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.

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.

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.

Does allergic rhinitis make a difference to the respiratory resistance and reactance of asthma?

BACKGROUND: Concomitant allergic rhinitis (AR) in asthmatic patients can contribute to increased asthma exacerbations and poorer symptom control. A recent study indicated that impulse oscillometry is a more sensitive measure of change in airway function than spirometry, but this has not been used to compare asthmatic patients with or without AR. OBJECTIVE: We used impulse oscillometry (Mostgraph-01) to examine the impact of AR on asthma. METHODS: Impulse oscillometry and spirometry were assessed in 50 patients with asthma only and 95 patients with asthma and AR. RESULTS: Mean age in the asthma only group was significantly higher than in the asthma with AR group. Therefore, analysis of covariance adjusted for age was used to compare between these two groups. Percentage of mean forced expiratory volume in 1 s (FEV1), respiratory resistance at 5 Hz (R5) minus respiratory resistance at 20 Hz (R20), and resonant frequency (Fres) in the asthma with AR group were significantly less severe than in the asthma only group. Parameters of resistance and reactance were correlated with age and body mass index only in the asthma with AR group but not in the asthma only group. Correlations were observed between rate of change of maximum mid-expiratory flow and impulse oscillometry values of R5 and Fres in the asthma only group, but not between the rate of change of FEV1 and impulse oscillometry values. CONCLUSION: Asthma with AR was associated with higher lung function and better values of resistance and reactance than asthma only.

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.

Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches.

Drug-induced interstitial lung disease (DILD) is not uncommon and has many clinical patterns, ranging from benign infiltrates to life-threatening acute respiratory distress syndrome. There are two mechanisms involved in DILD, which are probably interdependent: one is direct, dose-dependent toxicity and the other is immune-mediated. Cytotoxic lung injury may result from direct injury to pneumocytes or the alveolar capillary endothelium. Drugs can induce all types of immunological reactions described by Gell and Coombs; however, most reactions in immune-mediated DILD may be T cell-mediated. DILD can be difficult to diagnose; diagnosis is often possible by exclusion alone. Identifying the causative drug that induces an allergy or cytotoxicity is essential for preventing secondary reactions. One method to confirm the diagnosis of a drug-induced disease is re-exposure or re-test of the drug. However, clinicians are reluctant to place patients at further risk of illness, particularly in cases with severe drug-induced diseases. Assessment of cell-mediated immunity has recently increased, because verifying the presence or absence of drug-sensitized lymphocytes can aid in confirmation of drug-induced disease. Using peripheral blood samples from drug-allergic patients, the drug-induced lymphocyte stimulation test (DLST) and the leukocyte migration test (LMT) can detect the presence of drug-sensitized T cells. However, these tests do not have a definite role in the diagnosis of DILD. This study explores the potential of these new tests and other similar tests in the diagnosis of DILD and provides a review of the relevant literature on this topic.

Effectiveness of omalizumab in a patient with severe asthma, low serum IgE level, and lack of sensitized allergens induced by oral steroid therapy: the usefulness of impulse oscillation for assessment of omalizumab therapy.

BACKGROUND: Omalizumab is a humanized monoclonal anti-IgE antibody that was recently approved for the treatment of severe allergic asthma. However, omalizumab is not licensed for allergic asthma in patients with a low serum IgE level (<30 IU/mL) or negative results for specific allergen tests. CASE HISTORY: We present a patient with severe asthma and low serum IgE levels who had negative results for specific allergens induced by oral steroid therapy. Omalizumab administration improved asthma exacerbated forced expiratory volume in 1 s (FEV(1)) and respiratory resistance measurements based on the impulse oscillation technique (Mostgraph-01). The response to omalizumab therapy was evidenced by a decrease in airway resistance at 1 month. CONCLUSIONS: The findings of this case report indicate that omalizumab treatment had beneficial effects in a patient with severe asthma and low total serum IgE levels with negative results for specific IgE, which may have been induced by long-term corticosteroid administration.

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.

COVID-19 in a Patient With Severe Eosinophilic Asthma on Benralizumab Therapy: A Case Report and Review of Literature.

