Leukotriene B₄ (LTB₄) is a lipid mediator with potent chemoattractant properties and that is rapidly generated from activated innate immune cells such as neutrophils, macrophages, and mast cells. Elevated levels of LTB₄ have been reported in various allergic diseases and these levels have been related to disease activity and response to treatment. Recent studies using LTB₄ receptor-1 (BLT1) antagonists or BLT1-deficient mice have revealed that ligation of BLT1 by LTB₄ is important for the activation and recruitment of inflammatory cells including neutrophils, eosinophils, monocytes/macrophages, mast cells, dendritic cells, and more recently, effector T cells to inflamed tissues in various inflammatory diseases. The LTB₄/BLT1 pathway appears to play an important role in the pathogenesis of severe persistent asthma, aspirin- and exercise-induced asthma, allergic rhinitis, and atopic dermatitis together with other mediators including cysteinyl leukotrienes, cytokines, and chemokines. LTB₄ production is in general resistant to corticosteroid treatment. In fact, corticosteroids can upregulate BLT1 expression on corticosteroid-resistant inflammatory cells such as neutrophils, monocytes, and effector memory CD8⁺ T cells. As a result, this corticosteroid-resistant LTB₄/BLT1 pathway may contribute to the development of inflammation in allergic diseases that do not respond to the introduction of corticosteroids. Inhibition of this pathway has potential therapeutic benefit in various allergic diseases that have involvement of corticosteroid-insensitivity.

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Asthma pathobiology is remarkable for chronic airway inflammation that fails to spontaneously resolve. No curative therapy is currently available. A growing body of evidence indicates that, in health, inflammation resolution is an active process orchestrated by specific chemical mediators that are elaborated to restore tissue homeostasis. Activated cell membranes release polyunsaturated fatty acids from phospholipids for enzymatic conversion to biologically active mediators with profound regulatory effects on innate and adaptive immunity. Some of these mediators carry anti-inflammatory and pro-resolving actions that are transduced in a cell-type specific manner via specific recognition sites that initiate regulatory intracellular signals, such as presqualene diphosphate remodeling, to limit pro-phlogistic cell activation. Some of these counter-regulatory lipid mediators have been identified in the airway during asthma and defects in their production are associated with disease severity. In this review, we describe the biosynthesis and bioactions of pro-resolving chemical mediators and provide examples of select mediators and their structural analogs with particular relevance to asthma.

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Prostaglandin D₂ (PGD₂) is one of the most abundant lipid mediators present in the airways of asthmatics. However, little was known of the role it plays in the pathophysiology of asthma, until the identification of DP (DP1, PTGDR) and CRTH2 (DP2), two PGD₂-specific transmembrane receptors with different distribution and intracellular signaling. Pharmacological tools, such as receptor-specific agonists and antagonists, and genetically-engineered mice, which lack either DP or CRTH2, have helped understand the complex effects of PGD₂ in allergic inflammation of the airways. Furthermore, genetic association studies have shown a positive linkage of the genetic polymorphisms in DP and CRTH2, with asthma phenotypes from specific ethnic backgrounds, further highlighting the importance of PGD₂ and its receptors in the pathophysiology of asthma.

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Cysteinyl leukotrienes (CysLTs: leukotrienes C₄, D₄, and E₄) have long been implicated in the pathogenesis of asthma and several allergic diseases. LTE₄ has been identified as a major metabolite of LTC₄, and urinary LTE₄ (U-LTE₄) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From recent studies on the U-LTE₄ associated with adult stable asthma we identified four factors for hyperleukotrieneuria, namely, aspirin intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP, there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin sensitivity, and ENP is the most important factor for the overproduction of CysLTs in asthmatics. We also demonstrated that anaphylaxis and eosinophilic pneumonia (EP) are associated with a marked increase in the U-LTE₄ concentration. Under these disease conditions, U-LTE₄ may be one of the candidate biomarkers. Moreover, the changes in U-LTE₄ concentrations may provide valuable information concerning therapeutic targets.

