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Successful treatment of eosinophilic gastroenteritis with suplatast tosilate To the Editor: We report the first case of eosinophilic gastroenteritis successfully treated with suplatast tosilate, a novel antiallergic drug that suppresses cytokine production, including IL-4 and IL-5 from TH2 cells.1-3 A 55-year-old man was admitted to our hospital with uncontrolled asthmatic symptoms. He had been given a prescription for theo- phylline and a short-acting inhaled β2-agonist on an as-needed basis at a local clinic. He had a 13-year history of asthma, chronic sinusi- tis, and urticaria and had several episodes of severe asthmatic attacks after the intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Laboratory data on admission revealed a white blood cell (WBC) count of 6000/µL with 6% eosinophils and a total IgE of 340 U/mL. Skin prick testing and specific IgE analysis were positive for Japan- ese cedar pollen. Lung function tests revealed an FEV1 of 78.1% of predicted, morning peak expiratory flow (PEF) of 43.9% of predict- ed, and PEF variability of 24.6%. Airway hyperresponsiveness and the diagnosis of aspirin-induced asthma were confirmed by provoca- tive methacholine and sodium tolmetin inhalation challenges, respec- tively. Urinary leukotriene (LT) E4 concentration was 1559 pg/mg creatinine, which was markedly higher than the mean value of 30 pg/mg creatinine of 5 subjects with non–aspirin-induced asthma. Fluticasone propionate 800 µg and pranlukast 450 mg, an LT-recep- tor antagonist, were added to his treatment regimen, and his symptoms gradually improved. After 4 weeks, lung function tests revealed a morn- ing PEF of 80.8% of predicted and PEF variability of 11.5%. The uri- nary LTE4 concentration was 36 pg/mg creatinine. Although asthmatic symptoms subsided at this time, he began to have recurrent abdominal pain and diarrhea of an unknown cause. Urticaria and slight wheezes occasionally accompanied the gastrointestinal symptoms. Abdominal radiography, CT, and ultrasonography findings were all normal. Fecal examination did not reveal any parasitic infestation. The eosinophil per- centage was elevated to 41% with a WBC count of 7900/µL, and serum eosinophil cationic protein was 54.0 µg/L (normal range < 15.7 µg/L). Upper and lower endoscopy findings were macroscopically normal, but gastric and colonic biopsy specimens revealed a diffuse, marked infil- trate of eosinophils (Fig 1), leading to the diagnosis of eosinophilic gas- troenteritis. Churg-Strauss syndrome was thought to be unlikely because of the absence of pulmonary infiltrates and neuropathy and by a normal erythrocyte sedimentation rate and a negative serum myeloperoxidase-antineutrophil cytoplasmic antibody. After the administration of 300 mg of suplatast tosilate without the discontinua- tion of the pranlukast, the patient made a good clinical recovery with resolution of gastrointestinal symptoms and rapid normalization of blood eosinophilia after 3 weeks. At follow-up 3 months after the ini- tial diagnosis, he remained asymptomatic. The eosinophil percentage was 4%, with a WBC count of 7200/µL. Suplatast tosilate—(±)-[2-[4-(3-ethoxy-2-hydroxy-propoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate—is a selective TH2 cytokine inhibitor that has inhibitory effects on allergen-induced eosinophilic infiltration, IgE production, and gob- let-cell metaplasia in mice.1-3 A recent double-blind randomized study reported a considerable steroid-sparing effect and effective- ness in treating steroid-dependent asthma,4 suggesting the useful- ness of this drug in the treatment of other allergic diseases in which eosinophils play an important role. Montelukast, an LT-receptor antagonist, has been reported to be effi- cacious in treating eosinophilic gastroenteritis.5 However, we speculate that it was unlikely that cysteinyl LTs were associated with the onset of the eosinophilic gastroenteritis in this patient because the LT antagonist was administered before the onset of gastrointestinal symptoms, and the urinary LTE4 level after treatment was decreased. Furthermore, it is unlikely that the pranlukast was the cause of eosinophilic gastroenteri- tis because the symptoms improved without discontinuation. In addi- tion to the ocular, nasal, and respiratory symptoms, patients with aspirin-induced asthma sometimes have gastrointestinal symptoms, including abdominal pain and diarrhea, after intake of NSAIDs.6,7 However, our patient differed from those patients in that no NSAIDs had been ingested. Further studies are needed to determine whether the development of eosinophilic gastroenteritis is associated with underly- ing aspirin-induced asthma and whether