Patients with coronavirus disease 2019 (COVID-19) can develop eosinopenia. Eosinophils have various functions, including immunoregulation and antiviral activity, in addition to modulation of an inflammatory reaction. Benralizumab is an anti-interleukin-5Rα monoclonal antibody that selectively depletes eosinophils through enhanced antibody-dependent cell-mediated cytotoxicity. Whether eosinophil depletion affects COVID-19 prognosis is yet to be elucidated. Here, we present a case of a 60-year-old patient with severe asthma on benralizumab therapy, who tested positive for an acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The patient experienced an asymptomatic COVID-19 course without deterioration of asthma control. Eosinophil depletion did not contribute to a deterioration of the clinical status. Comorbidities play a major role in the severity of COVID-19 in patients with asthma. The findings of our case and a literature review revealed that benralizumab therapy is not associated with a significant negative impact on the disease course in COVID-19 patients.

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.

Deterioration of asthma in a patient with diffuse panbronchiolitis (DPB) after macrolide therapy.

Diffuse panbronchiolitis (DPB), an important cause of progressive obstructive lung disease in the Far East, is a distinctive sinobronchial syndrome with characteristic radiologic and histologic features. Asthma is a chronic inflammatory disease characterized by airway narrowing. The major inflammatory cells involved in the pathogenesis of asthma are type 2 helper T (Th2) cells, eosinophils, and mast cells. The authors' patient was diagnosed with DPB and asthma. Although macrolide therapy led to the disappearance of the radiologic abnormalities indicating centrilobular nodular lesions, the respiratory symptoms and pulmonary function worsened. Administration of inhaled corticosteroids improved the respiratory symptoms and pulmonary function. To the authors' knowledge, no case of DPB with asthma has been reported in the English-language literature.

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.

Eosinophils depletion therapy for severe asthma management following favorable response to mepolizumab.

We described three severe asthmatics whose asthma symptoms were rapidly improved by benralizumab following favorable response to mepolizumab. Benralizumab-induced eosinophil depletion contributed to clinical improvement of severe asthma after mepolizumab-induced eosinophil reduction; thus, prior favorable responses to mepolizumab may predict benralizumab efficacy.

Asthma and sinusitis: association and implication.

BACKGROUND: Sinusitis occurs frequently in asthmatic patients. Epidemiologic data on sinusitis and lower airway disease must be evaluated with caution because they are based mostly on symptoms and do not include nasal endoscopic or computed tomography (CT) findings. Clinical support and evidence for this association are lacking. We evaluated the impact of sinusitis on lower airway disease in patients with well-characterized asthma. METHODS: Subjects (n = 188) completed a questionnaire designed to provide information about their signs and symptoms related to asthma, allergic rhinitis (AR) and sinus disease. Patients (n = 104) were divided into four groups based on the presence or absence of sinusitis and/or AR. Clinical findings were compared in asthma patients with and without diagnosed sinusitis, by an otorhinolaryngologist or based on sinus CT findings. RESULTS: The prevalence of sinusitis in patients with asthma was 36.7%. Sinus CT scan abnormalities were detected in 66.3% of patients with asthma. The scans revealed abnormal opacity in 17.9% of asthmatic patients without a history of sinusitis. There was a significant correlation between the rate of asthma severity and sinus morphologic abnormalities in patients with and without sinusitis. In adult-onset asthma (>or=16 years old), sinusitis frequently preceded asthma, whereas in non-adult-onset asthma (<16 years old) it preceded sinusitis. The complication rate of sinusitis in asthmatic patients was significantly higher in adult-onset asthma than in non-adult-onset asthma. CONCLUSIONS: Our findings suggest that bronchial asthma is closely related to sinusitis and the onset age of asthma is important when considering allergic disease frequency. Whether sinus disease directly affects the intensity of bronchial inflammation remains to be elucidated.

Age-related pulmonary crackles (rales) in asymptomatic cardiovascular patients.

