Real-world efficacy of anti-IL-5 treatment in patients with allergic bronchopulmonary aspergillosis.

Despite standard treatment with systemic corticosteroids and/or antifungal triazoles, a substantial proportion of patients with allergic bronchopulmonary aspergillosis (ABPA) experience frequent relapses and require long-term treatment despite unfavorable adverse effects. We investigated the efficacy and safety of anti-interleukin (IL)-5/IL-5 receptor α chain (Rα) monoclonal antibodies (mAbs) in patients with ABPA complicated by asthma. ABPA cases treated with anti-IL-5/IL-5Rα mAbs were collected from 132 medical institutes in 2018 and published case reports in Japan. Clinical outcomes, laboratory and physiological data, and radiographic findings during 32 weeks before and after treatment were retrospectively evaluated. We analyzed 29 cases of ABPA: 20 treated with mepolizumab and nine with benralizumab. Treatment with anti-IL-5/IL-5Rα mAbs reduced the frequency of exacerbations (p = 0.03), decreased the dose of oral corticosteroids (p < 0.01), and improved pulmonary function (p = 0.01). Mucus plugs in the bronchi shrank or diminished in 18 patients (82%). Despite the clinical/radiographical improvement, serum levels of total IgE, the key biomarker for the pharmacological response in ABPA, were unchanged. Anti-IL-5/IL-5Rα mAbs that directly target eosinophils are promising candidates for the treatment of patients with ABPA, especially those with mucus plugs in the bronchi.

Effects of Oral Morphine on Dyspnea in Patients with Cancer: Response Rate, Predictive Factors, and Clinically Meaningful Change (CJLSG1101).

BACKGROUND: Although the efficacy of parenteral morphine for alleviating dyspnea has been previously demonstrated in several studies, little is known regarding the efficacy of oral morphine for dyspnea among patients with cancer, including its response rate and predictive factors of effectiveness. Therefore, the aim of this study was to clarify the effectiveness of oral morphine on dyspnea in patients with cancer and elucidate the predictive factors of its effectiveness. SUBJECTS, MATERIALS, AND METHODS: In this multicenter prospective observational study, we investigated the change in dyspnea intensity in patients with cancer before and after the administration of oral morphine by using a visual analog scale (VAS). We also administered a self-assessment questionnaire to determine whether the patients believed oral morphine was effective. RESULTS: Eighty patients were enrolled in the study, and 71 of these patients were eligible. The least square mean of the VAS scores for dyspnea intensity was 53.5 at baseline, which decreased significantly to 44.7, 40.8, and 35.0 at 30, 60, and 120 minutes after morphine administration, respectively. Fifty-four patients (76.1%) reported that oral morphine was effective on the self-assessment questionnaire. Among the background factors, a high score for "sense of discomfort" on the Cancer Dyspnea Scale (CDS) and a smoking history of fewer pack-years were associated with greater effectiveness. CONCLUSION: Oral morphine was effective and feasible for treating cancer-related dyspnea. A higher score for "sense of discomfort" on the CDS and a smaller cumulative amount of smoking may be predictive factors of the effectiveness of oral morphine. IMPLICATIONS FOR PRACTICE: This study demonstrated that oral morphine was effective in alleviating cancer-related dyspnea due to multiple factors including primary lung lesions, airway narrowing, and pleural effusion. Approximately 76% of patients reported that oral morphine was effective. A higher score for "sense of discomfort" on the Cancer Dyspnea Scale and a lower cumulative amount of smoking may be predictive factors for the effectiveness of oral morphine. Interestingly, respiratory rates in patients who reported the morphine to be effective decreased significantly after oral morphine administration, unlike the respiratory rates in "morphine-ineffective" patients.

Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.

BACKGROUND: Appropriate initial antibiotic treatment and avoiding administration of unnecessary broad-spectrum antibiotics are important for the treatment of pneumonia. To achieve this, assessment of risk for drug-resistant pathogens (DRPs) at diagnosis is essential. PURPOSE: The aim of this study was to validate a predictive rule for DRPs that we previously proposed (the community-acquired pneumonia drug-resistant pathogen [CAP-DRP] rule), comparing several other predictive methods. PATIENTS AND METHODS: A prospective observational study was conducted in hospitalized patients with community-onset pneumonia at four institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP-DRPs. RESULTS: CAP-DRPs were identified in 73 (10.1%) of 721 patients analyzed. The CAP-DRP rule differentiated low vs high risk of CAP-DRP at the threshold of ≥3 points or 2 points plus any of methicillin-resistant Staphylococcus aureus specific factors with a sensitivity of 0.45, specificity of 0.87, positive predictive value of 0.47, negative predictive value of 0.87, and accuracy of 0.79. Its discrimination performance, area under the receiver operating characteristic curve, was 0.73 (95% confidence interval 0.66-0.79). Specificity of the CAP-DRP rule against CAP-DRPs was the highest among the six predictive rules tested. CONCLUSION: The performance of the predictive rules and criteria for CAP-DRPs was limited. However, the CAP-DRP rule yielded high specificity and could specify patients who should be treated with non-broad-spectrum antibiotics, eg, a non-pseudomonal ß-lactam plus a macrolide, more precisely.

Mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: Impact of ß-lactam plus macrolide combination therapy.

BACKGROUND AND OBJECTIVE: Drug-resistant pathogen (DRP) risk stratification is important for choosing a treatment strategy for community-onset pneumonia. Evidence for benefits of non-antipseudomonal ß-lactam plus macrolide combination therapy (BLM) on mortality is limited in patients at low DRP risk. Risk factors for mortality remain to be clarified. METHODS: Post hoc analysis using a prospective multicentre study cohort of community-onset pneumonia was performed to assess 30-day differences in mortality between non-antipseudomonal ß-lactam monotherapy (BL) and BLM groups. Logistic regression analysis was performed to assess the therapeutic effect and risk factors for mortality in patients at low DRP risk. RESULTS: In total, 594 patients with community-onset pneumonia at low DRP risk (369 BL and 225 BLM) were analysed. The 30-day mortality in BL and BLM was 13.8% and 1.8%, respectively (P < 0.001). Multivariate analysis showed that BLM reduced the 30-day mortality (adjusted odds ratio: 0.28, 95% CI: 0.09-0.87) compared with BL. Independent prognostic factors for 30-day mortality included arterial partial pressure of carbon dioxide (PaCO2 ) > 50 mm Hg, white blood cell count < 4000/mm3 , non-ambulatory status, albumin < 3.0 g/dL, haematocrit < 30%, age ≥ 80 years, respiratory rate > 25/min and body temperature < 36°C. CONCLUSION: In patients with community-onset pneumonia at low DRP risk, BLM treatment reduced 30-day mortality compared with BL. Independent risk factors for mortality are potential confounding factors when assessing antibiotic effects in randomized clinical trials.

Can we predict the development of serious adverse events (SAEs) and early treatment termination in elderly non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy?

PURPOSE: Predicting the feasibility of platinum-based chemotherapy remains an important issue in elderly (over 70 years) patients with non-small cell lung cancer (NSCLC). The aim of this study was to identify the risk factors for the early serious adverse events (SAEs) (during cycles 1-2) in elderly receiving platinum-based chemotherapy, and to explore the clinical characteristics of patients who require early treatment termination without progressive disease (PD). METHODS: One hundred and ninety-eight consecutive elderly NSCLC patients receiving platinum-based chemotherapy were retrospectively reviewed. RESULTS: The median age was 73 years (range 70-83). 161 (81 %) were males, and 190 (95 %) were PS 0-1. Fifty-one (29 %) and 39 (19 %) patients developed early non-hematological SAEs and hematological SAEs, respectively. Multivariate analysis identified low serum albumin (<3.0 g/dl) as an independent risk factor for non-hematological SAEs, while low creatinine clearance (<45 ml/min) for hematological SAEs. In all, 24 (12 %) patients needed early treatment termination without PD. The major reason for this event was the development of non-hematological SAEs (4.5 %), followed by grade 2 non-hematological adverse events (AEs) (3 %). In multivariate analysis, age over 75 years and low serum albumin were associated with this event. The median overall survival (OS) in patients with this event was only 6.0 months, while the development of early SAE was not associated with poor OS. CONCLUSION: Baseline serum albumin might be useful for predicting the feasibility of platinum-based chemotherapy, and the risk estimation of early treatment termination without PD might be beneficial for the treatment selection in elderly NSCLC patients.

Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.

