Download SMAS_442.1 Medicines_QA_NSAIDs_chickenpox

Medicines Q&As
Q&A 442.1
Do NSAIDs increase the risk of severe skin reactions in children
with chickenpox?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 20/06/2016
Background
Chickenpox is an acute disease predominantly occurring in childhood (1). It is caused by varicellazoster virus and is characterised by a vesicular rash, and often fever or malaise. Secondary
complications are rare and the most frequent complications are secondary bacterial infections of the
skin. The causative organisms in these infections are usually group A Streptococcus and
Staphylococcus aureus (1).
It has been suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may be a risk factor for
severe skin and soft tissue infections with varicella infection (2). Serious skin reactions are recognised
as a potential complication of NSAID use in general, as these have been rarely reported (3-5).
Additionally several manufacturers of paediatric preparations of ibuprofen suggest it is advisable to
avoid the use of NSAIDs in cases of varicella, and provide a caution for patients or carers in the
corresponding patient information leaflet (PIL) (4-8). On the other hand, this caution is not present in
every manufacturer’s prescribing information, and patients or their carers may therefore be unaware
of any potential risk (9,10). This Q&A looks at the evidence regarding the association between NSAID
use and severe skin reactions in children with chickenpox.
Answer
Several mechanisms have been proposed to explain how NSAIDs may promote bacterial skin
complications including (2):
 The suppression of granulocyte functions such as chemotaxis, oxidative burst, phagocytosis
and bacterial killing resulting in an impaired immune response.
 NSAID enhanced production of tumour necrosis factor (TNF), a cytokine that is a major
mediator of septic shock and organ failure.
 Masking of the severity of the infection through antipyretic and analgesic effects due to
inhibition of prostaglandin synthesis. It has been proposed that NSAID use in patients with
skin infections may improve the symptoms and signs of inflammation, which may in turn
provide false reassurance to the patient and clinician, thereby delaying diagnosis, resulting in
development of a more severe infection.
As early as 1966 several reports of serious soft tissue infections and NSAID exposure were reported
(11). In 1995 concerns were raised to the FDA after a series of children were hospitalised with group
A streptococcal infections secondary to varicella after treatment with ibuprofen. In 2004 the French
Health Authority recommended the addition of a precautionary statement to the summary of product
characteristics of all NSAIDs (12). A small number of case control studies and cohort studies have
reported associations between NSAID exposure and skin and soft tissue complications of varicellazoster virus infection, and these are discussed in more detail below (3,11,13-16).
One nested case-control study matched 386 cases of severe skin or soft tissue complications with
varicella infection with 2402 controls from a cohort of patients with a varicella diagnosis (13). They
found that the use of NSAIDs was associated with an increased risk of severe skin and soft tissue
complications in varicella, which mostly included children (adjusted rate ratio 4.9, 95% CI 2.1,11.4).
One limitation of this study was that prescription databases and GP records were analysed and
therefore the effect of exposure to over-the-counter NSAIDs was not reported.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
A 1-year prospective cohort study in Northern France studied children admitted with varicella infection
during the study period (15). 44 patients out of the 159 children in the study were identified with
secondary bacterial skin complications on admission and 21 of these patients had at least one severe
skin complication. After multivariate analysis, NSAID use was associated with severe varicella-related
bacterial skin complication (adjusted odds ratio 8.1, 95% CI 1.6-14.4). Persistent or recurrent fever
≥38.5°C for ≥3 days after the onset of varicella infection was also associated with severe varicellarelated bacterial skin complications and it is therefore difficult to determine causality from the results
of this study.
A prospective multicentre case-control study identified cases who were children (18 years or under)
hospitalised with primary varicella complicated by invasive group A streptococcal (GAS) infection or
necrotising soft tissue infection (16). Controls were children with uncomplicated primary varicella
residing in the same communities as the cases. 52 cases were compared to 172 controls and risk of
invasive GAS infection was increased among children who had received ibuprofen (odds ratio 3.9,
95% CI: 1.3-12). However, in an analysis of subgroups, the association between ibuprofen and
invasive GAS infection was restricted to children who had received both paracetamol and ibuprofen.
Additionally, the risk of necrotising soft tissue infection was not associated with the use of ibuprofen.
