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‚æ31"ƒ-01-‹Éﬁ¡łıﬁÖJourn. Dept. Educ., Teikyo Univ. 31: 1–6 Treatment of hypereosinophilic syndrome with the anti-allergic drugs
azelastine hydrochloride or fexofenadine, and biscoclaurine alkaloids*
Department of Education, School of Liberal Arts, Teikyo University 359 Otsuka, Hachioji-shi, Tokyo 192-0395 This is the first report which suggests the azelastine hydrochloride (AZE) or fexofenadine (FEX) HCL and biscoclaurine alkaloids (Cepharanthin®: CEPH) are useful in the treatment of hypereosinophilic syndrome (HES). A 9-year-old boy was referred to our hospital because of fever and a cutaneous eruption. His full blood examination showed a normal hemoglobin level with a leukocytosis of 66,400/µl with 95% mature eosinophils. There was no history of allergy, no clinical or serological evidence of a parasitic infection, and no evidence of a connective tissue disease, neoplastic disease, leukemia, or immunodeficiency. He was treated with prednisolone, which induced a rapid but not sustained remission.
CEPH was then given to reduce the dose of the intermittent courses of prednisolone required. AZE, prescribed by an otolaryngologist for perennial rhinitis when she was also receiving also CEPH, unexpectedly reduced and maintained the eosinophil count at normal levels. Ultimately AZE alone was tried, with this being ceased after 3.5 months, however five weeks after the discontinuation, the eosinophil count had risen again to >25,000/µl. After reinstitution of AZE with CEPH, followed by AZE alone, the patient did well for 30 months, so the AZE was ceased. Eleven months later the eosinophil count again rose. Reinstitution of AZE with CEPH in doses proportional to the weight increase which had occurred in the interim resulted in further disease control, however low dose steroid therapy needed to be added because the eosinophil count rose to >5,148/µl. In May 1993, FEX was given together with low- dose steroid therapy. On FEX alone, the patient did well for 5 months, then the eosinophil count rose to >7,943/µl. Low-dose steroid followed by FEX plus CEPH therapy was therefore started. This resulted in a complete resolution of symptoms. AZE or FEX, with or without CEPH might be effective in HES patients, enabling the adverse effects of long-lasting steroid therapy to be minimized.
Key words: azelastine hydrochloride, biscoclaurine alkaloids, fexofenadine, hypereosinophilic
vincristine, 6-mercaptopurine, cyclosporine, Hypereosinophilic syndrome (HES) is a disorder recombinant interferon alpha, allogeneic bone marrow characterized by a sustained eosinophilia of at least 6 transplantation, and imatinib.1-3 This paper reports the months duration, multiple organ system infiltration, and first case of HES that responded well to treatment with lack of evidence of known causes of eosinophilia.1, 2 the drug azelastine hydrochloride (Azeptin®: AZE) or Various modalities have been used to treat HES, fexofenadine HCL (Allegra®: FEX), and biscoclaurine including corticosteroids, hydroxyurea, leukopheresis, alkaloids (Cepharanthin®: CEPH).
*This paper was presented at the World Allergy Organization Congress, June 2005, Munich.
A previously healthy 9-year-old Japanese boy was Ito : Treatment of hypereosinophilic syndrome with the anti-allergic drugs Fig. 1. Clinical course of a 9-year-old boy with hypereosinophilic syndrome
Journ. Dept. Educ., Teikyo Univ. 31 (March 2006) taken to his local physician because of a 4-day history of WBC count 66,400/µl with 1% banded neutrophils, 4% fever. The fever persisted, and a cutaneous eruption lymphocytes and 95% eosinophils (actual eosinophil associated with pruritus developed 5 days later. The count was 63,080/µl); platelet count 270,000/µl; child's initial white blood cell (WBC) count revealed a erythrocyte sedimentation rate 66mm/h; a normal leukocytosis (18,800/µl) and marked eosinophilia leukocyte alkaline phosphatase level; and no (10,500/µl or 56%). He was referred to our hospital on chromosomal abnormalities (Table 1). A bone marrow April 25, 1996. His birth weight was 3,250g, and his aspirate was normocellular with 70% mature birth and medical history were unremarkable. The family eosinophils. No abnormal cells were present.
had no pets, and there was no history of travel before the Immunoglobulin G (IgG), IgA, IgM and IgE levels were onset of the rash. Both parents were healthy. Physical all normal. Stool analyses for ova and parasites were examination findings were unremarkable except for negative. Titers for visceral larva migrans were also small cervical lymph nodes.