a TH2 cytokine inhibitor is effective in the treatment of allergic diseases, including eosinophilic gastroenteritis, in which eosinophils play a crucial role. Toshihiro Shirai, MDa Dai Hashimoto, MDa Kenichiro Suzuki, MDa Satoru Osawa, MDa Miyuki Aonahata, MDa Kingo Chida, MDb Hirotoshi Nakamura, MDb aDepartments of Internal Medicine and Pathology Fujinomiya City General Hospital 3-1 Nishiki-cho, Fujinomiya, Japan bSecond Department of Internal Medicine Hamamatsu University School of Medicine 3600 Handa-cho, Hamamatsu, Japan REFERENCES 1. Yamaya H, Basaki M, Tokawa M, Kojima M, Kiniwa M, Matsuura N. Down-regulation of TH2 cell-mediated murine peritoneal eosinophilia by antiallergic agents. Life Sci 1995;56:1647-54. 2. Zhao GD, Yokoyama A, Kohno N, Sakai K, Hamada H, Hiwada K. Effect of suplatast tosilate (IPD-1151T) on a mouse model of asthma: inhibition of eosinophilic inflammation and bronchial hyperresponsiveness. Int Arch Allergy Immunol 2000;121:116-22. 3. Shim JJ, Dabbagh K, Takeyama K, Burgel PR, Dao-Pick TP, Ueki IF, et al. Suplatast tosilate inhibits goblet-cell metaplasia of airway epithelium in sensitized mice. J Allergy Clin Immunol 2000;105:739-45. 4. Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al. Effect of suplatast tosilate, a TH2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 2000;356:273-8. 5. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast [letter]. J Allergy Clin Immunol 1999;104:506. 6. Bosso JV, Schwartz LB, Stevenson DD. Tryptase and histamine release Letters to the Editor FIG 1. Biopsy specimen of the descending colon showing diffuse eosinophilic infiltration of the submucosa (hematoxylin-eosin stain; original magnification ×300). 924 May 2001 J ALLERGY CLIN IMMUNOL J ALLERGY CLIN IMMUNOL VOLUME 107, NUMBER 5 Letters to the Editor 925 during aspirin-induced respiratory reactions. J Allergy Clin Immunol 1991;88:830-7. 7. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in patho- genesis and management. J Allergy Clin Immunol 1999;104:5-13. 1/8/114705 doi:10.1067/mai.2001.114705 Insect sting fatality 9 years after venom treatment (venom allergy, fatality) To the Editor: I am reporting to our readers a case of fatality after an insect sting in a patient who had previously received immunotherapy with venom. The patient had first had an adverse reaction in 1985. He had been a farmer most of his life. He was stung on the arm while in his truck. He drove a block to his home and felt as if his face were on fire. His wife, a nurse, gave him a pill (probably diphenhydramine HCl). He may have passed out for several seconds. Two days later he was stung by a swarm of bees after mowing over a nest. He went to his truck, took a Benadryl, and lay down for several hours. He drove about 10 miles to his home. His wife took his blood pressure, which was low. No hives were reported, and he had no difficulty breathing. His physician prescribed an adrenaline kit. He was tested for venom allergy in 1987. He was found to be sensi- tive to bee venom at the 0.1 µg/mL strength. After treatment options were discussed, he began venom immunotherapy with honey bee venom. He was retested in May of 1991, and his honey bee venom response decreasedat 1 µg/mL. We discussed the possibility of discon- tinuing venom immunotherapy based on the studies published at that time. I advise all patients to have adrenaline available even during venom treatment because of the small percentage of reactions. All patients who discontinue venom treatment are asked to have adrenaline available and to notify the office if any future stings occur. The patient continued therapy until June of 1991 (4 years and 3 months). He had tolerated a honey bee sting in November of 1990 without incident. The patient did not report any further stings or problems, although he was not seen for follow-up in the office. According to the newspaper, in June of 2000 while at the family farm, he was stung. He took a medication, which I believe was antihistamine, and called his wife, who called other relatives who lived nearby. The rel- atives arrived within 15 minutes, but CPR was unsuccessful, and he died. The patient was 72 years old. No details as to change in gen- eral health or whether any intervening stings occurred are known. The type of insect that stung the patient is not known. A Report of the Committee on Insects1 is a very thoughtful analysis of the information in the literature to assist the allergist in counseling his or her patient about the discontinuation of venom immunotherapy. I have great respect for the members of this com- mittee. This may be the first report of a patient who has had a fatal reaction after venom treatment. Should all patients continue immunotherapy indefinitely? Should all older patients continue immunotherapy indefinitely? I believe the patient should participate in choosing his or her own treatment given the information at hand. I will now counsel patients that it is possible for a very serious reac- tion to occur in the future but that the overall incidence of reactions is small based on the data from the literature. Wilma C. Light, MD Laurel Asthma and Allergy Associates 1100 Ligonier St Latrobe, PA 15650 REFERENCE 1. The discontinuation of Hymenoptera venom immunotherapy. Report from the Committee on Insects. J Allergy Clin Immunol 1998;101:573-5. 