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Background: Pollen information is indispensable for allergic individuals and clinicians. This study aimed to develop forecasting models for the total annual count of airborne pollen grains based on data monitored over the last 20 years at the Mie Chuo Medical Center, Tsu, Mie, Japan.
Methods: Airborne pollen grains were collected using a Durham sampler. Total annual pollen count and pollen count from October to December (OD pollen count) of the previous year were transformed to logarithms. Regression analysis of the total pollen count was performed using variables such as the OD pollen count and the maximum temperature for mid-July of the previous year.
Results: Time series analysis revealed an alternate rhythm of the series of total pollen count. The alternate rhythm consisted of a cyclic alternation of an "on" year (high pollen count) and an "off" year (low pollen count). This rhythm was used as a dummy variable in regression equations. Of the three models involving the OD pollen count, a multiple regression equation that included the alternate rhythm variable and the interaction of this rhythm with OD pollen count showed a high coefficient of determination (0.844). Of the three models involving the maximum temperature for mid-July, those including the alternate rhythm variable and the interaction of this rhythm with maximum temperature had the highest coefficient of determination (0.925).
Conclusions: An alternate pollen dispersal rhythm represented by a dummy variable in the multiple regression analysis plays a key role in improving forecasting models for the total annual sugi pollen count.

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Background: The differentiation of Th1 and Th2 is strictly regulated by humoral and cellular factors. The imbalance between Th1 and Th2 is considered to be the pathogenesis of allergic and autoimmune disorders. It is important to elucidate the effect of environmental factors, such as temperature, on the expression of cytokines of Th1 and Th2.
Methods: We investigated the expression of IFN-gamma, IL-4, IL-5, IL-10 and IL-12 from LPS- or PHA-stimulated PBMCs at 30°C or 37°C using ELISA and Real-time PCR. We measured the change of NF-kappaB activity at 30°C or 37°C with LPS stimulation using the reporter gene assay.
Results: IFN-gamma production from LPS-stimulated PBMCs at 30°C was up-regulated compared with 37°C. IL-5 and IL-10 production from PHA-stimulated PBMCs at 30°C were down-regulated compared with 37°C. This augmented IFN-gamma production was caused by the up-regulation of IL-12 production from CD14⁺ blood monocytes. Both IL-12 mRNA and IL12 protein at 30°C were up-regulated compared with 37°C. NF-kappaB, the key molecule for the expression of IL-12, was also augmented at 30°C compared with 37°C.
Conclusions: Hypothermia up-regulated the expression of IL-12 and IFN-gamma due to the augmented NF-kappaB activity. It is suggested that hypothermia modifies the pattern of cytokine gene expression.

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Background: The Asthma Health Questionnaire (AHQ)-Japan is useful for assessing quality of life (QOL) in Japanese patients with asthma. However, no studies have compared the AHQ-Japan to other QOL instruments.
Methods: The AHQ-33-Japan and the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) were completed simultaneously by 126 Japanese patients with asthma (48 men, 78 women; 58.1 ± 17.3 years of age), and the data were compared.
Results: Poor negative correlations (correlation coefficient (r) = -0.20 to -0.44, P < 0.05) were observed for 38 combinations of the subscales of these QOL instruments. As the severity of the patients' asthma increased, the scores of most subscales of both QOL instruments became worse. However, the AHQ-33 was more sensitive for severity than the SF-36. On logistic regression analysis, high Asthmatic Symptoms, Factors which Worsened Symptoms, Emotion, Daily Activity, and Social Activity subscale scores, as well as a high total 32-item score, of the AHQ-33 were associated with an increased risk of moderate to severe asthma. On the other hand, only the Physical functioning subscale score of the SF-36 was associated with an increased risk of moderate to severe asthma.
Conclusions: Our results show that the AHQ-33 is useful as a disease-specific QOL instrument in Japanese patients with asthma and that it is better than the SF-36, which is a generic QOL instrument. In the future, the AHQ-33 should be compared to other asthma-specific questionnaires.

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Background: The histamine releasing test which detects histamine released from basophils in vitro is safe, sensitive and widely used for clinical examination in the field of allergy. However, basophils of certain individuals do not release histamine, because of dysfunctions in their intracellular signal transduction (non-responder). To overcome potential shortcomings of the histamine releasing test, we applied surface plasmon resonance (SPR) to detect the activation of basophils.
Methods: Basophils of patients with allergy, and those of non-allergic volunteers were isolated from peripheral blood. A batch of basophils obtained from a healthy volunteer was treated with lactic acid and IgE of a patient with atopic dermatitis in order to replace their endogenous IgE. They were fixed on the sensor chip of the SPR apparatus, pretreated with or without various inhibitors for intracellular signal transduction, and exposed to the antigens or anti-IgE antibody.
Results: When basophils were sensitized with antigen specific IgE, they immediately caused the increase of resonance angle (AR) in response to either anti-IgE antibody or corresponding antigens, even when they did not release histamine. Moreover, the dose dependent reactions of basophils were reflected by the increase of AR as well as the release of histamine. The increase of AR in response to anti-IgE antibody was reduced by pre-treatment of basophils with inhibitors for intracellular signal transduction, but not more than the level for histamine release.
Conclusions: SPR biosensors may be superior to the histamine release test for studying functions of human basophils including those not releasing histamine.

