July 1996
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On behalf of Whitehall-Robins Healthcare, makers of Advil (ibuprofen), I would like to respond to your article, entitled "Extreme pain at site of skin lesion could herald streptococcal toxic shock," in Infectious Diseases in Children dated January 1996. Although the article states a connection between the use of ibuprofen and invasive group A strep (GAS) disease has not been documented, a professor of pediatrics from Temple University is quoted recommending acetaminophen for the treatment of fever. I would like to respond to this issue by reviewing the information from the Seattle researchers and commenting on Dr. Long's statement.
The report of the 14 Seattle cases of invasive GAS was published in Pediatric Infectious Disease Journal, 1195, 14:588-94 by Dr. T. V. Brogan and colleagues. This report does not mention all the other medications besides ibuprofen that children were taking prior to developing the complications to varicella. In reality, most of the patients had received a variety of antipyretics and other medications. The antipyretic used most often was acetaminophen and not ibuprofen. There was insufficient data from the report or from chart review to implicate any particular medication in a casual relationship with the development of invasive GAS reported in those children. The absence of a link was recognized and publicly stated by Dr. Ben Schwartz of the Centers for Disease Control and Prevention in Atlanta, who stated in the Jan. 30, 1995 edition of USA Today, "They (the Seattle Health Department) haven't really shown any link between taking these drugs and subsequent disease."
In addition, it is important to note that this article was a report of a series of cases that were retrospectively reviewed and did not involve a placebo or control group. Finally, Dr. Long's statement recommending acetaminophen for the treatment of fever is shortsighted; ibuprofen may be used for treating the fever of infectious illness, including varicella; varicella is not a contraindication. A review of the literature does not substantiate an association between nonsteroidal anti-inflammatory drugs (NSAIDs) (specifically ibuprofen) and invasive GAS.
Ibuprofen continues to be a valuable treatment for children's fever.
I would appreciate your informing your readers of these points at the next available opportunity. If there are any questions or if you wish additional information, please contact me at your convenience.
Robert Melis, MD
Director, Medical and Clinical Affairs
Whitehall-Robins
Madison, N. J.
Coincident with increase in the incidence of severe, invasive infection caused by GAS, numerous case reports and a few case series have linked occurrence with use of NSAIDs.1-13 Two studies, although limited, have used case-control methodology, one reporting that 47% of 51 patients with necrotizing GAS cellulitis had received NSAID compared with 24% of 45 patients with uncomplicated cellulitis (p<0.05)9; and the other study (87 children with varicella, 25 of whom had invasive GAS) reporting an odds ratio of 8.29 for invasive GAS in NSAID users (confidence interval 0.62-442).13 These do not prove an association, much less a causal role. They do, however raise serious concern. Are NSAIDs the major contributing factor in invasion of streptococci during varicella? No, most children with this complication have not received NSAIDs. Is there biologic plausibility for adverse effect of NSAIDs? Yes. NSAIDs 1) suppress neutrophil chemotaxis, phagocytosis and bacterial killing; 2) augment production of tumor necrosis factor; 3) attenuate cardinal manifestations of inflammation, potentially delaying diagnosis.
If fever control is deemed necessary during the course of varicella, my stated preference for acetaminophen comes from a remarkable avenue of data. In the meticulously performed case-control studies in the early 1980s that proved the association of aspirin use and Reye syndrome, acetaminophen use appeared to protect against Reye syndrome and was not associated with any other adverse effect.15-17 Since many children in these studies had varicella (and almost all had viral illnesses), we do have specific data (as well as a long track record) with acetaminophen. What to do about the potential association of NSAIDs and invasive streptococcal disease reminds me of the early days of the potential association of aspirin and Reye syndrome. My answer is the same today as in 1978. Once a valid question has been raised, and until non-association with a highly fatal complication has been proved by careful prospective case-control study, why use a nonessential therapy, with no primary antiviral effect, that is potentially contributory?
In fact, as everyone knows from years of careful investigation, except as fever or an increased metabolic rate compromise an underlying condition, fever is good, a part of the upregulated host anti-infective response that participates in making viral infections "self-limited." In an era when therapeutic intervention seemingly is preferred to observation, I would wager that administering an antipyretic to a child with chickenpox satisfies the physician or parent's needs more than the child's. Finally, the resurgence of invasive group A streptococcal disease is strong incentive to eliminate varicella, through immunization.
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