BACKGROUND: Appropriate initial antibiotics are essential for the treatment of infectious diseases. However, some patients with pneumonia might develop adverse outcomes, despite receiving appropriate initial antibiotics. We aimed to clarify the risk factors for 30-day mortality in patients who received appropriate initial antibiotics and to identify potential candidates who would benefit from adjunctive therapy. METHODS: From March 15, to Dec 22, 2010, we did a prospective, observational study at ten medical institutions in hospitalised patients (aged ≥20 years) with pneumonia. We did a multivariable logistic regression analysis to calculate odds ratios (ORs) and 95% CI to assess the risk factors for 30-day mortality. This study was registered with the University Medical Information Network in Japan, number UMIN000003306. FINDINGS: The 30-day mortality was 11% (61 of 579 patients) in the appropriate initial antibiotic treatment group and 17% (29 of 168) in the inappropriate initial antibiotic treatment group. Albumin concentration of less than 30 mg/L (adjusted OR 3·39, 95% CI 1·83-6·28), non-ambulatory status (3·34, 1·84-6·05), pH of less than 7·35 (3·13, 1·52-6·42), respiration rate of at least 30 breaths per min (2·33, 1·28-4·24), and blood urea nitrogen of at least 7·14 mmol/L (2·20, 1·13-4·30) were independent risk factors in patients given appropriate initial antibiotic treatment. The 30-day mortality was 1% (one of 126 patients), 1% (two of 168), 17% (23 of 137), 22% (20 of 89), and 44% (14 of 32) for patients with no, one, two, three, and four or five risk factors, respectively. INTERPRETATION: Patients with two or more risk factors were at a higher risk of death during the 30 days assessed than were individuals with no or one risk factor, despite appropriate initial antibiotic treatment. Therefore, adjunctive therapy might be important for improving outcomes in patients with two or more risk factors. FUNDING: Central Japan Lung Study Group.

First-line gefitinib therapy for elderly patients with non-small cell lung cancer harboring EGFR mutation: Central Japan Lung Study Group 0901.

BACKGROUND: The population of elderly patients with lung cancer is increasing worldwide. Although first-line gefitinib is one of the standard treatments for advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, few data have been reported regarding gefitinib and elderly patients. PATIENTS AND METHODS: Chemotherapy-naïve patients aged 70 years or older with stage IIIB or IV NSCLC harboring EGFR-activating mutation were enrolled and treated with 250 mg of gefitinib daily until disease progression. The primary end point was response rate, and secondary end points were survival, safety, and quality of life. RESULTS: Twenty patients were enrolled, and the median age was 79.5 years (range 72-90). Overall response rate was 70% (95% CI 45.7-88.1%), and the disease control rate was 90% (95% CI 68.3-98.7%). The median progression-free survival and overall survival time were 10.0 and 26.4 months, respectively. The Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) scores improved significantly 4 weeks after the initiation of gefitinib (P = 0.037) and maintained favorably over a 12-week assessment period. Among the seven items of FACT-LCS, shortness of breath and cough improved significantly after 4 weeks of treatment (P = 0.046 and P = 0.008, respectively). The most common adverse events were rash and liver dysfunction. Although Grade 1 pneumonitis developed in one patient, no treatment-related death was observed. CONCLUSION: First-line gefitinib therapy is effective and feasible for elderly patients harboring EGFR mutation, and improves disease-related symptoms, especially pulmonary symptoms like shortness of breath and cough.

Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.

RATIONALE: Identification of patients with drug-resistant pathogens at initial diagnosis is essential for treatment of pneumonia. OBJECTIVES: To elucidate clinical features of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP), and to clarify risk factors for drug-resistant pathogens in patients with CAP and HCAP. METHODS: A prospective observational study was conducted in hospitalized patients with pneumonia at 10 institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP drug-resistant pathogens (CAP-DRPs). MEASUREMENTS AND MAIN RESULTS: In total, 1,413 patients (887 CAP and 526 HCAP) were analyzed. CAP-DRPs were more frequently found in patients with HCAP (26.6%) than in patients with CAP (8.6%). Independent risk factors for CAP-DRPs were almost identical in patients with CAP and HCAP. These included prior hospitalization (adjusted odds ratio [AOR], 2.06; 95% confidence interval [CI], 1.23-3.43), immunosuppression (AOR, 2.31; 95% CI, 1.05-5.11), previous antibiotic use (AOR, 2.45; 95% CI, 1.51-3.98), use of gastric acid-suppressive agents (AOR, 2.22; 95% CI, 1.39-3.57), tube feeding (AOR, 2.43; 95% CI, 1.18-5.00), and nonambulatory status (AOR, 2.45; 95% CI, 1.40-4.30) in the combined patients with CAP and HCAP. The area under the receiver operating characteristic curve for counting the number of risk factors was 0.79 (95% CI, 0.74-0.84). CONCLUSIONS: The clinical profile of HCAP was different from that of CAP. However, physicians can predict drug resistance in patients with either CAP or HCAP by taking account of the cumulative number of the risk factors. Clinical trial registered with https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004001&language=E ; number UMIN000003306.