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Background: In young children with wheezing or bronchiolitis, especially with respiratory syncitial virus, blood eosinophilia and a high eosinophil cationic protein level in nasal secretions predicts subsequent wheezing in later childhood. However, whether eosinophil activation results from virus-induced inflammation or local eosinophilia per se precedes the onset of wheezing remains unknown. In the present study, we examined the association between the presence of nasal eosinophils during respiratory tract infection (RTI) and subsequent wheezing in young children.
Methods: A total of 35 young children less than 3 years of age who visited our outpatient clinic with rhinorrhea between April and July 2004 were enrolled in this prospective cohort study. Subjects who were given diagnoses of allergic rhinitis were excluded. In all the subjects, the presence of eosinophils in nasal secretions was determined. The subjects were followed, and the cumulative incidences of wheezing during the subsequent 2- and 12-month periods were examined.
Results: According to a logistic regression analysis adjusted for age, sex, family history, allergies, and wheezing at entry, young children with nasal eosinophil infiltration during acute RTI had a significantly higher risk of wheezing during the subsequent 2 months, compared with those without nasal eosinophil infiltration (adjusted odds ratio, 27.618, p = 0.016).
Conclusions: Our findings not only suggest that nasal eosinophil testing may serve as a convenient clinical marker for identifying young children at risk for subsequent wheezing, but also shed new light on the role of eosinophils in the onset of wheezing in young children.

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Background: While interleukin-18 (IL-18) plays an important role in the innate and adaptive immune responses, it can also cause severe allergic inflammatory reactions. Thus it is a molecule currently being targeted for therapy. The natural intrinsic inhibitor of IL-18 receptor activation, IL-18 binding protein (IL-18BP), shows a great potential for the treatment of allergy.
Methods: Expression and purification of recombinant human IL-18BP (rhIL-18BP) were performed using the baculovirus system to develop a therapeutic molecule for the treatment of IL-18-related diseases and to investigate the structural basis of its inhibitory mechanism.
Results: Purified rhIL-18BP potently inhibited the production of interferon-gamma by peripheral blood mononuclear cells in the presence of lipopolysaccharide and by human myelomonocytic KG-1 cells in the presence of IL-18 (IC50 = 0.4 nM). Surface plasmon resonance showed a high affinity (Kd = 0.46 nM) for rhIL-18BP in binding hIL-18. Structural analysis indicated that the stoichiometry between IL-18 and IL-18BP is 1 : 1 in solution and the model structure of the complex suggests that the key residues on IL-18 (L5, K53, S55) and the estimated key residues on IL-18BP (F93,Y97, F104) could have interactions. The structural mechanism of IL-18BP inhibition might be a competition for Site 2 on rIL-18 so that IL-18BP can prevent IL-18 receptor alpha from binding to Site 2 and inhibit IL-18 receptor activation.
Conclusions: IL-18BP has unique features with respect to its structure, binding mode and inhibitory mechanism. It is a molecule that has a great potential for the therapy of allergy.

