Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma

Background/Aims@#Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. @*Methods@#This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. @*Results@#Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). @*Conclusions@#Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma

Background/Aims@#Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. @*Methods@#This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. @*Results@#Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). @*Conclusions@#Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Expression of Muscarinic Receptors and the Effect of Tiotropium Bromide in Aged Mouse Model of Chronic Asthma / 결핵및호흡기질환

BACKGROUND: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling. METHODS: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M2 and M3 receptors were examined. RESULTS: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M2 but decreased expression of M3 in all aged groups of OVA. CONCLUSION: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M3 and M2 muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.

Clinical outcomes of extracorporeal membrane oxygenation support in patients with hematologic malignancies

BACKGROUND/AIMS: The clinical outcomes of patients with hematologic malignancies who were treated with extracorporeal membrane oxygenation (ECMO) after the failu re of optimal conventional therapy were determined. METHODS: The medical records of all patients administered ECMO during their stay in a medical intensive care unit of Seoul St. Mary's Hospital between February 2010 and July 2013 were reviewed retrospectively. RESULTS: In total, 15 patients with hematologic malignancies were compared to 33 immunocompetent patients with documented cardiorespiratory failure. Underlying hematologic malignancies were significantly associated with lower overall survival (0.0% vs. 24.2%, p = 0.044). Mortality was significantly associated with a higher 24 hours ECMO inspired fraction of oxygen (0.71 +/- 0.24 vs. 0.47 +/- 0.13, p = 0.015), the development of infection after ECMO (87.5% vs. 25.0%, p = 0.001), and the presence of hyperbilirubinemia (70.0% vs. 0.0%, p < 0.001). Matching of the patients based on their Acute Physiology and Chronic Health Evaluation II scores confirmed the greater risk of mortality in patients with hematologic malignancies (survival: 0.0% vs. 40.0%, p = 0.017). The mean difference in inotropic-equivalent scores after ECMO was significantly lower in the immunocompetent patients than in those with hematologic malignancies (-59.22 +/- 97.83 vs. 53.87 +/- 164.46, p = 0.026). CONCLUSIONS: Patients with hematologic malignancies who require ECMO for respiratory support have poor outcomes. The incidence of complications in these patients did not significantly differ from that in immunocompetent patients.

New Guidelines for Asthma Management / 대한내과학회지

Asthma is a chronic airway inflammatory disease that is characterized by symptoms such as shortness of breath, wheezing, chest tightness, and nighttime or early morning coughing, together with variable expiratory airflow limitation. Asthma is a heterogeneous disease involving various underlying processes that have been described based on causal or exacerbating factors, the pattern of airflow obstruction, severity of disease, pattern of cellular inflammation, and structural changes among patients with asthma. However, there is considerable overlap among these clinical variants, which are not correlated strongly with specific pathological processes or treatment responses. The Global Strategy for Asthma Management and Prevention 2014 (GINNA 2014) emphasizes the importance of confirming the diagnosis to minimize both under- and over-treatment with respect to the heterogeneity of asthma. To assess asthma control, it is necessary to assess not only the symptom control but also the future risks of an adverse outcome. Lung function is the most used indicator of future risk. This article reviews the treatment of adult asthma, including patients already receiving treatment according to GINA 2014 and the Health Insurance Review and Assessment Service.

Interstitial Lung Diseases: Respiratory Review of 2013 / 결핵및호흡기질환

Interstitial lung diseases are heterogeneous entities with diverse clinical presentations. Among them, idiopathic pulmonary fibrosis and connective tissue disease-associated interstitial lung disease are specific categories that pulmonologists are most likely to encounter in the clinical field. Despite the accumulated data from extensive clinical trial and observations, we continue to have many issues which need to be resolved in this field. In this update, we present the review of several articles regarding the clinical presentation, prognosis and treatment of patients with idiopathic pulmonary fibrosis or connective tissue disease-associated interstitial lung disease.

