Factors Affecting the Ability to Discontinue Oral Corticosteroid Use in Patients with EGPA Treated with Anti-Interleukin-5 Therapy.

INTRODUCTION: Patients with eosinophilic granulomatosis with polyangiitis (EGPA) and some with severe eosinophilic asthma require continuous long-term oral corticosteroid (OCS) treatment for disease control. The anti-interleukin-5 agent, mepolizumab, has recently become available for the treatment of severe eosinophilic asthma and EGPA, with promising results and safety profiles. The proportion of patients with EGPA who discontinued oral steroids was 18% in the MIRRA trial. To compare patients with EGPA who were able to discontinue steroids with mepolizumab with those who could not. METHODS: Twenty patients with EGPA treated with mepolizumab were evaluated at Osaka Habikino Medical Center. The OCS dose, asthma control test score, fractional exhaled nitric oxide levels, peripheral eosinophil count, and spirometric parameters were evaluated before and after treatment. RESULTS: There was a significant reduction in the mean OCS dose from a prednisolone equivalent of 8.88 ± 4.99 mg/day to 3.18 ± 3.47 mg/day (p < 0.001). In this study, 40% of patients discontinued oral steroids. The most common reason for the failure to discontinue steroids in patients was poor asthma control. The percentage of predicted forced expiratory volume in 1 s significantly improved in patients with EGPA who could discontinue steroids after receiving mepolizumab. CONCLUSION: In this real-world study, treatment with mepolizumab for EGPA was associated with a significant reduction in OCS use; however, poor asthma control was identified as an inhibiting factor for steroid reduction.

Successful Treatment of Eosinophilic Chronic Rhinosinusitis and Secretory Otitis Media in Refractory Asthma With Thymic Stromal Lymphopoietin (TSLP) Receptor Monoclonal Antibody.

Eosinophilic chronic rhinosinusitis (ECRS) is a type 2 inflammatory disease that frequently co-occurs with bronchial asthma. The current treatment options for ECRS include endoscopic sinus surgery and oral corticosteroid therapy (OCS). However, recurrence after surgery is common, and OCS therapy may cause side effects. We present the case of a 74-year-old woman with severe asthma, ECRS, and secretory otitis media with possible eosinophilic otitis media, who experienced significant improvement in both conditions after treatment with tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) antibody. Tezepelumab treatment led to a reduction in blood and tissue eosinophil counts. It improved the nasal polyp and computed tomography scores, tympanic and hearing test results, and asthma symptoms without using OCSs. Our findings suggest that tezepelumab may be a promising option for those patients with asthma, ECRS, and secretory otitis media who do not respond well to conventional treatment because upstream of the type 2 inflammation pathway is suppressed. Further to this case report, future studies are required to confirm the long-term efficacy and safety of tezepelumab in treating ECRS and secretory otitis media due to type 2 inflammation.

Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes.

RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.

Benralizumab monotherapy was insufficient to induce remission in patients with active eosinophilic granulomatosis with polyangiitis.

Eosinophils play an important pathogenetic role in the development of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA has long been treated with systemic corticosteroids and immunosuppressive agents. However, in recent years, biologic agents targeting eosinophils (anti-IL-5 antibody; mepolizumab) have also been used. Evidence regarding the effectiveness of using benralizumab, anti-IL-5 receptor α monoclonal antibody that depletes eosinophils via antibody-dependent cell-mediated cytotoxicity, has been growing. Benralizumab is used as a steroid-sparing treatment option for EGPA. Clinical studies have evaluated the effects of using mepolizumab or benralizumab in combination with steroids for the treatment of EGPA. However, to date, there have been no reports of using biologics alone. Herein, we describe the case of a patient with active EGPA refractory to benralizumab monotherapy. The patient achieved significant improvement in symptoms after administration of corticosteroids during hospitalization. Benralizumab monotherapy might not be considered a therapeutic option for patients with active EGPA in whom corticosteroids are initially indicated.

Retropharyngeal edema: A rare manifestation of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by excessive eosinophil accumulation in the peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. Although upper airway and neck involvement is seen in patients with EGPA, retropharyngeal inflammation has never been reported. We report a case of retropharyngeal edema in a 70-year-old woman with EGPA. Her symptoms improved and the retropharyngeal edema disappeared on computed tomography following treatment. EGPA should be considered as a differential diagnosis in patients with asthma presenting with neck swelling and dysphagia.

