An Association Between Ibuprofen Use and Necrotizing Fasciitis
June 1, 1999
An Association Between Ibuprofen Use and Necrotizing Fasciitis
ABSTRACT & COMMENTARY
Synopsis:These data add to the literature suggesting an association between ibuprofen use and the development of Necrotizing Fasciitis (NF) and complicated NF in previously healthy children with varicella.
Source: Zerr DM, et al. Pediatrics 1999;103:783-790.
Zerr and colleagues set out to investigate ibuprofen use and other risk factors for Necrotizing Fasciitis (NF) in the setting of varicella in children. Data are from December 1993 through June 1995—a time period in which ibuprofen was a prescription-only medication. Nineteen previously healthy children diagnosed with NF within three weeks of varicella were included in the study. Controls were 29 previously healthy children hospitalized for serious soft-tissue infections other than NF complicating varicella. All subjects were admitted to the same hospital. Data were reviewed from the inpatient charts, and interviews were conducted with the subjects’ parents, most often within one month of hospitalization.
Prior to hospitalization, cases and controls did not differ in clinical manifestations of fever, pain, swelling, and erythema, and were also similar in their use of acetaminophen, antibiotics, and other symptomatic treatments. In the majority of subjects, ibuprofen was started after the onset of symptoms of secondary infection.
Ibuprofen was used prior to hospitalization in nine of the 19 cases, compared with just four of the 29 controls (odds ratio 5.0; 95% confidence interval, 1.03-26). Similar numbers of doses of ibuprofen were taken by cases and controls. This association did not change when only subjects with documented group A streptococcal infections were analyzed; eight of 16 cases used ibuprofen compared with zero of eight controls (P = 0.02). Even after controlling for age, gender, and group A streptococcal infection, cases were 16 times more likely than controls to have used ibuprofen prior to hospitalization. Cases with NF complicated by renal insufficiency or toxic shock syndrome were 16 times more likely to have used ibuprofen than cases with uncomplicated NF.
Comment by Leonard Friedland, MD
These data add to the literature suggesting an association between ibuprofen use and the development of NF and complicated NF in previously healthy children with varicella. The use of a control group of hospitalized children with varicella with serious soft-tissue infections was an excellent choice, as these children should have been just as likely as the cases to receive prehospitalization prescription ibuprofen for their pain and fever.
In the majority of subjects, ibuprofen was started after the onset of symptoms of secondary infection. This could imply that ibuprofen’s antipyretic and anti-inflammatory effects might mask symptoms and contribute to a delay in diagnosis. Indeed, both cases and controls who used ibuprofen had a longer duration of secondary symptoms than cases and controls who did not use ibuprofen. It is also possible that ibuprofen was more likely to be used by those who went on to develop NF because NF causes more pain and fever than the other serious soft-tissue infections. However, cases and controls were equally as likely to use acetaminophen and other symptomatic treatments.
Is there an explanation, other than masking disease recognition, for why ibuprofen may contribute to the development of NF and complicated NF? NSAIDs can inhibit neutrophil function (adherence, phagocytosis, and bactericidal activity) and augment inflammatory cytokine production (increasing levels of tumor necrosis factor a and interleukins 1 and 6). These effects may contribute to the sudden onset of shock, organ failure, and fulminant evolution of soft-tissue infections in susceptible patients. Patients with varicella may be particularly susceptible as the varicella lesions alter the skin barrier and can allow bacteria to enter.
Until large-scale trials can be performed that investigate the relationship between NSAID use and severe bacterial infections, including NF in patients with varicella, clinicians should be leery of using ibuprofen in children and adults with varicella. Acetominophen should be used as the analgesic and antipyretic for patients with varicella. In addition, be suspicious for severe secondary infections in patients with varicella, especially those with focal pain, swelling, erythema, refusal to bear weight/move an extremity, or fever beyond the third day of illness. (Dr. Friedland is Associate Professor of Pediatrics and Medicine, Director of Pediatric Emergency Medicine, Temple University Childrens Medical Center, Philadelphia, PA.)
In children with varicella, all of the following are correct except:
a. acetaminophen is not the analgesic and antipyretic of choice.
b. there appears to be an association between ibuprofen use and the development of necrotizing fasciitis.
c. ibuprofen's anti-inflammatory effects may mask signs of serious disease progression.
d. physicians should be suspicious for the development of serious secondary bacterial infections.
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