What’s the evidence: Does Ibuprofen cause skin and blood infections in children with chickenpox?

NOT A DOCTOR. NOT MEDICAL ADVICE. Only for thought.

Does Ibuprofen cause skin and blood infections in children with chickenpox?

What are doctors told?

The National Institute for Health and Clinical Evidence (NICE) Clinical Knowledge Summary “Scenario: management of an otherwise healthy child or adult with chickenpox”:1

NICE Clinical Knowledge Summary “Analgesics / Antipyretics”:2

What evidence is used to tell doctors this?Evidnec pyramid

What we’re hoping for is the highest quality of evidence to answer our question so we can be more certain in the answer. Mostly, the best evidence is at the top of the pyramid, and the quality of the evidence decreases as you move down the pyramid.

The guidelines reference three papers to support their recommendations:

Heininger and Seward, 2006

Bilj, 2010

Mikaeloff et al., 2008

Heininger and Seward, 2006 is a review, but it isn’t a systematic review, so it isn’t at the top of the evidence pyramid. We need to look at where they got their evidence from.

They reference two papers:

Lesko et al., 2001

Zerr et al., 1999

So, we can see that the guidelines for doctors are based on 4 original research papers (although these papers reference other papers too). What is the quality of this evidence?

Bilj, 2010

I couldn’t access this paper. This is very annoying. It means we can’t assess the quality of the research. It is also completely unreasonable that guidelines for treating us are based on evidence we can’t see.

Mikaeloff et al., 2008

The study design

A case-control study, half-way down the quality of evidence pyramid. Using the General Practice Research Database it looked at UK patients with chickenpox or shingles for at least two days, between 1994 and 2005. 386 patients with chickenpox had “severe skin or soft tissue complications”. They matched each of these patients with 10 of the patients who had chickenpox but no skin or soft-tissue infections. Then they worked out how much more likely the patients with skin infections were to have been given a prescription for ibuprofen.

The results

12 of 386 patients with severe skin or soft tissue complications took ibuprofen. 14 of 2402 patients without severe skin or soft tissue complications took ibuprofen. The relative risk is 5.2 (patients taking ibuprofen were 5x more likely to have severe skin or soft tissue complications). The absolute risk increase is 0.025 (patients taking ibuprofen increased their risk of severe skin or soft tissue complications by 0.025). The number of patients that would have to be prescribed ibuprofen for one patient to be harmed is 40.

The problems

Case-controls studies are subject to more and greater biases than research further up the pyramid. The patients in this study are adults and children – they have an average age of about 11 years old, but we don’t know the age of the patients who developed skin or soft-tissue infections – and we want to know the answer for children. They found 386 patients with severe skin or soft tissue complications, of whom only 26 had taken ibuprofen. This is very few patients if you want to work out the role of ibuprofen, which, if it is a risk factor, is likely to be a very small risk factor. With numbers this small the results are highly subject to chance. The way that they found out who took ibuprofen was to look at who had been prescribed ibuprofen – this will over-count patients who received a prescription but didn’t collect it from the pharmacy or didn’t take it, and will not count patients who buy their ibuprofen over the counter (30p a packet).

Can we trust the results?

I think not. This study ignored patients who took ibuprofen bought over the counter, which is how almost all of us access ibuprofen. Patients who were more ill, and more likely to develop skin or soft-tissue infections would have been more likely to see a GP and to have a record of a prescription for ibuprofen. These factors will make ibuprofen look much worse than it is. The number of patients is very very small (26 who were prescribed ibuprofen). It is highly likely that this result has arisen by chance.

 

Lesko et al., 2001

The study design

The study design is a case-control study, half-way down the quality of evidence pyramid. They included children who had been admitted to hospital in the USA, with chickenpox and “invasive or necrotising soft tissue infection”, between 1996 and 1998. 52 patients with chickenpox had invasive Group A streptococcal infection. They matched each of these patients with 4 of the patients who had chickenpox but invasive Group A streptococcal infection. Then they worked out how much more likely the patients with skin infections were to have been given a prescription for ibuprofen.