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Background: We have previously shown that short-course treatment with Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) before the ragweed season modifies the response of the nasal mucosa to allergen challenge in ragweed-sensitive patients by increasing Th1 cytokines and decreasing both Th2 cytokines and eosinophilia after the ragweed season. The effect of AIC immunotherapy on CD4⁺CD25⁺ T cell expression in the nasal mucosa is unknown.
Objective: To determine the in vivo effect of short-course AIC immunotherapy on CD4⁺CD25⁺ regulatory T cells in the nasal mucosa of ragweed-sensitive subjects.
Methods: 19 ragweed-sensitive patients with allergic rhinitis were randomly assigned to receive either 6 escalating doses of AIC (0.06-12μg; n = 12) or placebo (n = 7) at weekly intervals immediately before the 2001 ragweed season. Nasal biopsies were taken at baseline prior to immunization and again post immunization 24 hours after ragweed allergen challenge at the start and end of the ragweed season. The expression of T regulatory cells, IL-10 and TGF-β was assessed at each time point by immunohistochemistry.
Results: The numbers of allergen-induced CD4⁺-, CD4⁺CD25⁺-, IL-10- and TGF-β-positive cells in the nasal mucosa after AIC immunization before the ragweed season did not differ between the two groups. Repeat challenge after the ragweed season led to a significant increase in CD4⁺CD25⁺ cells in AIC-compared with placebo-treated subjects. A trend toward an increase in IL-10-positive cells in the AIC-treated group did not reach statistical significance.
Conclusions: Short-course AIC immunotherapy increases CD4⁺CD25⁺ regulatory T cell infiltration in the nasal mucosa following allergen challenge after seasonal ragweed-pollen exposure.

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Background: During the course of development of montelukast, a cysteinyl leukotriene receptor 1 antagonist, for treatment of seasonal allergic rhinitis, a double-blind, non-inferiority study was carried out to evaluate the efficacy and safety of montelukast 5mg and 10mg compared with pranlukast 450mg, which has a similar mechanism of action.
Methods: Montelukast 5mg, 10mg or pranlukast 450mg and the corresponding placebo were orally administered to patients with seasonal allergic rhinitis three times a day for 2 weeks. Non-inferior efficacy of montelukast 5mg and 10mg to pranlukast 450mg was investigated by the change from the baseline in the composite nasal symptoms scores over the 2-week treatment period.
Results: Montelukast 5mg, 10mg once daily and the pranlukast 450mg/day showed significant improvements in the change from the baseline in the composite, daytime and nighttime nasal symptom scores, and the improvement lasted for 2 weeks. Montelukast 5mg and 10mg were non-inferior to pranlukast 450mg in the change from the baseline in the composite nasal symptoms scores. The incidence rates of adverse experiences and drug-related adverse experiences were not significantly different among the three treatment groups.
Conclusions: The results indicate that administration of montelukast 5mg and 10mg once daily are potent alternatives for the treatment of seasonal allergic rhinitis and demonstrated that the efficacy and the safety profiles are comparable with pranlukast 450mg/day.

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Background: Beyond their role in hemostasis and thrombosis, platelets are important for modulating inflammatory reactions. Activated platelets play a role in the pathomechanism of inflammatory diseases such as asthma, but little is known about platelet activation in chronic skin inflammation, including atopic dermatitis (AD) and psoriasis. Furthermore, the relationship between platelet activation and disease severity is not understood. This work was performed to investigate plasma levels of β-thromboglobulin (β-TG) and platelet factor 4 (PF4) as platelet activation markers in patients with AD or psoriasis, and to determine the relationships between these markers and disease severity.
Methods: Plasma levels of β-TG and PF4 were measured by enzyme-linked immunoassay in 22 healthy controls, 44 patients with AD, and 16 patients with psoriasis. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophilia, serum IgE and serum lactate dehydrogenase were investigated in AD patients, and relationships with the psoriasis area and severity index (PASI) score were examined in psoriatic patients.
Results: Plasma β-TG and PF4 levels were significantly higher in patients with AD or psoriasis compared with healthy controls. β-TG and PF4 levels correlated with the SCORAD index, and PF4 levels correlated with PASI scores. Elevated β-TG and PF4 levels were significantly reduced after treatments.
Conclusions: Our results show that blood platelets are activated in patients with AD or psoriasis, suggesting that activated platelets play a role in the pathomechanism of chronic skin inflammation. Furthermore, plasma β-TG and PF4 may be markers for the severity of AD and psoriasis.