A Case of Microscopic Polyangiitis Presented as Pleural Effusion / 결핵및호흡기질환

Microscopic polyangiitis is a necrotizing vasculitis, characterized by inflammation of small vessels (capillaries, venules, and arterioles) with few or no immune deposits. The kidneys are the most commonly affected organs and are involved in 90% of patients, whereas pulmonary involvement occurs in a minority of cases (10% to 30%). In cases of lung disease, diffuse alveolar hemorrhage with pulmonary capillaritis is the most common manifestation. Microscopic polyangiitis is strongly associated with antineutrophil cytoplasmic autoantibody, which is a useful diagnostic serological marker. We report a case of microscopic polyangiitis presented as pleural effusion in a 67-year-old female. Pleural effusions have been reported in some cases previously, but the number of cases were small and their characteristics have not been well described. This report describes characteristic findings of pleural fluid and its histological features in a case of microscopic polyangiitis.

A Case of Welder's Lung Disease and Concurred Non-Tuberculotic Mycobacterial Infection Confirmed with Thoracoscopic Lung Biopsy / 결핵및호흡기질환

Pulmonary siderosis, or Welder's lung disease is an occupational lung disease caused by iron-inhalation. Diagnosis of pulmonary siderosis is based on occupational history of the patient, radiologic findings, and pathologic findings of iron-laden macrophages within lung tissue or broncho-alveolar lavage fluid. We observed a case of a 43 years-old welder diagnosed with pulmonary siderosis via thoracoscopic lung biopsy. Sputum culture along with pathology also identified a non-tuberculotic mycobacterial infection with a sputum culture and the pathologic findings. The patient was treated with anti-tubercular medication and cessation of iron-exposure. And his condition improved within a few months.

Pulmonary Cryptococcosis Mimicking Primary Lung Cancer with Multiple Lung Metastases / 결핵및호흡기질환

Cryptococcosis is an invasive fungal infection, which is more common in immunocompromised patients. However, pulmonary cryptococcosis can occur in immunocompetent patients and should be considered on a differential diagnosis for nodular or mass-like lesions in chest radiograph. Recently, we experienced a patient with pulmonary cryptococcosis, successfully treated with oral fluconazole therapy. A 74-year-old female patient was referred for an evaluation of abnormal images, a large consolidative mass with multiple nodular consolidations and small nodules that mimics primary lung cancer with multiple lung to lung metastases. Computed tomography-guided lung biopsy confirmed the diagnosis of pulmonary cryptococcosis. The follow-up image taken after 4 months with oral fluconazole treatment showed marked improvement.

A Case of Pulmonary MALT Lymphoma Arising from Lymphocytic Interstitial Pneumonitis / 결핵및호흡기질환

Pulmonary mucosa-associated lymphoid tissue-derived (MALT) lymphoma is a rare disease. This disorder is considered to be a model of antigen-driven lymphoma, which is driven either by autoantigens or by chronic inflammatory conditions. Low-grade B-cell MALT lymphoma may develop from a nonneoplastic pulmonary lymphoproliferative disorder, such as lymphocytic interstitial pneumonitis (LIP). A recent estimate predicts that less than 5% of LIP patients acquire malignant, low-grade, B-cell lymphoma. In Korea, there has been no previous report of malignant low-grade, B-cell lymphoma, acquired from LIP. Here, we present the case of a patient with LIP that developed into pulmonary MALT lymphoma, six years after diagnosis.

A Case of Pulmonary Cryptococcosis in a Patient with Psoriatic Arthritis Treated with Adalimumab

Psoriatic arthritis is an immune-mediated chronic inflammatory disease triggered and maintained by inflammatory mediators, including tumor necrosis factor-alpha. Although TNF-alpha antagonist is effective for the treatment of psoriatic arthritis, infections caused by tuberculosis or fungus have emerged as significant complications of therapy. We report a case of pulmonary cryptococcosis in a patient with psoriatic arthritis treated with adalimumab.