Several other risk factors for invasive GAS infection were identified in this study including persistent
high fever. The authors of this study concluded that the data was too confounded to determine if
NSAID use resulted in an increased risk of non-necrotising GAS infection and that NSAID use was
not associated with necrotising GAS infections. It cannot be ruled out that patients with worse
infections may be more likely to receive NSAIDs as a result of the severity of their infection.
A retrospective cohort study of 89 cases of dermatologic superinfection among 7,013 children with
recent varicella infection found that children dispensed ibuprofen before varicella were 3.1 times more
likely to be diagnosed with a superinfection (11). There was no way in the study to confirm whether
ibuprofen was taken or not, nor to establish whether ibuprofen may have been consumed from other
sources. The authors noted that the study was not sufficiently powered to resolve the question of
whether use of ibuprofen increases the risk of bacterial superinfections associated with varicella, and
that a much larger study would be required with greater NSAID exposure prevalence. The authors
concluded that the results were consistent with a broad range of effects, including no association.
Another case control study reported that ibuprofen use was associated with necrotising fasciitis in the
setting of primary varicella (14). However, the number of participants in this study was small (n=19)
and only 9 cases were exposed to ibuprofen. Therefore the significance of these results is uncertain.
Finally a retrospective case control study analysed 38 cases of necrotising soft tissue infections
(NSTI) against 228 random controls (3). 25 of the cases of NSTI were exposed to ibuprofen and 24
presented with varicella. There were strong associations between NSAID use and NSTI, particularly
in children (under 15 years) with varicella treated with ibuprofen. However the number of cases was
very low and the study had several limitations, so it was not possible to conclude that NSAIDs
increased the risk of necrotising complications.
As can be seen from the above studies, an association between NSAID use and the progression of
varicella infection to severe skin reactions has been reported. However a confounding factor is
present in all these studies, as patients with more severe disease or with secondary complications
could be more likely to receive NSAIDs as a result of their illness. Therefore NSAIDs may be given as
a response to severe infection in patients, rather than being the cause of the complication.
Nevertheless, an association has been reported in several studies and the possibility that NSAIDs
may increase the risk of severe secondary skin complications cannot be ruled out. Therefore it would
be wise to use these agents with caution and preferably avoid in children suffering from this infection.
Paracetamol is the recommended alternative for symptomatic management, however as for NSAIDs,
the risks of masking symptoms of severe infections must be considered (17).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Summary
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Associations between NSAID use in chickenpox (varicella) and severe skin and soft tissue
reactions have been reported in the literature, particularly with ibuprofen in children.
Not all patient information leaflets for paediatric preparations of ibuprofen contain warnings
regarding this association.
Although the majority of studies document an association between NSAID use and skin and
soft tissue complications, there are several limitations to the available evidence including
limited numbers of trial participants and the presence of confounding factors.
It is not certain that these reactions are a consequence of NSAID exposure. NSAIDs may be
given as a response to severe infection in patients, rather than being the cause of the severe
disease.
Due to repeated results suggesting a link between NSAIDs and skin and soft tissue
complications of varicella, these agents should be avoided in children suffering from this
infection.
Paracetamol is the recommended alternative for symptomatic management. However, like
NSAIDs, the risks of masking symptoms of severe infections must be considered.
Limitations
The majority of data from these trials analysed ibuprofen in paediatric patients with varicella. The
applicability of this information to other populations, including adult patients, may not be appropriate.
The evidence regarding the safety of agents other than NSAIDs for symptomatic management has
not been reviewed.
References
(1) Heininger U., Seward J.F. Varicella. Lancet. 2006; 368: 1365-76
(2) Stevens D.L. Could nonsteroidal antiinflammatory drugs (NSAIDs) enhance the progression
of bacterial infections to toxic shock syndrome? Clinical Infectious Diseases 1995: 21: 977–
980.