The results

18 of 52 patients with invasive Group A streptococcal infection took ibuprofen. 36 of 172 patients without invasive Group A streptococcal infection took ibuprofen. The relative risk is 1.7 (patients taking ibuprofen were nearly 2x more likely to have invasive Group A streptococcal infection). The absolute risk increase is 0.14 (patients taking ibuprofen increased their risk of severe skin or soft tissue complications by 0.14). The number of patients that would have to be prescribed ibuprofen for one patient to be harmed is 7.

The problems

Case-controls studies are subject to more and greater biases than research further up the pyramid. The cases in this study have been hospitalised but control patients haven’t. It seems likely that sicker children are more likely to be hospitalised, and more likely to have been given more medication (including ibuprofen). They found 52 patients with severe skin or soft tissue complications, of whom only 18 had taken ibuprofen. This is very few patients if you want to work out the role of ibuprofen, which, if it is a risk factor, is likely to be a very small risk factor. With numbers this small the results are highly subject to chance. The way that they found out who took ibuprofen was either to examine medical records (cases) or to interview the parents (controls). Asking people what they remember giving to their child before something dramatic (hospitalisation) didn’t happen, is not likely to be a reliable source of data, and exposure (to ibuprofen) may well be underreported.

Can we use and trust the results?

Maybe. If sicker children are more likely to be hospitalised and more likely to have been given more medication then these results will make ibuprofen look worse than it is. The number of patients is very small (54 who took or reported taking ibuprofen). It is quite possible that this result has arisen by chance.

 

Zerr et al., 1999

The study design

A case-control study, half-way down the quality of evidence pyramid. It compares children hospitalised for necrotising fasciitis who recently had chickenpox, with children hospitalised for a “different soft tissue infection” who recently had chickenpox. Between 1993 and 1994 48 patients were examined. Then they worked out how much more likely the patients with necrotising faciitis were to have taken ibuprofen.

The results

9 of 19 patients with necrotising fasciitis took ibuprofen. 4 of 26 patients with a different soft tissue infection took ibuprofen. The relative risk is 3.2 (patients taking ibuprofen were 3x more likely to have necrotising faciitis than a different soft tissue infection). The absolute risk increase is 0.32 (patients taking ibuprofen increased their risk of necrotising fasciitis by 0.32). The number of patients that would have to be prescribed ibuprofen for one patient to get necrotising fasciitis is 3.

The problems

Case-controls studies are subject to more and greater biases than research further up the pyramid. All these patients had an infection – so we are comparing different types of infections – but what we want to know is whether ibuprofen causes any infection. They found 48 patients with skin or soft tissue complications, of whom only 13 had taken ibuprofen. This is very very few patients if you want to work out the role of ibuprofen, which, if it is a risk factor, is likely to be a very small risk factor. And, as we saw before, this study isn’t even asking the question we want to answer – which is whether ibuprofen increases any infection. With numbers this small the results are highly subject to chance. This study tests 20 different risk factors. The more risk factors you look at, the greater the chance of one of them giving a positive result by chance. P=0.05 is commonly used as a measure of significance. Using this p value there is a 1/20 chance that a positive result will arrive by chance. This paper has looked at 20 outcomes… so we would expect that one would be positive just by chance.

Can we use and trust the results?

I think not. The question being tested is related to, but is not the question we want to answer. The number of patients is very very small (13 who were prescribed ibuprofen), and the authors examined 20 risk factors. It is highly likely that this result has arisen by chance.

In summary

I don’t think that any of these three studies is reliable. The hidden study might be better, but how do we know? All three visible studies give a hint that ibuprofen might be a problem. But none of them show that ibuprofen is a risk-factor for skin and blood infections in children with chickenpox, and they don’t demonstrate that ibuprofen causes skin and blood infections. The clinical guidelines (which doctors often rely upon) are based on very unreliable evidence. There is other evidence out there but it will take longer than I have to trawl through. Bearing in mind that NICE are probably better equipped for this than me, and that these are the papers they referenced, I think it is unlikely that any better quality research exists.

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So, what’s the evidence? Does Ibuprofen cause skin and blood infections in children with chickenpox?

We don’t know. There is very shaky clinical evidence to suspect it might, and no reliable clinical evidence to show it does.

STILL NOT A DOCTOR. STILL NOT MEDICAL ADVICE. Hope it makes you think though.

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