The Soluble Tumor Necrosis Factor-Alpha Receptor Suppresses Airway Inflammation in a Murine Model of Acute Asthma

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. TNF-alpha blocking strategies are now being tried in asthma patients. This study investigated whether TNF-alpha blocking therapy inhibits airway inflammation and airway hyperresponsiveness (AHR) in a mouse model of asthma. We also evaluated the effect of TNF-alpha blocking therapy on cytokine production and adhesion molecule expression. MATERIALS AND METHODS: Ovalbumin (OVA) sensitized BALB/c female mice were exposed to intranasal OVA administration on days 31, 33, 35, and 37. Mice were treated intraperitoneally with soluble TNF-alpha receptor (sTNFR) during the OVA challenge. RESULTS: There were statistically significant decreases in the numbers of total cell and eosinophil in bronchoalveolar lavage fluid (BALF) in the sTNFR treated group compared with the OVA group. However, sTNFR-treatment did not significantly decrease AHR. Anti-inflammatory effect of sTNFR was accompanied with reduction of T helper 2 cytokine levels including interleukin (IL)-4, IL-5 and IL-13 in BALF and vascular cell adhesion molecule 1 expression in lung tissue. CONCLUSION: These results suggest that sTNFR treatment can suppress the airway inflammation via regulation of Th2 cytokine production and adhesion molecule expression in bronchial asthma.

A Case of Pulmonary Thromboembolism with JAK2 Mutation / 결핵및호흡기질환

The incidence of pulmonary thromboembolism increases with age. The risk factors of pulmonary thromboembolism include surgery, malignancy, obesity, lupus anticoagulants, and vascular conditions such as deep vein thrombosis. Thromboembolism in younger patients or in unusual locations, the possibility of primary thrombophilic conditions should be considered. Primary thrombophilic states include myeloproliferative disorders (MPD). JAK2 V617F mutation is found commonly in patients diagnosed with MPD, in 90~95% of polycythemia vera (PV) and in 50~60% of essential thrombocytosis (ET) patients. Sometimes the JAK2 V617F mutation is found in cases without MPD. The relationship between JAK2 V617F mutation and thrombosis has not been defined. Recently, clinical evidence suggests that this mutation may be variably associated with thrombosis. We present one case of pulmonary thromboembolism in a young patient, who was positive for the JAK2 V617F mutation and did not have MPD.

Two Cases of Pulmonary Thromboembolism in Young Patients with Hyperhomocysteinemia / 결핵및호흡기질환

Incidences of pulmonary thromboembolism markedly increase with age. Risk factors of pulmonary thromboembolism are surgery, trauma, acute medical illness, immobilization, pregnancy, usage of hormone, and advanced age. In the cases of thrombomembolism occurred in young age, the possibility of thrombophilc state is needed to be investigated. Among many diseases or state associated thrombophilic state, homocyteinemia should be considered a cause of thromboembolism before fifth decade. Homocyteinemia is caused by deficiency of N-5-methyltetrahydrofolate, cystathionie beta-synthase and vitamin B12. The presence of the mutation of 5,10-methyleneterahydrofolate lead to homocyteinemia by deficiency of N-5-methyltetrahydrofolate. Homocysteine is acknowledged the risk factor of cardiovascular event, and storke. Homocysteinemia can be the cause of thromboemboism via damaging endotheial cell. We present two cases of pulmonary thromboembolism in young age which seem to be associated with homocysteinemia precipitated by mutation of 5,10-methyleneterahydrofolate.