(3) Souyri C., Olivier P., Grolleau S. et al. Severe necrotizing soft-tissue infections and
nonsteroidal antiinflammatory drugs, Clinical and Experimental Dermatology, 2008: 33, 249255
(4) Summary of Product Characteristics for Fenpaed Ibuprofen 100mg/5ml suspension,
Pinewood Healthcare, Last updated 08/02/2016, Accessed via
www.medicines.org.uk/emc/medicine/24493 on 16/06/2016
(5) Summary of Product Characteristics for Boots Ibuprofen 3 Months Plus 100 mg/5 ml Oral
Suspension Strawberry Flavour, The Boots Company PLC, Last updated 12/04/2016,
Accessed via http://www.medicines.org.uk/emc/medicine/24512 on 16/06/2016
(6) Patient information leaflet for Boots Ibuprofen 3 Months Plus 100 mg/5 ml Oral Suspension
Strawberry Flavour, The Boots Company PLC, Last updated January 2016, Accessed via
http://www.medicines.org.uk/emc/PIL.24278.latest.pdf on 11/08/2016
(7) Summary of Product Characteristics for Ibuprofen 100mg/5ml suspension, Actavis UK Ltd,
Last updated 05/02/2016, Accessed via www.medicines.org.uk/emc/medicine/31303 on
16/06/2016
(8) Patient information leaflet for Ibuprofen 100mg/5ml suspension, Actavis UK Ltd, Updated May
2016, Accessed via http://www.medicines.org.uk/emc/PIL.31304.latest.pdf on 11/08/2016
(9) Summary of Product Characteristics for Nurofen for Children / Nurofen for Children Orange 3
months to 12 years, Reckitt Benckiser Healthcare (UK) Ltd, Last updated 02/10/14 Accessed
via http://www.medicines.org.uk/emc/medicine/20102 on 16/06/2016
(10)Patient information leaflet for Nurofen for Children 3months/9 years orange/strawberry
100mg/5ml oral suspension, Updated June 2014, Accessed via
http://www.medicines.org.uk/emc/PIL.23497.latest.pdf on 11/08/2016
(11)Choo P.W., Donahue J.G., Platt R., Ibuprofen and skin and soft tissue superinfections in
children with varicella, Annals of epidemiology, 1997: 7(7): 440-5
(12)Van den Anker J., Use of ibuprofen in paediatric populations, Journal of the Royal Society of
Medicine, 2007; 100(Suppl. 48):18-22
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
(13)Mikaeloff Y., Kezouh A., Suissa S., 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, 2007: 65(2): 203-9
(14)Zerr D.M., Alexander E.R., Duchin J.S. et al. A case-control study of necrotizing fasciitis
during primary varicella, Pediatrics, 1999: 103(4): 783-790
(15)Dubos F., Hue V., Grandbastien B. et al. Bacterial skin infections in children hospitalized with
varicella: a possible negative impact of non-steroidal anti-inflammatory drugs? Acta DermatoVenereologica, 2008:88:26-30
(16)Lesko S.M., O’Brien K.L., Schwartz B. et al, Invasive Group A Streptococcal infection and
nonsteroidal anti-inflammatory drug use among children with primary varicella. Pediatrics,
2001: 107(5): 1108-15
(17) NICE Clinical Knowledge summaries, Chickenpox, Last revised June 2015, Accessed via
http://cks.nice.org.uk/chickenpox#!prescribinginfosub:1 on 03/05/2016
Quality Assurance
Prepared by
Joshua McKie, Southampton Medicines Advice Service, University Hospital Southampton NHS
Foundation Trust
Contact
[email protected]
Date Prepared
20/06/2016
Checked by
Samantha Owen, Southampton Medicines Advice Service, University Hospital Southampton NHS
Foundation Trust
Date of check
11/08/2016
Search strategy
Electronic Medicines Compendium – Accessed via www.medicines.org.uk
Embase: [Nonsteroid anti-inflammatory agent/ and [Chickenpox or Herpes Zoster/]]
Medline: [Anti-Inflammatory Agents, Non-Steroidal/ and [Chickenpox or Herpes Zoster/]]
Micromedex
Martindale
AHFS
In-house database: MIDatabank enquiry number 259226
NICE CKS: Chickenpox – Analgesics/Antipyretics Last updated June 2015 Available online at
http://cks.nice.org.uk/chickenpox#!prescribinginfosub:1 Accessed 03/05/2016
Available through NICE Evidence Search at www.evidence.nhs.uk
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