[Show abstract][Hide abstract] ABSTRACT: Chronic eosinophilic pneumonia (CEP) or eosinophilic gastroenteritis (EG), or both, with asthma precede the onset of eosinophilic granulomatosis with polyangiitis (EGPA) in half of all EGPA patients. It is not known what determines whether patients with CEP or with EG following asthma will develop EGPA.
We studied 17 EGPA patients and 12 patients with CEP but without EGPA. We assayed serum ICAM-1, VCAM-1, and VEGF, and the percentage of peripheral blood CD4 + T cells producing IL-17 (Th17 cells), at both onset and remission. We also examined the numbers of submucosal eosinophils and the basement membrane-to-crypt and crypt-to-crypt distance to evaluate edema in the colon submucosa at onset and remission in EGPA and at onset in CEP.
Nine of 12 (75.0 %) CEP patients had symptoms or endoscopic findings. Colonic submucosal eosinophil counts and edema in EGPA at onset were greater than at remission or in CEP at onset. Th17 cells (%) and serum ICAM-1 levels at onset were greater in EGPA than in CEP. In EGPA, peripheral blood Th17 cells (%) were significantly correlated with serum ICAM-1 level, colonic submucosal eosinophil count, and degree of edematous change; inversely correlated with serum VEGF level; but not correlated with VCAM-1 level.
Eosinophilia and colonic submucosal edematous change were greater in EGPA than in CEP. The mechanism of vasculitis in EGPA appears related to increases in serum Th17 cell numbers and ICAM-1 levels and decreases in VEGF levels.
[Show abstract][Hide abstract] ABSTRACT: Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by respiratory reactions on ingestion of COX-1 inhibitors and cysteinyl leukotriene overproduction. The hypersensitivity reaction is induced by low doses of aspirin that inhibit COX-1 in platelets. Objective: We sought to explore the role of platelets in the pathogenesis of AERD in patients under stable conditions and during an aspirin challenge test. Methods: Stable patients with AERD (n= 30), aspirin-tolerant asthma (ATA; n= 21), or idiopathic chronic eosinophilic pneumonia (n= 10) were enrolled. Platelet activation was estimated based on expression levels of P-selectin (CD62P), CD63, CD69, and GPIIb/IIIa (PAC-1) in peripheral platelets; percentages of circulating platelet-adherent leukocytes; and plasma levels of soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L). Results: In the stable condition, expression of all surface markers on platelets, the percentage of platelet-adherent eosinophils, and the plasma levels of sP-selectin and sCD40L were significantly higher in patients with AERD compared with those in patients with ATA. P-selectin and CD63 expression on platelets and plasma sP-selectin and sCD40L levels were positively correlated with the percentage of platelet-adherent eosinophils. Among these markers, P-selectin expression and plasma sP-selectin levels positively correlated with urinary concentrations of leukotriene E4. Additionally, plasma sP-selectin and sCD40L levels were negatively correlated with lung function. In contrast, platelet activation markers in patients with AERD did not change during the aspirin challenge test. Conclusion: Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.
Full-text · Article · Jul 2015 · The Journal of allergy and clinical immunology
[Show abstract][Hide abstract] ABSTRACT: Background and Aims: Asthma is a chronic disease characterized by airway inflammation; it is sometimes difficult to diagnose. For clinical diagnosis, forced oscillation technique (FOT) measures airway reactance and resistance. By FOT, we investigated respiratory resistance and ventilation perfusion ratio inequality in adults with mild asthma. Methods: We examined 58 adult patients with mild asthma having no inhaled corticosteroid treatment, and 10 adult patients with post-infectious prolonged cough. Using a MostGraph-01 FOT instrument, we evaluated these patients before and after bronchial hyperresponsiveness to acetylcholine (ACh) or histamine (Hist). We measured the following conditions: change of resistance at 5Hz (R5) and 20Hz (R20), R5-R20, reactance at 5Hz, frequency of resonance (Fres), low-frequency reactance area (ALX), and forced expiratory volume in 1 second (FEV1). Results: There were significant changes of R5, R20, R5-R20, X5, Fres, ALX after provocations for ACh or Hist in all patients with asthma, but not in patients with post-infectious prolonged cough. We calculated the percent decrease in FEV1 after provocation with ACh or Hist. For Ach, this decrease in FEV1 correlated with changes in R20 and Fres for all patients. For Hist, the percent decrease in FEV1 correlated with changes in R5, R20, Fres, and ALX for all patients. Furthermore, we investigated these correlations in patients with normalized bronchial hyperresponsiveness to ACh or Hist. For Ach, the percent decrease in FEV1 correlated with changes in Fres or R5-R20. For Hist, this decrease in FEV1 correlated with changes in R5, R20, and Fres. ROC analysis was used to evaluate the diagnostic value of the ratio of change of Fres in BHR to Hist. The area under the curve was 0.7808 (95% CI = 0.657-0.904). A reasonably high specificity (100.0%) and a high sensitivity (53.8%) with a cut-off point of 1.5 in the ratio before and after of Fres were obtained. Conclusion: The changes in FOT parameters (before and after bronchial airway responses) may detect airway resistance and ventilation perfusion ratio inequality even in adult patients with asthma having normalized bronchial hyperresponsiveness to ACh or Hist. That results may be useful for an early diagnosis of asthma.