1/8/114985 doi:10.1067/mai.2001.114985 Fatal insect allergy after discontinuation of venom immunotherapy To the Editor: There are few reports of fatal and near-fatal reactions after dis- continuation of venom immunotherapy (VIT),1,2 and the case reported by Dr Light is a timely and harsh reminder that pitfalls abound in the management of insect sting allergy. Although early studies suggested that VIT could be stopped after 3 to 5 years, the cited Committee Report3 describes studies suggesting caveats to the previous guidelines, which are also reflected in recent practice param- eters.4 Significant risk factors include honeybee (versus vespid) allergy, less than 5 years of therapy, patient age, severity of the pre- VIT sting reaction, and any systemic reaction during therapy (either to a sting or a venom injection). The patient described by Dr Light had 4 of those 5 risk factors, which were, unfortunately, not yet rec- ognized in 1991 when he discontinued VIT. However, because they now exist in the literature, these reports should promote informed decisions by allergists and patients. We have stressed that the pas- sage of time and the development of negative venom skin tests do not guarantee that a sting will not cause a dangerous reaction. This case also illustrates 2 important principles. The first is the existence of epinephrine-resistant anaphylaxis5 such that carrying an epinephrine self-injector (EpiPen) is still not a guarantee of safety. Some patients experience rapid and abrupt hypotensive shock unre- sponsive to epinephrine or intravenous fluids, and such patients often have very low (or even undetectable) venom skin test sensitivity. The second principle is the difference in relative risk between the frequency of potential reactions and the severity of the reaction. Even when there is a low chance of having a reaction, that reaction could still be severe or fatal, particularly in high-risk patients. Of secondary interest are factors that could affect the outcome of similar cases, even though no information is available in this case. Was he receiving β-blockers or angiotensin-converting enzyme inhibitors at the time of the event? Had his maintenance dose been 50 or 100 µg? Did he get injections regularly for the full 4 years? Do we know the number of insects that stung him at his final reaction? Patients with severe insect allergy should have intermittent review by the allergist to assess the many factors that determine the outcome of a sting. Patients should be reminded to inform the allergist of any changes in their medical condition or treatment during or after VIT. There is no specific recommendation for re-testing after discontinu- ing VIT if the patient is stung but has no systemic reaction. Dr Light poses very reasonable questions about the potential need for indefinite VIT. The greatest risk exists in patients with the most severe history of reaction before VIT, and we have advised such patients to continue VIT indefinitely.2 It is less clear whether indefinite therapy should be considered simply because of other risk factors, but once again, the severity of the pre-VIT reaction will often determine the preferred choice. Most patients are still eligible to discontinue VIT after 5 years. Our approach is to inform patients who are considering dis- continuing VIT (1) that the chance of a systemic reaction will be about 10% per sting, even 10 to 20 years later, and even with negative venom skin test results; (2) that although most such reactions are mild, there is a small chance of a life-threatening reaction; and (3) that the only way to maintain the lowest risk (2%) is to continue to receive VIT. Finally, I must agree with Dr Light that patients should be fully informed of the potential risks and alternatives and should participate in the clinical decision to the best of their abilities. Clearly, further research is needed to define the factors that will most accurately predict which patients will have severe reactions to a sting, before or after VIT. David B. K. Golden, MD Johns Hopkins Allergy Center 5501 Hopkins Bayview Circle Baltimore, MD 21224