[A case of secondary pulmonary malignant lymphoma with multiple pulmonary nodules and spiculation].

A 72-year-old man presented to our hospital with fatigue and anemia. Chest CT showed multiple nodular shadows. We first suspected lung cancer and multiple metastatic lesions because some nodules had spiculation. However, PET-CT revealed the small intestine, thyroid and rib as well as these nodules to be positive for FDG uptake, suggesting malignant lymphoma and lung involvement. For diagnosis, lung biopsy by video-assisted thoracic surgery (VATS) was performed. Pathologic examination of the lung biopsy specimen showed diffuse large B-cell lymphoma. We diagnosed secondary pulmonary malignant lymphoma.

[A case of myeloid sarcoma in the anterior mediastinum].

We report a case of myeloid sarcoma in the anterior mediastinum. The patient was a 33-year-old man with a chief complaint of right shoulder pain, right upper limb edema, and cough. Chest contrast-enhanced computed tomography (CT) revealed a partially enhanced anterior mediastinal tumor. A CT-guided biopsy was then performed, and a Hematoxylin-eosin (HE) stain revealed mitosis of tumor cells and other cells, including eosinophils. Immunohistochemical stains with myeloperoxidase, CD34, CD43, CD68 and c-Kit tests were positive for tumor cells. Due to a pathological diagnosis of myeloid sarcoma, he was treated with chemotherapy based on a diagnosis of acute myelogenous leukemia. After complete remission was obtained, the patient visited another hospital to receive an unrelated bone marrow transplantation. Although it rarely occurs as a mediastinal tumor, the prognosis of myeloid sarcoma is unfavorable, and thus should be taken into consideration as a differential diagnosis.

Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404.

Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-naïve patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3-43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial.

[A case of severe asthma responsive to omalizumab treatment despite a low serum IgE level and lack of sensitized allergens].

A 49-year-old female patient suffering from severe intractable asthma uncontrolled even with high-dose inhaled glucocorticosteroids (fluticasone 1000 µg/day+ciclesonide 800 µg/day), salmeterol inhaler (100 µg/day) and oral betamethasone (1 mg/day) was admitted to our hospital because of severe asthma attack. The total serum IgE level was low at 9 (IU/mL). Though perennial allergens was also negative, administration of 150 mg omalizumab was started in August 2009 with the patient's consent, resulting in noticeable improvements in asthma symptoms and the peak expiratory flow (PEF) were achieved. Due to her weight gain and general malaise, the drug was discontinued after the second administration, resulting in worsening of asthma symptoms. Omalizumab therapy was restarted in January 2010 and marked improvements in asthma symptoms and PEF were noted. The effects continued for approximately three weeks after administration. After the sixth administration, the dose of oral betamethasone successfully reduced to 0.5 mg/day. When comparing the six-month pre- and post-omalizumab therapy period, asthma-related events such as unscheduled hospital visits were also reduced, and the dose of oral betamethasone could also be reduced to 64% of the pre-therapy period after the omalizumab treatment. This case strongly suggests the therapeutic effect of omalizumab in the treatment of severe intractable asthma with low serum IgE level without identifiable allergens.

[A case of rapidly progressing lung spindle cell carcinoma presenting as Pancoast syndrome].

We report a case of rapidly progressing spindle cell carcinoma presenting as Pancoast syndrome. The patient was a 59-year-old woman with a chief complaint of right forearm paresthesia. A chest computed tomography revealed a huge tumor in S1 and S2 in the right lung, invading the upper mediastinum and the first rib. A CT-guided lung biopsy was performed. H-E stain of the tissue revealed spindle-shaped tumor cells proliferating diffusely in a streaming pattern without definitive squamous or glandular differentiation. Immunohistochemical stains with CAM 5.2 and vimentin were positive for tumor cells. Based on a pathological diagnosis of spindle cell carcinoma (cT4N3M1, stage IV) she was treated with chemoradiotherapy. Despite treatment, the patient died 6 months after presenting.

[Pasteurella multocida pneumonia with molecular evidence of zoonotic transmission].