[Show abstract][Hide abstract] ABSTRACT: Distinguishing between patients with allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus (Af)-sensitized asthmatic patients without ABPA is sometimes difficult owing to the IgE-cross-reactivity between Af and other fungal allergens.
To establish the usefulness of molecular-based allergy diagnostics using allergen components from Af in distinguishing ABPA from Af-sensitized asthma without ABPA.
Sera from Japanese patients with ABPA (n=53) and Af-sensitized asthma without ABPA (n=253) were studied. The levels of IgE and IgG antibodies to allergen components from Af and IgE antibodies to different fugal allergen extracts were measured by ImmunoCAP. Comorbid atopic dermatitis (AD) was taken into consideration in the sensitization profile analysis.
ABPA patients possessed significantly higher levels of IgE antibodies to Asp f 1, and Asp f 2 than asthmatic patients without ABPA. The areas under the receiver operating characteristic curves for the levels of IgE to Asp f 1 and Asp f 2 as diagnostic markers of ABPA were 0.75 and 0.78, respectively. The presence of IgE positivity to Asp f 1 and/or Asp f 2 resulted in increased sensitivity while losing little specificity. Comorbid AD was associated with higher levels of IgE to Asp f 6 (manganese superoxide dismutase from Af, a ubiquitous pan-allergen in fungi) and low but positive levels of IgE to other Af-components, which hampered the serological discrimination of ABPA.
The levels of IgE to Asp f 1 and/or Asp f 2 can effectively differentiate ABPA from Af-sensitized asthma, suggesting that the amounts of IgE specific for these molecules are markers for genuine Af-sensitization in ABPA. However, comorbid AD must be taken into consideration in the interpretation of high IgE to Asp f 6. Establishing of IgE-sensitization profiles using panel of Af-allergen components provides valuable information for distinguishing genuine versus cross-reactive sensitization in Af-sensitized patients. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Jun 2015 · Clinical & Experimental Allergy
[Show abstract][Hide abstract] ABSTRACT: Regulatory T (Treg) cells are implicated in the development and progression of eosinophilic granulomatosis with polyangiitis (EGPA). We previously showed beneficial effects of intravenous immunoglobulin (IVIG) therapy combined with corticosteroid and immunosuppressant treatment on clinical symptoms, including mononeuritis multiplex and cardiac dysfunction, and Treg cell frequency, during EGPA. Whether the timing of administration (during initial treatment or at relapse after remission) or previous treatment affects the clinical and immunologic efficacy of IVIG is unknown. We evaluated whether the frequency of Treg cells varied depending on when IVIG was provided relative to the start of conventional therapy for EGPA.
The patient population for this retrospective analysis comprised 17 patients with severe mononeuritis multiplex or heart failure whose EGPA did not respond to corticosteroids combined with immunosuppressant therapy. Ten patients first received IVIG during initial treatment, whereas the remaining 7 patients first received IVIG on relapse after remission. We measured the percentage of Treg cells, defined as FOXP3(+)CD4(+) T cells, present before the first round of IVIG and at 1 month after the last IVIG treatment.
FOXP3(+)CD4(+) T cells were increased in patients who required only a single course of IVIG to achieve remission compared with those who needed two or more courses. The dosage of prednisolone at initial IVIG was inversely correlated with the ratio of the number of FOXP3(+)CD4(+) T cells before IVIG and that at 1 month thereafter.
Patients with severe EGPA who receive IVIG after nonresponse to high-dose prednisolone during initial treatment may need multiple courses of IVIG to achieve remission. An increase in the frequency of Treg cells after IVIG may predict the need for additional IVIG in EGPA.