Rapid effect of benralizumab for severe asthma with chronic rhinosinusitis with nasal polyps.

BACKGROUND: The anti-interleukin (IL)-5 agent benralizumab has recently become available for treatment of severe asthma with promising results; however, it appears effective only in specific subgroups of asthma patients. Severe asthma with chronic rhinosinusitis/nasal polyps (CRSwNP or eosinophilic chronic rhinosinusitis, ECRS) is a severe eosinophilic asthma phenotype that necessitates individualized treatment. OBJECTIVE: To assess differences in response to benralizumab between severely eosinophilic asthma patients with and without CRSwNP. METHODS: Seventeen outpatients with severe eosinophilic asthma treated with benralizumab for 1 year were evaluated at the Osaka Habikino Medical Center. Blood eosinophil count, Asthma Control Questionnaire 5 (ACQ5), Asthma Quality of Life Questionnaire (AQLQ), fractional exhaled nitric oxide (FeNO), and spirometry were recorded at weeks 0, 4, 16, 24, and 50. RESULTS: ACQ5 and AQLQ in CRSwNP(+) groups improved significantly after 4, 16, 24, and 50 weeks (p = 0.0195, 0.0156, 0.0117, and 0.0078 and p = 0.0098, 0.0098, 0.0029, and 0.0098, respectively) of benralizumab treatment. ACQ5 in CRSwNP(-) groups did not improve significantly after benralizumab treatment, but AQLQ improved significantly after 24 (p = 0.0313) and 50 weeks (p = 0.0313). Forced expiratory volume in 1s (FEV1) predicted in CRSwNP(+) groups were improved significantly after 4 weeks (p = 0.0137), 16 weeks (p = 0.0127), 24 weeks (p = 0.0098) and 50 weeks (p = 0.0420) of benralizumab treatment. %FEV1 in CRSwNP(-) groups were improved significantly after 24 weeks (p = 0.0313) and 50 weeks (p = 0.0313) of benralizumab treatment (Fig. 3). Forced vital capacity (FVC) predicted in CRSwNP(+) groups were improved significantly after 24 weeks (p = 0.0195) and %FVC in CRSwNP(-) groups improved significantly after 50 weeks (p = 0.0313) of benralizumab treatment. Maximum mid-expiratory flow rate predicted in CRSwNP(+) groups were improved significantly after 16 (p = 0.0137 and 50 weeks (p = 0.0371) of benralizumab treatment. CONCLUSIONS: Benralizumab can exert a very rapid therapeutic action, detectable 4 weeks after treatment initiation in patients with severe eosinophilic asthma with CRSwNP. However, severe eosinophilic asthma without CRSwNP takes longer to respond to benralizumab treatment.

Flare of eosinophilic granulomatosis with polyangiitis related to pregnancy: Case report and review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by excessive eosinophil accumulation in the peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. It is strongly associated with asthma and ear-nose-throat disease. It often affects patients between the ages of 40 and 60 years. It is unknown whether pregnancy impacts the disease activity of EGPA, including initial diagnosis or relapse. Because of its rarity and age of susceptibility, there are few reported cases describing pregnancy in women with quiescent or active EGPA. Here, we describe a young woman who experienced EGPA relapse during pregnancy and subsequently underwent an elective caesarean section for non-reassuring fetal status at 37 weeks without complication.

Increased serum ADAM8 concentration in patients with drug-induced eosinophilic pneumonia-ADAM8 expression depends on a the allergen route of entry.

BACKGROUND: ADAM8 (a disintegrin and a metalloprotease 8) has been linked to asthma and eosinophilic pneumonia (EP). ADAM8 cleaves a variety of substrates and is a sheddase for CD23, the low affinity IgE receptor. The concentration of soluble ADAM8 (sADAM8) is increased in bronchoalveolar lavage fluid (BALF) from patients with smoking-induced acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP), but not drug-induced EP (Drug-EP). In AEP, the BALF sADAM8 concentration significantly correlates with the soluble CD23 concentration (sCD23). METHODS: To evaluate the involvement of ADAM8 in the pathogenesis of eosinophilic pneumonia, we measured the concentrations of sADAM8 and its substrate, soluble CD23 (sCD23), in serum from patients with AEP, CEP, and Drug-EP. We also measured the change in the sADAM8 concentration after a provocation test. RESULTS: In contrast to the BALF findings, serum sADAM8 concentrations were increased in Drug-EP (mean+/-SEM; 639.6+/-49.15) and serum ADAM8 levels correlated positively with the serum sCD23 levels in patients with Drug-EP (P=0.0080, R(2)=0.8465). Serum sADAM8 concentrations were also increased in AEP (409+/-76.91) and CEP (644.7+/-87.03). Serum ADAM8 concentrations were also elevated after the provocation test. CONCLUSION: Serum ADAM8 concentrations were elevated in Drug-EP, although the sADAM8 concentrations were not increased in the BALF in Drug-EP. Thus, the pathogenesis of AEP and Drug-EP may be distinct with regard to allergen exposure; AEP may be caused by the inhalation of antigens, whereas Drug-EP may be caused by bloodstream antigens. These findings indicate that ADAM8 levels reflect the route of eosinophilic inflammation in EP.