Laboratory data showed: hemoglobin 12.0 g/dl; Laboratory data at first visit Banded neutrophils Mature eosinophils IgE, IgG, IgA, IgM Nucleated cell counts Mature eosinophils No malignant cells Leukocyte alkaline phosphatase Lymphocyte subsets CD4 14.5%, CD8 20.5%, CKDR 46.4%, CD24 34.6%, CD38 84.1%, CD11b 1.3%, CD34 3.5% Chromosome analysis Ova and parasites Visceral larva migrans On April 25 1996, oral prednisolone (2 mg/kg per after its commencement. The patient then did well day) was begun (Fig 1). The eosinophil count began to without any therapy until October 1996, at which time decrease on day 2, and had decreased to 124/µl on day 6.
the eosinophil count was found to have risen to The steroid was then tapered and discontinued 14 days >20,000/µl. Prednisolone (1 mg/kg per day orally) was Ito : Treatment of hypereosinophilic syndrome with the anti-allergic drugs restarted. The eosinophil count again decreased rapidly, the lack of response to these drugs might have been due and the steroid was tapered and stopped within the next to an underdose because the patient's weight had 10 days. This short course steroid therapy was repeated doubled during the intervening six years, the doses were again 2 months later. doubled; AZE dose was increased to 2mg twice daily, In February 1997, 9.5 months after the treatment and CEPH to 14 0mg per day. After increasing the was started initially, a fourth episode of worsening of doses, the disease was well controlled. AZE and CEPH eosinophilia was defined. Following the obtaining of were ultimately ceased again in August 2002. parental consent, CEPH4 treatment was begun in oral In January 2003, five months after the discontinuation of doses of 70 mg (1.5 mg/kg) per day in an attempt to drugs, the eosinophil count had risen to >5,148/µl. Low- decrease the steroid dose administered, with the dose steroid therapy followed by AZE and CEPH prednisolone being given in a dose of 0.05-0.5 mg/kg therapy was restarted. In May 2003, FEX in oral doses per day for 14 days. Because of increasing eosinophil of 60 mg twice daily was given together with a tapered counts and the development of an urticarial rash, this low-dose steroid course. FEX alone was continued after combination therapy was repeated on four occasions at this combined therapy and the patient did well for next 5 intervals of 1-2 months.
months, however in November, the eosinophil count had In October 1997, 17.5 months after the patient was risen to >7,943/µl. Low-dose steroid followed by FEX first seen, AZE in dose of 1mg twice daily, orally, was plus CEPH therapy was therefore started, with this given by an otolaryngologist because of perennial resulting in a complete resolution of symptoms until rhinitis. At this time the CEPH was still being administered. AZE is an anti-allergic drug that inhibits the release of various chemical mediators from mast cells, and it has been widely used in Japan.5 The criteria for the diagnosis of HES as outlined by Surprisingly, two weeks after starting the AZE, the Chusid et al.1 are: (1) a persistent eosinophilia of eosinophil count had decreased from 3,038/µl to 710/µl.
1,500/µl for longer than 6 months; (2) lack of evidence Since the patient was doing well for the next 5 weeks on of any known cause of eosinophilia; and, (3) evidence of AZE and CEPH, the CEPH was ceased. On AZE alone, organ system involvement. Many diseases are associated the eosinophil count remained controlled for the next 2.5 with various degrees of eosinophilia.2 Our patient had no months, so the AZE was discontinued in January, 1998.
history of allergy, no clinical or serological evidence of a Five weeks later, the eosinophil count had risen to parasitic infection and no evidence of connective tissue disease, neoplastic disease, leukemia, or AZE with low-dose prednisolone was restarted, with the steroid being tapered and ceased after 14 days.
Various therapeutic strategies for HES have been CEPH was restarted in April, because of a slight increase reported. Prednisolone has been the drug of choice if the in eosinophil count while on AZE as single therapy. The patient manifests significant symptomatology. In our disease was then well controlled for 10 months before patient, the blood eosinophilia was rapidly suppressed by the CEPH was again discontinued in January 1999. On a short course of this drug. However, 2-4 months after AZE alone, the patient did well for next 21 months, so the cessation of the steroid, the eosinophil count the AZE was ceased. Eleven months later the eosinophil increased again. In an attempt to decrease the steroid count had again risen, this time to a level of >7,965/µl.
dose, CEPH treatment was started in February 1997.
AZE with low-dose prednisolone was again restarted, CEPH is a partially purified alkaloid preparation of with the steroid tapered and stopped after 14 days.
Stephania cepharantha Hayata and is mainly composed CEPH was also added, because of an increase in of six alkaloids.4 CEPH has been to be effective for eosinophil count. This combination therapy was repeated increasing platelet counts in patients with chronic idiopathic thrombocytopenic purpura, and is used as a In April 2002, after considering the possibility that drug for reducing the steroid dosage required.6 By using Journ. Dept. Educ., Teikyo Univ. 31 (March 2006) CEPH in our patient, it seemed that the dose of the drowsiness. So far, the efficacy of FEX seems to be steroid could be decreased, but still the steroid therapy similar to that of AZE.
could not be discontinued.
