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Published: November 2000

Necrotising Fasciitis Associated with Non-Steroidal Anti-Inflammatory Drugs

Prescriber Update 20: 4-7
November 2000

Dr Lesley Voss, FRACP
Paediatrician to Infectious Diseases Services
Starship Children's Hospital, Auckland

For some time published case reports and case series have described cases of necrotising fasciitis (NF) in patients who have recently used an NSAID, and an association has been postulated.  Recently a case-control study gave further support to this postulate.  The study involved 19 children with NF and varicella infection and 29 control children with serious skin and soft-tissue infection and also with varicella.  The odds ratio for use of ibuprofen among those with NF was 5.0 (95% CI 1.03-26.6).

The mechanism by which NSAIDs increase the risk of NF may be by impairment of the immune response, or by masking of the symptoms of secondary infection, leading to delayed diagnosis and treatment.

Although the evidence for this association is weak due to the small number of case patients, it would be prudent to use ibuprofen with caution in children with varicella infection, particularly if there is a possibility of secondary infection.

Temporal association between NSAIDs and necrotising fasciitis in case reports

Necrotising fasciitis (NF) is a rare soft tissue infection most frequently due to group A β-haemolytic streptococcus, although a number of other organisms have been isolated.  Cases occurring in several countries over the last 10-15 years have suggested an association between this disease and the use of non-steroidal anti-inflammatory drugs (NSAIDs).1-5  Whether this effect is due to masking of symptoms of early NF by NSAIDs, or whether the frequent use of NSAIDs for nonspecific musculo-skeletal symptoms plays a role in the pathogenesis of NF, has not been clarified.

In New Zealand, a retrospective review undertaken at Dunedin Hospital found seven cases of NF over a 4.5 year period, five of whom had received NSAIDs prior to hospitalisation.4  The authors concluded that NSAIDs should be prescribed with caution in any patients with suspicion of infection.  They also expressed concern over whether the increased availability of NSAIDs as over-the-counter drugs results in an increase in cases of serious infection.

Case-control study: possible association between NSAIDs and NF in varicella

A case-control study conducted in Washington State and evaluating NF and ibuprofen use, investigated the use of ibuprofen and other risk factors for NF, in the setting of primary varicella.6  There is a well recognised risk of serious secondary group A streptococcal infections complicating chickenpox.7  Nineteen children with chickenpox and NF were compared with 29 control subjects who had serious soft tissue infection, other than NF, complicating varicella.  NF cases were five times more likely to have received ibuprofen before hospitalisation than controls (95% CI 1.03-26.6).  After adjustment for group A streptococcal isolation, age, and gender, the odds ratio increased to 10.2 (95% CI 1.3-79.5).  Other risk factors were also assessed including use of paracetamol, diphenhydramine, calamine lotion, pre-existing medical conditions, attendance at a day care, and duration of symptoms of secondary infection prior to hospitalisation.  No significant difference was found between cases and controls for these other risk factors.  A subset analysis of children with NF complicated by renal insufficiency and/or streptococcal toxic shock, markers of increased morbidity, found that these complicated cases were more likely to have used ibuprofen than were cases without complications (odds ratio 16.0; 95% CI 1.0-825.0).  These cases with complicated NF also had a longer duration of symptoms associated with secondary infection before hospitalisation than those with uncomplicated disease. 

A limitation of this study is the small patient numbers resulting in wide confidence intervals.  This study suggests an association between ibuprofen use and the development of NF among children with varicella, and also an association between ibuprofen use and severe complications of NF.

Mechanism: impairment of immune response or masking of symptoms?