[An autopsy case of sarcomatoid malignant mesothelioma mimicking adenocarcinoma with sarcomatoid elements of lung].

A 62-year-old man with pain in his hip joints and back was admitted to our hospital. His chest radiograph and CT showed a huge mass extending from the left upper pericardium to the left hilum, but no pleural effusion or other lesions. A contrast-enhanced abdominal CT showed multiple metastases to bones and both kidneys. Bronchoscopy revealed obstruction of the left B3 by a visible tumor. The biopsy specimens of the initial immunohistochemical staining were slightly positive for calretinin. However, we diagnosed the condition as sarcomatoid carcinoma of the lung on the basis of the clinical evaluation. Although radiotherapy was administered, his condition rapidly deteriorated and he died due to progression of the disease. Autopsy revealed extensive invasion, suggesting mesothelioma. Therefore, immunohistochemical staining was performed; the findings revealed sarcomatoid malignant mesothelioma. In conclusion, we encountered a rare case of sarcomatoid malignant mesothelioma (stage IV).

Circulating thymus- and activation-regulated chemokine/CCL17 is a useful biomarker for discriminating acute eosinophilic pneumonia from other causes of acute lung injury.

BACKGROUND: The presentation of acute eosinophilic pneumonia (AEP) closely resembles that of acute lung injury (ALI)/ARDS, including its idiopathic form, acute interstitial pneumonia (AIP). AEP usually lacks peripheral eosinophilia at the acute phase; therefore, the establishment of serum biomarkers for AEP would be clinically useful. METHODS: We measured the levels of thymus- and activation-regulated chemokine (TARC)/CCL17, eotaxin/CCL11, KL-6, and surfactant protein-D (SP-D) in serum for patients with acute parenchymal lung diseases including AEP (n = 17), AIP (n = 13), pneumonia-associated ALI/ARDS (n = 12), and alveolar hemorrhage (n = 7). To evaluate diagnostic ability, each marker was estimated by measuring the area under the receiver operating characteristic curve (AUC). RESULTS: Serum TARC/CCL17 levels of AEP patients were much higher than those of patients in other disease groups. More importantly, high circulating TARC/CCL17 levels were observed in AEP even at acute phase when peripheral eosinophilia was absent. TARC/CCL17 showed the largest AUC, and the TARC/CCL17 levels with cutoff points from 6,259 to 7,039 pg/mL discriminated AEP from other syndromes with sensitivity and specificity of 100%. The KL-6 level was low in most patients with AEP, and the sensitivity was 81.6% in cutoff with 100% specificity. The AUC for eotaxin/CCL11 and SP-D was small, with values of 0.73 (95% confidence interval [CI], 0.60 to 0.86) and 0.53 (95% CI, 0.31 to 0.64), respectively. CONCLUSIONS: This study indicates that the measurement of circulating TARC/CCL17 and KL-6 is useful for discriminating AEP from other causes of ALI.

Corynebacterium ulcerans infection of the lung mimicking the histology of Churg-Strauss syndrome.

We report the first case of pulmonary Corynebacterium ulcerans infection mimicking Churg-Strauss syndrome (CSS). Productive cough, fever, general fatigue, and weight loss developed in a 50-year-old man. Laboratory data revealed prominent eosinophilia and elevated serum IgE. On chest images, multiple nodules and cavities were predominantly detected in the right lung. Histopathologic examination showed necrotizing granulomas and vasculitis with massive eosinophilic infiltration identical to the findings seen in CSS; however, clusters of Gram-positive, coryneform rods were observed in the alveolar spaces. A toxigenic strain of C ulcerans was isolated from lung tissue. The patient was treated with antibiotics, and a favorable clinical course ensued.

