Affiliations: Kyoto Prefectural University of Medicine, Kyoto, Japan,
Hospital Ramon y Cajal, Madrid, Spain
Correspondence to: Kenichiro Inoue, MD, Naka Central Hospital, 1733-1, Iida, Naka-cho, Naka-gun, 311-0134 Japan; e-mail: firstname.lastname@example.org
Martin-Garcia et al (June 2002)1–
have indicated the safety of a cyclooxygenase (COX)-2 inhibitor, rofecoxib, in patients with aspirin-induced asthma (AIA). The roles of COX-2 in allergen-induced lung inflammation remain poorly understood. When COX-1-deficient and COX-2-deficient mice are immunized with ovalbumin (OVA), lung inflammation indices (ie, number of cells in BAL fluid, proteins, IgE, and lung histology) are significantly greater in both mice than in wild-type mice.2
In contrast, the short-term inhibition of both COX-1 and COX-2 during allergen sensitization in BALB/c OVA-sensitized mice resulted in significantly greater airway hyperresponsiveness and higher levels of interleukin-13 in lung supernatants than was the case in untreated mice that had been OVA-sensitized.3
Although these murine models are not believed to be models of AIA, these two in vivo studies indicate that both the lack of COX genes during development and short-term COX inhibition may exacerbate allergic airway inflammation.
An increase in the release of cysteinyl leukotrienes (Cys-LTs) has been suggested to play a pivotal role in the pathogenesis of AIA. The decrease in prostaglandin E2 release due to aspirin-induced COX inhibition increases the level of Cys-LTs. A report4–
has demonstrated that Cys-LT protein is overexpressed in bronchial biopsy specimens from patients with AIA. It also has been documented that the increase in Cys-LT levels following aspirin stimulation is unique to patients with AIA, compared with aspirin-tolerant asthma patients and healthy control subjects.5
Therefore, large amounts of COX-2 inhibitor may cause the deterioration of asthmatic symptoms resulting from higher levels of Cys-LT concentrations in patients with AIA. Further careful experimental and clinical studies are needed to establish definitive guidelines for the safe use of COX-2 inhibitors in AIA.
We thank Dr. Ken-ichiro et al for their comments regarding our article that was published in CHEST (June 2002).1–
After going through the content of the letter, we would like to highlight that aspirin-induced asthma (AIA) is not mediated by allergic mechanisms but by the shared pharmacologic actions of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs).2–
So, the murine models of ovalbumin-induced bronchial hyperreponsiveness in mice with cyclooxygenase (COX)-1 and/or COX-2 knockout are not appropriate models of AIA. We agree that the biosynthesis of cysteinyl leukotrienes is up-regulated in AIA, but it is not clear that large amounts of COX-2 inhibitor may cause deterioration of asthmatic symptoms in patients with AIA. Rofecoxib was found to be well-tolerated by AIA patients and did not trigger cysteinyl leukotrienes and prostaglandin D2 release.3
Moreover, recent clinical reports4–6
have indicated the safety of using highly selective COX-2 inhibitors to treat AIA patients as well as NSAID-intolerant patients with urticaria and/or angioedema.
These findings may indicate that COX-2 inhibitors should play a major role in the treatment of pain and inflammation in AIA patients. Nevertheless, further challenge procedure studies performed with higher doses of rofecoxib and other highly selective COX-2 inhibitors in larger series of AIA patients will be necessary in order to determine the safety of using these new drugs in treating AIA patients. Until these studies have been carried out, we know that the usual daily doses of rofecoxib, 25 mg, do not appear to cause asthmatic attacks in patients with AIA and NSAID-induced asthma.
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