PURPOSE: The presence of age-related pulmonary crackles (rales) might interfere with a physician's clinical management of patients with suspected heart failure. We examined the characteristics of pulmonary crackles among patients with stage A cardiovascular disease (American College of Cardiology/American Heart Association heart failure staging criteria), stratiffed by decade, because little is known about these issues in such patients at high risk for congestive heart failure who have no structural heart disease or acute heart failure symptoms. METHODS: After exclusion of comorbid pulmonary and other critical diseases, 274 participants, in whom the heart was structurally (based on Doppler echocardiography) and functionally (B-type natriuretic peptide <80 pg/mL) normal and the lung (X-ray evaluation) was normal, were eligible for the analysis. RESULTS: There was a significant difference in the prevalence of crackles among patients in the low (45-64 years; n = 97; 11%; 95% CI, 5%-18%), medium (65-79 years; n = 121; 34%; 95% CI, 27%-40%), and high (80-95 years; n = 56; 70%; 95% CI, 58%-82%) age-groups (P <.001). The risk for audible crackles increased approximately threefold every 10 years after 45 years of age. During a mean follow-up of 11 +/- 2.3 months (n = 255), the short-term (< or =3 months) reproducibility of crackles was 87%. The occurrence of cardiopulmonary disease during follow-up included cardiovascular disease in 5 patients and pulmonary disease in 6. CONCLUSIONS: Recognition of age-related pulmonary crackles (rales) is important because such clinically unimportant crackles are so common among elderly patients that, without knowledge of this phenomenon, their existence might interfere with the physician's management of cardiopulmonary patients.

Reduced IgG levels found during acute eosinophilic pneumonia, which normalize during recovery from disease.

Clinically there are several different types of eosinophilic pneumonia (EP), but other than for tropical pulmonary eosinophilia, the humoral immune response between different types of EP, such as acute eosinophilic pneumonia (AEP), chronic EP, drug-induced EP, allergic bronchopulmonary aspergillosis, and Churg-Strauss syndrome, has not been examined. Immunoglobulin G (IgG) and E (IgE) serum concentrations were analyzed in patients with EP, or bacterial pneumonia, and in age-matched controls. Patients with AEP had lower IgG levels than the age-matched controls. Serum IgG levels in patients with AEP were significantly lower than in patients with other types EP or bacterial pneumonia. IgG2 and IgG4 were also significantly decreased in AEP, compared to age-matched controls. In AEP, the serum IgG levels were significantly decreased during active disease and increased during remission, but the serum IgE levels did not change significantly, indicating a decrease in serum IgG is a common feature of AEP. Low IgG levels were significantly correlated with serum surfactant protein D and absolute eosinophil counts in the bronchoalveolar lavage fluid of patients with AEP. This is the first reported study of immunoglobulin levels in AEP. The pathogenesis of AEP might negatively affect serum IgG levels, but not IgE levels. The present findings might indicate that serum IgG reflects the inflammatory response in AEP.

Amoxapine-associated acute respiratory distress.

A 37-year-old woman was admitted to our hospital because of acute respiratory distress. Two weeks previously, amoxapine (75 mg/day) had been administered for the first time. Ten days later she developed a high fever, severe hypoxaemia and pulmonary infiltrates on chest CT, including patchy areas of ground-glass opacity, thickening of the interlobular septae and bronchial walls and pleural effusions. BAL showed a predominance of neutrophils, lymphocytes and erythrocytes but not eosinophils. Amoxapine was stopped, resulting in complete resolution of the pulmonary infiltrates. When the patient was re-exposed to amoxapine (52.5 mg total dose), high fever, reduced SaO(2) and pulmonary infiltrates reappeared. We concluded that acute respiratory distress may be associated with amoxapine treatment.

[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).

Spontaneous Regression of Allergic Bronchopulmonary Mycosis Due to Curvularia lunata.

Allergic bronchopulmonary mycosis (ABPM) is a pulmonary hypersensitivity disease mainly caused by Aspergillus fumigatus. The mainstay treatment for ABPM is systemic corticosteroid therapy. A 25-year-old man presented with pulmonary infiltrates. His peripheral eosinophil, total serum IgE, and serum Aspergillus-specific IgE levels were elevated. The patient tested positive in a skin test for Aspergillus. However, sputum cultures revealed a Curvularia lunata infection. We therefore diagnosed ABPM possibly caused by C. lunata, which is rare in Japan. The clinical state of the patient improved under observation. Identification of the causative fungus is an important aspect of the ABPM diagnosis.