[Show abstract][Hide abstract] ABSTRACT: The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. Clinical application of FeNO measurement in Japan is expected increase because the procedure is now covered through health insurance. However, the measurement system used is known to affect FeNO results, and it remains unknown whether results from offline methods correlate with those from traditional online methods, such as NO breath®.
The study population comprised 48 patients at our hospital. FeNO levels were measured by using two offline methods (Sievers and CEIS) and a standard online method, NO breath®
FeNONO breath levels were significantly correlated with FeNOSievers(r=0.875) and FeNOCEIS(r=0.888) levels. FeNONO breath levels were nearly equal to FeNOSievers results (FeNONO breath=1.05×FeNOSievers), but both of these levels were lower (p=0.02) than FeNOCEIS data (FeNONO breath=0.74×FeNOCEIS). A Bland-Altman plot of values obtained by the NO breath® and Sievers methods revealed that the NO breath® result was lower than the Sievers level when FeNO was low but was higher than the Sievers level when FeNO was high.
Differences exist in the levels of FeNO measurement by three methods (two offline methods and NO breath®): conversion equations are needed to compare the FeNO levels obtained by using these three methods. In addition, NO breath® may be more useful to distinguish asthmatic patients from non-asthmatics, compared with Sievers method.
No preview · Article · Nov 2014 · Arerugī = [Allergy]
[Show abstract][Hide abstract] ABSTRACT: Background
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by the presence of allergic granulomatosis and necrotizing vasculitis with eosinophilic infiltration. The etiology of EGPA is unknown. Dendritic cells (DCs) are not only critical for the induction of primary immune responses; they may also be important for the induction of immunological tolerance and the regulation of the type of T-cell-mediated immune response. To investigate whether DC maturation is associated with EGPA disease status, we examined the relationship between the maturation of DCs and the differentiation of regulatory T (Treg) cells in EGPA patients. We exposed the CD14+ blood monocytes of 19 patients with EGPA in remission or relapse to stimulation with GM-CSF and IL-4 for 6 d and lipopolysaccharide for 24 h to obtain mature CD83+ DCs and immature CD206+ DCs. Using immunohistochemistry, we examined four patients for the presence of CD83+ and CD206+ DCs in the lung at the onset of EGPA .ResultsThe percentage of CD83+ cells among DCs differentiated from CD14+ monocytes was lower for EGPA patients in relapse than in remission. The percentage of CD83+ DCs was inversely correlated with the percentage of CD206+ DCs and was significantly correlated with the numbers of naturally occurring CD4+ regulatory Treg (nTreg; FOXP3+CD4+) cells and inducible Treg (iTreg; CD4+CD25+ T cells producing IL-10 or TGF-ß) cells but not the number of eosinophils. The percentage of CD206+ DCs was significantly inversely correlated with the percentages of nTreg and iTreg cells but not the number of eosinophils. Immunohistochemistry revealed both CD206+ DCs and CD83+ DCs in alveoli and interstitial spaces at the onset of EGPA.Conclusion
The maturation of DCs from monocytes was related to disease activity in patients with EGPA. Increased CD83+ DCs in EGPA patients may induce the differentiation of iTreg and nTreg cells, thereby suppressing inflammation and disease activity.
[Show abstract][Hide abstract] ABSTRACT: An open-label, non-randomized, single-arm study was performed to investigate the safety and efficacy of high-dose leukocytapheresis (pulse LCAP) for refractory asthma. Six patients who fulfilled the ATS workshop criteria for refractory asthma were enrolled and completed this clinical study. After 4 weeks of observation, pulse LCAP using a large LCAP filter, Cellsorba(A (R)) CS-180S, was performed twice with a 1-week interval at a target dose of 5 L per treatment session. The clinical response was assessed by monitoring the peak expiratory flow rate (PEFR) twice a day. The asthma control test (ACT) was used to evaluate the condition of asthma symptoms. The fraction of exhaled nitric oxide (FeNO) as a biomarker for eosinophilic airway inflammation was measured using a chemiluminescence analyzer. PEFR in the morning or the evening and the sum total of the score on the ACT were increased after two consecutive sessions of pulse LCAP. FeNO decreased after pulse LCAP. The results suggest the efficacy of pulse LCAP for refractory asthma.
No preview · Article · Jul 2014 · Inflammation Research
[Show abstract][Hide abstract] ABSTRACT: Background:
Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mite-contaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital.
In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan.
Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases.
Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.
Full-text · Article · Mar 2014 · Allergology International