ibuprofen may have delayed initial medical consultation for complications at an earlier stage, which could have prevented subsequent hospitalisation.

So how can we definitively answer this question? We probably can’t without randomising children to ibuprofen vs paracetamol in the setting of varicella, which is not likely to happen.

How do we manage this potential risk?

Most authorities have taken a risk-averse standpoint (including NICE) to avoid ibuprofen due to the presence of uncertainty regarding this association, given that a perfectly acceptable alternative exists in paracetamol. Seems reasonable.

However, professionally, we are often in a scenario where the child is in hospital, paracetamol hasn’t cut the mustard, and we want to use it. Are you running a risk? Are parents who are desperate for symptom relief putting their child in imminent danger if they give ibuprofen?

Allow me some back-of-the-envelope maths for the Worst Case Scenario (WCS).

The annual incidence of varicella in the UK is roughly 13,000 cases per 100,000 children <5 years.

The incidence of necrotising fasciitis from chickenpox is roughly 0.05/100,000 children per year.

If (WCS) we assume they ALL occur in the under 5 group, this gives a rate of roughly 0.04/10,000 cases of necrotising fasciitis in chickenpox per year.

Let’s say ibuprofen has an Odds Ratio of 5 for necrotising fasciitis in varicella (WCS). This means if you have chickenpox and you are given ibuprofen, your risk goes from 0.04 in 10,000 to 0.2 in 10,000.

An Absolute Risk increase of 0.0016% (WCS).

Bottom line

Ultimately, everyone admits there is a huge degree of uncertainty in the possibility of ibuprofen increasing your risk of complications in varicella. You must assess the risk for yourself and decide what you feel most comfortable advising people. A reasonable approach might be to advise using paracetamol in the first instance and to consider the use of ibuprofen with a low threshold for consulting a medical professional if the child remains distressed.