Amoxicillin-Induced Eosinophilic Pneumonia with Granulomatous Reaction: Discrepancy between Drug-Induced Lymphocyte Stimulation Test Findings and the Provocation Drug Test.

: A 59-year-old man was admitted to the hospital with pulmonary infiltration, fever, erythema, and eosinophilia. Two weeks before admission, he received amoxicillin, acetaminophen, and shoseiryu-to (a Japanese herbal medicine) for a common cold. Bronchoalveolar lavage was performed, and an increased number of eosinophils was recovered. Transbronchial biopsy specimens showed granuloma and interstitial thickening with eosinophils and lymphocytes. Drug-induced eosinophilic pneumonia was suspected, so all drugs were discontinued. The symptoms and infiltration shadow disappeared. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen but not for amoxicillin. In contrast to the DLST, a provocation test revealed that amoxicillin induced the drug allergy. A very striking observation was the coexistence of pulmonary eosinophilia and granulomatous lung infiltrations. In addition, there was a discrepancy between the DLST and provocation test findings. To our knowledge, there is no previous report of drug-induced eosinophilic pneumonia with a granulomatous reaction.

Elevated soluble ADAM8 in bronchoalveolar lavage fluid in patients with eosinophilic pneumonia.

BACKGROUND: ADAM (a disintegrin and metalloprotease) family members, characterized by a metalloprotease and a disintegrin domain, are membrane-anchored glycoproteins involved in proteolysis and cell adhesion. ADAM8 might have an important role in allergic inflammation. It can cleave a variety of substrates and is a sheddase for VCAM-1 and CD23, the low-affinity IgE receptors. METHODS: To evaluate the contribution of ADAM8 to the pathogenesis of eosinophilic pneumonia (EP), we measured the concentrations of soluble ADAM8 (sADAM8) and its substrates, soluble VCAM-1 (sVCAM-1) and soluble CD23 (sCD23), in bronchoalveolar lavage fluid from patients with smoking-induced acute eosinophilic pneumonia (AEP), chronic idiopathic eosinophilic pneumonia (CEP), and drug-induced eosinophilic pneumonia (drug-EP). RESULTS: The sADAM8 and sVCAM-1 concentrations were increased in AEP and CEP. The sCD23 concentration was elevated in AEP. In AEP, but not CEP, the sADAM8 concentration significantly correlated with those of both sVCAM and sCD23. CONCLUSION: The pathogenesis of AEP, CEP, and drug-EP was distinct with regard to ADAM8. Our results are the first to associate ADAM8 with eosinophilic responses and lung inflammation in humans.

[A case of drug-induced pneumonitis due to bepridil].

A 66-year-old man had been given bepridil for the treatment of atrial fibrillation since April 28, 2002. The patient developed exertional dyspnea with hypoxemia in the middle of June 2002 and was admitted to our hospital. The chest X-ray and chest CT scans showed diffuse reticulonodular infiltrates in the lower lung fields. Pulmonary function tests revealed depletion of diffusion capacity for carbon monoxide. Bronchoalveolar lavage fluid contained increased percentages of lymphocytes, neutrophils and eosinophils, and a CD4/8 ratio was low. The transbronchial lung biopsy specimens demonstrated alveolar septal thickening with infiltration of mononuclear cells and intraalveolar organization. As drug-induced pneumonitis was suspected, bepridil was discontinued, resulting in improvement of dyspnea and hypoxemia. The patient was then treated with corticosteroid, which led to complete resolution of infiltration on chest X-ray. According to the clinical data consistent with drug-induced pneumonia, the prompt improvement after cessation of bepridil and the absence of other possible causes, we diagnosed this case as bepridil-induce pnemonitis.

Role of ADAM8 in experimental asthma.