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Background: Lactobacillus gasseri OLL2809 strongly stimulates the production of interleukin (IL)-12 (p70) by innate immune cells. Thus, it is expected to ameliorate allergic diseases. We investigated whether the oral administration of heat-killed L. gasseri OLL2809 suppressed eosinophilia in cedar pollen antigen-challenged mice.
Methods: BALB/c mice sensitized with Japanese cedar pollen extract were intraperitoneally challenged with the same extract. The mice were orally given heat-killed L. gasseri OLL2809 at doses of 0.5, 1, or 2mg/day throughout the experimental period (21 d). After 24 hours of the challenge, the eosinophil number and cytokine levels in the peritoneal lavage fluid and the serum antigen-specific IgG levels were determined.
Results: On administering varying amounts of heat-killed L. gasseri OLL2809, the number of eosinophils among the total number of cells was significantly reduced in all groups. In addition, the eosinophil number significantly decreased, and the eosinophil-suppression rate significantly increased by 44% in the 2-mg group. Although the serum immunoglobulin (Ig) G2a and IgG1 levels were not affected, the IgG2a/IgG1 ratio increased significantly in the 2-mg group compared with that of the control group. Furthermore, the administration of heat-killed L. gasseri OLL2809 resulted in the induction of IL-2 and reduction in granulocyte-macrophage colony-stimulating factor levels in peritoneal lavage fluid.
Conclusions: We demonstrated that the oral administration of heat-killed L. gasseri OLL2809 suppresses eosinophilia via the modulation of Th1/Th2 balance. These observations suggested that heat-killed L. gasseri OLL2809 might potentially ameliorate the increased number of eosinophils in patients with Japanese cedar pollinosis.

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Background: Although prescribed drugs directly affect patient outcome, the variation in physicians' attitudes towards drug therapy for cedar pollinosis has not been quantitatively assessed. This research investigated the prescription patterns of drugs for cedar pollinosis by ear, nose, and throat specialists (ENTs), general physicians (GPs) and internal medicine doctors (IMs) in Yamanashi Prefecture, Japan.
Methods: A cross-sectional study was conducted by mailing questionnaires to 532 physicians in autumn 2006. The main part of the questionnaire constituted clinical vignettes of pollinosis cases with nasal and ocular symptoms ranging from mild to severe. We requested that the physicians fill out prescription medications they considered appropriate for each vignette.
Results: Responses from 172 physicians (32%) for six clinical vignettes were analyzed. The number of drugs prescribed by ENTs was significantly higher than that by GPs and IMs for vignettes representing moderate to severe cases (p < 0.004). The percentage of physicians who said they would prescribe nasal corticosteroid and eye drops was higher in the ENT group compared to the other two groups in these vignettes. In terms of second-generation antihistamines, no differences were observed between the three groups for all vignettes.
Conclusions: Our investigation suggested that, compared to ENTs, GPs and IMs have a lower tendency to concomitantly prescribe drugs for localized treatment such as nasal corticosteroids and eye drops with oral medication. There may be differences in prescription patterns of drugs for pollinosis between ENTs and non-specialist physicians.

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Background: Grass and birch pollens are known to induce asthma. However there are few reports about other pollen-induced asthma. Japanese cedar is the most common allergen in rhinitis in Japan but is controversial on whether it can provoke asthma.
Methods: To clarify Japanese cedar pollen-induced asthma, we studied adult patients who were sensitized only to the Japanese cedar (CAP-RAST > = 2) and had symptoms of asthma during the cedar season. We defined cedar asthma as a patient who satisfied the 2 criteria mentioned above.
Results: We found 6 adult asthma patients who fulfilled the two criteria. Five patients suffered from cedar pollinosis in addition to asthma, and 1 patient had no pollinosis. The cedar pollinosis preceded asthma in 3 cases and occurred at almost the same time in the other 2 cases. Pulmonary function was normal in these cases (FEV 1%, mean ± SD, 76.5 ± 10%), with a high threshold value in the non-specific airway hypersensitivity test (Ach-PC20, 2,696 to 20,000μg/ml, 9294 ± 2) and low total IgE (101 ± 86IU/ml). In the allergen provocation test, 3 subjects showed both an immediate and late asthmatic reaction.
Conclusions: We concluded that Japanese cedar pollen could provoke not only pollinosis but also asthma in adults.