Interleukin (IL)-5 in humans is restricted to The administration of CEPH together with AZE in stimulating eosinophil production. In our patient, the April 1998 lead to a decrease in the slightly elevated serum IL-5 level was high at the time of the first visit eosinophil count and this was maintained while on AZE (Table 1), and thereafter the increased number of single therapy; however a relapse occurred 11 months eosinophils in the blood correlated the high level serum after its cessation. In April 2002, the reinstitution and IL-5 levels (data not shown). Konno et al.10 have doubling the doses of CEPH together with AZE again reported that IL-2, IL-3, IL-4 and IL-5 production from lead to maintenance of a normal eosinophil count. In blood leukocytes was strongly suppressed when the cells November 2003, after the reinstitution of CEPH together were cultured in the presence of anti-allergic agents such with FEX, a normal eosinophilic count was maintained as AZE, terfenadine, ketotifen, oxatomide, and sodium again, however the role of CEPH in achieving this is cromoglycate; a significant decrease in blood eosinophil counts after the administration of AZE11 and a AZE, which was given by an otolaryngologist, was suppressive effect of terfenadine on eosinophilia has also unexpectedly effective in this patient. The efficacy of been reported.12 It is therefore likely that AZE and FEX AZE seemed to be apparent for the following reasons: 1) might have suppressed the secretion of after starting administration of this drug a normal eosinophilopoietic cytokines in our patient. eosinophil count was maintained for 3.5 months, in As shown in Table 1, the increased percentage of contrast to the relapse that occurred in the 1-2 month OKDR-positive lymphocytes in the bone marrow, and interval without AZE during the period of therapy with the high level of serum IL-5 in this patient, suggest the CEPH and prednisolone, 2) stopping the administration presence of activated T cells. The increased number of of this drug led to an increase in the eosinophil count, 3) mature eosinophils exhibiting occasional hypodense reinstitution of therapy with AZE plus CEPH, followed phenotypes is suggestive of eosinophil activation. The by AZE alone, led to a normal eosinophil count which clonal proliferation of type 2 helper T cells secreting IL- was maintained for the next 29 months, 4) in April 2002, 4 and IL-5 may contribute to the eosinophilia in HES8, 9, after reinstitution and doubling the doses of AZE and although it could be due to an immune reaction triggered CEPH, a normal eosinophil count was maintained again, by an as yet unknown antigenic stimulus leading to the 5) in January 2003, reinstitution of therapy with AZE release of IL-2, IL-3, IL-4, and IL-5 by activated T cells plus CEPH led to a normal eosinophil count.
resulting in stimulation of eosinophilopoiesis.3 In January 2003, FEX, the main active metabolite Also of interest in our patient, was the fact that an of terfenadine, was given in the place of AZE in the exacerbation of eosinophilia was also seen in association expectation of a lessening of the side-effect of with some viral infections including influenza. Analyses Fig. 2. Immunofluorescence analysis of T-cells
Ito: Treatment of hypereosinophilic syndrome with the anti-allergic drugs of circulating CD25+ T cells, on 16/12/2003 when he mucosa in bronchial asthma-suppression of cytokine had a viral infection, showed that both CD4+CD25+ T mRNA. Arerugi 1998; 47(6): 604-13 (in Japanese).
cells and CD3+CD25+ T cells were present at 9%; this Cogan E, Schandene L, Crusiaux A, Cochaux P, is consistent with T cell activation which may in turn Velu T, Goldman M. Clonal proliferation of type 2 have induced the eosinophilia (Fig.2). Recently, IL-5- helper T cells in a man with the hypereosinophilic producing T cells subsets have been identified in some syndrome. N Engl J Med 1994; 1330: 535-8.
patients with HES,13 however such abnormal clones Takamizawa T, Iwata T, Watanabe K et al. Elevated were not identified in our patient.
production of interleukin-4 and interleukin-5 by T In the present study, no adverse effects were cells in a child with idiopathic hypereosinophilic observed during AZE or FEX with or without CEPH syndrome. J Allergy Clin Immunol 1994; 93: 1076- therapy. AZE or FEX with or without CEPH might therefore be useful in preventing eosinophil-induced 10 Konno S, Asano K, Okamoto K, Adachi M.
organ damage and secondarily to prevent the side effects Inhibition of cytokine production from human of long-term corticosteroid therapy which might peripheral blood leukocytes by anti-allergic agents otherwise be required. Further studies are necessary to in vitro. Eur J Pharmacol 1994; 264(3): 265-8.
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