A disintegrin and metalloprotease (ADAM) family members, characterized by a metalloprotease and a disintegrin domain, are membrane-anchored glycoproteins involved in proteolysis and cell adhesion. ADAM8 is specifically induced in the experimental murine asthmatic lung. To evaluate novel pathways involved in asthma pathogenesis, using ADAM8 transgenic mice (ATMS2) in a murine model of asthma. Massive cellular infiltrates in peribronchovascular and interstitial lesions were observed in control mice, while in ATMS2 mice there were only occasional. Vascular cell adhesion molecule (VCAM-1) is involved in specific eosinophil adhesions via alpha4beta1 integrin. VCAM-1 shedding was mediated by the ADAM8 metalloprotease. Endothelial cell shedding of VCAM-1 was increased in ATMS2-stimulated human umbilical endothelial cells. ADAM8-mediated shedding of VCAM-1 might be important for the suppression of experimental asthma. Our data suggest that ADAM8 is a useful therapeutic target.

[A case of pulmonary langerhans cell histiocytosis presenting disappearance of coalescing air wall cysts after smoking cessation].

A 17-year-old adolescent was admitted to Oita University Hospital with non-productive cough and exertional dyspnea. She had been smoking approximately 10 cigarettes per day for two years. When the patient was three years old, she underwent surgical removal of skull tumor of Langerhans cell histiocytosis. Initial chest CT scans showed coalescing thick-walled air cysts surrounded by micronodules in both lungs, most predominantly in the middle and upper lung fields. Bronchoalveolar lavage fluid contained 2.3% of CD1a-positive cells and video-assisted thoracoscopic lung biopsy disclosed granulomatous lesions consisting of histiocytic cells containing S-100 protein but without CD68 antigen allowing a diagnosis of pulmonary Langerhans cell histiocytosis. She stopped smoking, resulting in spontaneous resolution of the coalescing air cysts which were replaced by funicular scarring within two years. In case of extra-pulmonary Langerhans cell histiocytosis in children, the close relationship between cigarette smoking and pulmonary involvement should be informed to the parents to prevent the patient starting smoking in the future.

[A case of sarcoidosis manifesting as acute febrile polyarthritis following bronchoalveolar lavage].

A 32-year-old man was incidentally found to have abnormal shadows on a chest X-ray film and was admitted on May 2004. His chest images showed mediastinal and bilateral hilar lymphadenopathy. The serum level of angiotensin-converting enzyme was elevated. We also found non-caseating epithelioid cell granulomas in transbronchial lung biopsy specimens, and confirmed the diagnosis of sarcoidosis. We carried out bronchoalveolar lavage (BAL) for evaluation of disease activity of sarcoidosis. After BAL, he suffered high fever and polyarthralgia. Both ankles were extremely inflamed. We suspected infectious arthropathy caused by atypical pathogens and thus administered antibiotics, but they had no effect at all. Also, no findings suggesting collagen-vascular disorders, including rheumatoid arthritis, were detected. His symptoms improved after three-weeks of treatment with non-steroidal anti-inflammatory drugs. Thus, this case was diagnosed as having acute sarcoid polyarthritis. BAL may have influenced the onset of febrile arthritis in this patient This case indicates that sarcoidosis should be considered as a possible cause of acute febrile polyarthritis.

A case of diffuse panbronchiolitis (DPB) in a patient positive for HTLV-1.

Diffuse panbronchiolitis (DPB), an important cause of progressive obstructive lung disease in the Far East, represents a distinctive sinobronchial syndrome with typical radiologic and histologic features. Human T-cell lymphotrophic virus (HTLV-1) is a retrovirus that clinically and experimentally suppresses T-cell function and immune responses. The clinical and immunologic features of DPB in HTLV-1 carriers are unclear, because DPB and HTLV-1 endemic areas around the world are mostly non-overlapping. However, both diseases are endemic in Japan. We present a patient with DPB positive for HTLV-1 whose cellular and humoral immune responses were markedly impaired. Six y after diagnosis of DPB, the patient developed respiratory failure and died in spite of treatment with clarithromycin.

Elevated concentrations of soluble IL-2 receptor in both bronchoalveolar lavage fluid and serum in a patient with BOOP.

Activated soluble IL-2 receptor (sIL-2R) levels are elevated in a variety of diseases associated with T-cell activation. There are no reports of sIL-2R elevations in broncholitis obliterans organizing pneumonia/cryptogenic organizing pneumonia (BOOP/COP), although activated T cells are increased in BOOP/COP. We present a patient with BOOP/COP with an elevated concentration of soluble IL-2 receptors in both serum and bronchoalveolar lavage fluid. Concomitant resolution of the high serum sIL-2R and the roentogenographic findings after steroid treatment suggested that serum sIL-2R levels increase in response to a localized lymphocytic inflammatory reaction in the lung.