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Background: As a non-injection route for immunotherapy, local nasal immunotherapy has been examined in allergic rhinitis patients. However, it is unclear how the immunotherapy affects sneezing, biphasic nasal blockage and nasal hyperresponsiveness. Thus, we evaluated the therapeutic effects of nasal immunotherapy on the symptoms of guinea pig allergic rhinitis. Additionally, we also evaluated whether the immunotherapy relieved pollen-induced allergic conjunctivitis.
Methods: Sensitized animals were repeatedly challenged by pollen inhalation once every week. After the 7th challenge, the pollen extract was intranasally administered 6 times a week until the 30th challenge. Sneezing frequency was counted after each of the challenges. As an indicator of nasal blockage, changes in specific airway resistance were measured. Nasal hyperresponsiveness was assessed by measuring leukotriene D₄-induced nasal blockage. Additionally, during the immunotherapy, we applied pollen onto the ocular surface to induce the allergic conjunctivitis symptoms.
Results: At the 11th-30th challenges, the nasal immunotherapy showed inhibition or a tendency to inhibit the biphasic nasal blockage although the inhibitions were variable at respective challenges. The development of nasal hyperresponsiveness was markedly suppressed by the immunotherapy. Nevertheless, neither sneezing nor antigen-specific IgE antibody production was substantially influenced by the immunotherapy. On the other hand, the nasal immunotherapy did not affect the induction of allergic conjunctivitis symptoms.
Conclusions: Local nasal immunotherapy may be clinically useful for allergic nasal blockage associated with nasal hyperresponsiveness. The mechanisms responsible for this effectiveness might not be related to IgE production. Additionally, the effectiveness for nasal tissue was dissociated from that seen for the ocular tissue.

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Background: The prevalence of patients with chronic rhinosinusitis (CRS) refractory to traditional therapy appears to be on the increase. In these cases, CRS tends to be associated with bronchial asthma (BA), especially, aspirin-intolerant asthma (AIA). On the other hand, arachidonic acid metabolites have been extensively investigated in the pathogenesis of BA. We sought to assess the role of prostaglandin D₂ (PGD₂) and prostaglandin E₂ (PGE₂) in the recalcitrant pathophysiology of CRS.
Methods: Samples were prepared from the nasal polyps and mucosa of 40 patients undergoing endoscopic sinus surgery (ESS) at our hospital. The nasal polyp specimens obtained from the patients with CRS were divided into three groups, as follows: the CRS-AIA group, consisting of specimens obtained from patients with CRS complicated by AIA, the CRS-ATA group, consisting of specimens obtained from patients with CRS associated with aspirin-tolerant asthma (ATA), and the CRS-NA group, consisting of specimens obtained from CRS patients without BA. PGD₂ and PGE₂ were extracted from the specimens and quantified.
Results: The concentrations of PGD₂ were significantly higher in the nasal polyps of the CRS-ATA group. The concentrations of PGE₂ were lowest in the nasal polyps of the CRS-AIA group. The PGD₂/PGE₂ ratio was highest in the CRS-AIA group.
Conclusions: It has previously been reported that CRS complicated by AIA is most likely to be characterized by repeated remissions and relapses, and is thus the most intractable. We may therefore say that the PGD₂/PGE₂ ratio reflects the intractable nature of CRS.

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Background: A 24 year-old woman with atopic dermatitis occasionally developed symptoms, including dyspnea and generalized urticaria, following ingestion of food containing cows milk. Similar episodes had continued, and had been treated empirically since the age of 16 years.
Case Summary: Although a skin test and IgE RAST showed positive reactions to cows milk, a provocation test with cows milk alone did not induce any symptoms. Therefore, food-dependent exercise-induced anaphylaxis (FDEIA) was suspected, but examination using various combinations of cows milk, aspirin and exercise failed to elicit any symptoms. Finally, a provocation test during the ovulatory phase with cows milk followed by aspirin and exercise evoked systemic urticaria, dyspnea and hypotension.
Discussion: The symptoms against cows milk began when she took baths with bath salts containing cows milk as its main ingredient for one year at the age 15 years. Sensitization to cows milk through eczematous skin is indicated from this history. Hormonal change during a premenstrual or ovulatory phase is also an important factor for the development of FDEIA in this case.

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Background: Angioedema due to angiotensin-converting enzyme inhibitors (ACEIs) therapy occurs not infrequently and is sometimes associated with life-threatening conditions.
Case Summary: A 59-year-old woman presented with recurrent angioedema of the tongue complicated by upper airway obstruction which required endotracheal intubation. Laboratory tests including complement levels were normal. ACEI-associated angioedema precipitated by NSAIDs was suspected. Her condition improved after discontinuation of imidapril and diclofenac without other specific treatment.
Discussion: ACEIs, and in particular concomitant use with NSAIDs, should be avoided in patients with a history of angioedema because continuing administration tends to lead to more severe attacks.

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