We report the case of a patient with pneumonia caused by Pasteurella multocida (P. multocida). An 83-year-old woman admitted for bronchiectasis, productive cough, and a high fever was found in chest radiography on admission to have a new infiltrative shadow in the left lower lung field. Chest computed tomography indicated bilateral bronchiectasis and an infiltrative lingular shadow. P. multocida was isolated from sputum samples. Biapenem and minocycline therapy ameliorated symptoms. Pulsed-field gel electrophoresis (PFGE) showed that the clinical isolate recovered was identical to the P. multocida isolate recovered from the pharyngeal swab specimen culture obtained from the patient's dog. Several years later, P. multocida subsp. gallicida isolates were recovered from human sputum and a canine pharyngeal swab specimen. PFGE confirmed these isolates to be identical and PFGE band patterns were identical to those of previous P. multocida isolates. These findings suggest that P. multocida was transmitted from the patient's dog to the patient and underscore the need to inform susceptible hosts at risk of contracting zoonotic agents about basic hygiene rules for keeping pets. PFGE data strengthened the evidence of zoonotic transmission of P. multocida through casual contact in a patient with a respiratory infection caused by this organism. PFGE should prove useful in both epidemiological tracing and preventing pasteurellosis and clarifying its pathology. Case reports of respiratory infections including pneumonia caused by P. multocida are increasing in humans, and P. multocida respiratory infections appear to occur mostly in patients with chronic respiratory disease. A history of pet exposure, even without bites or scratches, should alert the physician to P. multocida as a potential respiratory pathogen.

[Micafungin therapy for a case of chronic necrotizing pulmonary aspergillosis].

The patient was a 42-year-old man who visited a physician with fever, and was diagnosed with pulmonary abscess. Antibiotic therapy was ineffective, and he was referred to our hospital. Chest CT scanning revealed a lesion with cavity formation with an infiltrative shadow in the right upper lobe, and another infiltrative shadow in the left upper lobe. Chronic necrotizing pulmonary aspergillosis (CNPA) was diagnosed on the basis of positive culture of bronchial lavage specimens and positive serological test results for Aspergillus, in addition to the clinical and radiographic features. Intravenous administration of micafungin (MCFG) was initiated with combination therapy of percutaneous cavity drainage, inhaled amphotericin B and oral itraconazole. Clinical symptoms and findings gradually improved, and he was discharged after 40 days of MCFG therapy. MCFG was safe and effective therapy in this case, and may be considered a new therapeutic option for CNPA.

[Moderately differentiated adenocarcinoma of the lung presenting as multiple pulmonary metastases with thin-walled cavities].

A 63-year-old woman was admitted because of diabetes mellitus and abnormal chest radiographic findings. Computed tomographic scan showed a large mass in the S1 region of the right lung and many pulmonary nodules with thin-walled cavities in both lung fields. A transbronchial biopsy specimen revealed moderately differentiated adenocarcinoma of bronchial gland origin. The patient could not receive systemic chemotherapy because of her poor physical status, and died of respiratory failure due to advanced pulmonary metastases. Histopathological examination of an autopsy specimen confirmed the diagnosis of primary bronchial adenocarcinoma with multiple cavitary metastases. The cavity wall consisted of moderately differentiated adenocarcinoma cells, and central necrosis with neutrophil infiltration and fibrin precipitation were recognized. These findings suggest that the mechanism of cavity formation in this case may depend on the ischemic tumor necrosis or colliquative tumor necrosis associated with neutrophil infiltration into the central portion of metastatic lesion.

Evaluation of automated ribotyping system for characterization and identification of verocytotoxin-producing Escherichia coli isolated in Japan.

The usefulness of an automated ribotyping system (RiboPrinter) was evaluated for characterizing and identifying clinical isolates of 37 verocytotoxin-producing Escherichia coli (VTEC) strains and 16 non-VTEC strains. All strains were successfully ribotyped with satisfactory reproducibility and stability and characterized into 10 different ribogroups. All VTEC O157 strains were characterized into a specific ribogroup and correctly typed into the specific DuPont ID for VTEC O157:H7, while all of the non-VTEC O157 strains were clearly distinguished from VTEC O157. VTEC O26 and O111 strains, the most prevalent VTEC serotypes after O157, were also well characterized into specific ribogroups and identified. These results suggest that the RiboPrinter may have an advantage over other typing systems in that it can rapidly and easily discriminate VTEC from non-VTEC strains of the most prevalent VTEC serotypes in Japan, even though it provides a lesser degree of discrimination than pulsed-field gel electrophoresis (PFGE). With a hierarchical or sequential typing combining the RiboPrinter and PFGE, rapid and accurate typing can be achieved during an outbreak of VTEC, which may be useful in clinical and public health settings.