Although, the underlying mechanism of the association of NSAIDs and increased severity of streptococcal infections has not been defined, some indications that NSAIDs may alter the biological response to infection have been identified in in vitro studies.  NSAIDs are cyclo-oxygenase inhibitors and may have an adverse effect on neutrophil killing and cell mediated immunity.  NSAIDs interfere with the function of lymphocytes2 and inhibit monocyte superoxide production.8  They have also been found to augment the production of certain cytokines such as TNF alpha, IL-1, and IL-6 which are mediators in shock.9 

However, other studies including a randomised controlled trial have shown that ibuprofen in sepsis can improve physiologic parameters.10  In this study of 455 patients with sepsis, although those receiving intravenous ibuprofen had reduced levels of prostacyclin and thromboxane with an improvement in some clinical parameters, there was no improvement in clinical course or subsequent outcome.10  Use of ibuprofen for 48 hours was associated with no detected adverse effects.

It has also been suggested that the use of NSAIDs may mask the symptoms of early infection, resulting in delayed diagnosis of NF and severe disease.  The Washington study, found that both cases and controls who used ibuprofen had a longer duration of secondary symptoms before hospitalisation, than cases and controls who did not receive ibuprofen.6  The authors postulated that the use of ibuprofen contributed to partial masking of symptoms with delay in diagnosis which resulted in more severe disease. 

Use ibuprofen with caution in varicella, particularly with secondary infection

In conclusion this recent case control study suggests an association between the use of ibuprofen and NF in children with primary varicella.  Further studies will be required to better define the association.11  The implications of these findings to the use of ibuprofen, and other NSAIDs, in situations where there is no varicella infection are not clear. At this time it is recommended that ibuprofen be used with caution in patients with chickenpox and particularly if soft tissue infection is suspected.

Editor's note : Serious skin and soft-tissue infections occurring following use of the NSAIAs are adverse reactions of current concern.

Correspondence to Dr Lesley Voss, Paediatrician to Infectious Diseases Services, Starship Children’s Health, Private Bag 92024, Auckland.  Phone 09 307 8900 Ext 6473, fax 09 307 4913, e-mail LesleyV@ahsl.co.nz

References
  1. Brun-Buisson CJL, Saada M, Trunet P, Rapin M, et al.  Haemolytic streptococcal gangrene and non-steroidal anti-inflammatory drugs.  BMJ 1985;290:1786.
  2. Krige JEJ, Spence RAJ, Potter PC, Terblanche J.  Necrotising fasciitis after diflunisal for minor injury. Lancet 1985; No.8469/70:1432-3.
  3. Rimailho A, Riou B, Richard C, Auzepy P.  Fulminant necrotizing fasciitis and nonsteroidal anti-inflammatory drugs.  J Infect Dis 1987;155:143-6.
  4. Rietveld JA, Pilmore HL, Jones PG, Theis J-C, Bowie DA, et al.  Necrotising fasciitis: a single centre's experience.  NZ Med J 1995;108:72-4.
  5. Frankish PD, Mason GH, Allen PR, Milsom FP, Christmas TI.  Acute streptococcal necrotising fasciitis.  NZ Med J 1988;101:625-6.
  6. Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE.  A case-control study of necrotizing fasciitis during primary varicella.  Pediatrics 1999;103:783-90.
  7. Peterson CL, Vugia DJ, Meyers HB, Chao SM, Vogt J, et al.  Risk factors for invasive group A streptococcal infections in children with varicella: a case control study.  Pediatr Infect Dis J 1996;15:151-6.
  8. Bell AL, Adamson H, Kirk F, McCaigue MD, Rotman H.  Diclofenac inhibits monocyte superoxide production ex vivo in rheumatoid arthritis.  Rheumatol Int 1991;11:27-30.
  9. Spinas GA, Bloesch D, Keller U, Zimmerli W, Cammisuli S.  Pretreatment with ibuprofen augments circulating tumor necrosis factor-α, interleukin-6, and elastase during endotoxinemia.  J Infect Dis 1991;163:89-95.
  10. Bernard GR, Wheeler AP, Russell JA, Schein R, et al.  The effects of ibuprofen on the physiology and survival of patients and sepsis.  N Engl J Med 1997;336:912-8.
  11. Zerr DM, Rubens CE.  NSAIDS and necrotizing fasciitis.  Ped Infect Dis J 1999;18:724-5.

 

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