Prognostic Value of Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF) Expression in Resected Non-small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Tumor angiogenesis plays an important role in tumor growth, maintenance and metastatic potential. Tumor tissue produces many types of angiogenic growth factors. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have both been implicated to have roles in tumor angiogenesis. In this study, the expression of tissue VEGF and bFGF from non-small cell lung cancer (NSCLC) patients were analyzed. METHODS: We retrospectively investigated 35 patients with a histologically confirmed adenocarcinoma or squamous cell carcinoma of the lung, where the primary curative approach was surgery. An ELISA was employed to determine the expression of VEGF and bFGF in extracts prepared from 35 frozen tissue samples taken from the cancer patients. RESULTS: VEGF and bFGF concentrations were significantly increased in lung cancer tissue as compared with control (non-cancerous) tissue. The VEGF concentration was significantly increased in T2 and T3 cancers as compared with T1 cancer. Expression of VEGF was increased in node-positive lung cancer tissue as compared with node-negative lung cancer tissue (p=0.06). VEGF and bFGF expression were not directly related to the stage of lung cancer and patient survival. CONCLUSION: Expression of VEGF and bFGF were increased in lung cancer tissue, and the expression of VEGF concentration in lung cancer tissue was more likely related with tumor size and the presence of a lymph node metastasis than the expression of bFGF. However, in this study, expression of both VEGF and bFGF in tissue were not associated with patient prognosis.

Time Sequence of Airway Remodeling in a Mouse Model of Chronic Asthma: the Relation with Airway Hyperresponsiveness

During the course of establishing an animal model of chronic asthma, we tried to elucidate the time sequence of airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and associated cytokines. Seven-week-old female BALB/c mice were studied as a chronic asthma model using ovalbumin (OVA). After sensitization, mice were exposed twice weekly to aerosolized OVA, and were divided into three groups depending on the duration of 4 weeks, 8 weeks, and 12 weeks. At each time point, airway responsiveness, inflammatory cells, cytokines in bronchoalveolar lavage fluids (BALF), serum OVA-specific IgE, IgG1, IgG2a, and histological examination were carried out. AHR to methacholine, increased levels of OVA-specific IgG1 and IgG2a, and goblet cell hyperplasia were continuously sustained at each time point of weeks. In contrast, we observed a time-dependent decrease in serum OVA-specific IgE, BALF eosinophils, BALF cytokines such as IL-13, transforming growth factor-beta1, and a time-dependent increase in BALF promatrix metalloproteinase-9 and peribronchial fibrosis. In this OVA-induced chronic asthma model, we observed airway remodelings as well as various cytokines and inflammatory cells being involved in different time-dependent manners. However, increased airway fibrosis did not directly correlate with a further increase in airway hyperresponsiveness.

Inflammatory and Remodeling Events in Asthma with Chronic Exposure to House Dust Mites: A Murine Model

Although animal models with ovalbumin have been used to study chronic asthma, there are difficulties in inducing recurrence as well as in maintaining chronic inflammation in this system. Using a murine model of house dust mite (HDM)-induced bronchial asthma, we examined the airway remodeling process in response to the chronic exposure to HDM. During the seventh and twelfth weeks of study, HDM were inhaled through the nose for three consecutive days and airway responsiveness was measured. Twenty-four hours later, bronchoalveolar lavage and histological examination were performed. The degree of overproduction of mucus, subepithelial fibrosis, and the thickness of the peribronchial smooth muscle in the experimental group was clearly increased compared to the control group. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. In the bronchoalveolar lavage fluid, the number of total cells and eosinophils was increased; during the twelfth week, the number of neutrophils increased in the experimental group. With regard to changes in cytokines, the concentrations of IL-4, IL- 13, and transforming growth factor-beta (TGF-beta) were increased in the experimental group. The data suggest that eosinophils, IL-4, IL-13, and TGF-beta might play an important role in the airway remodeling process and that neutrophils may be involved with increased exposure time.

p16(INK4a) Promoter Hypermethylation in Sputum, Blood, and Tissue from Non-Small Cell Lung Cancer and Pulmonary Inflammation / 결핵및호흡기질환

BACKGROUND: The aberrant promoter hypermethylation of p16(INK4a), as a tumor suppressor gene, is contributory factor to non-small cell lung cancer(NSCLC). However, its potential diagnostic impact of lung cancer is unclear. This study measured the level of p16(INK4a) promoter hypermethylation in the sputum and blood, and compared this with the level measured in the tissue obtained from NSCLC and pulmonary inflammation. METHODS: Of the patients who visited the Our Lady of Mercy Hospital in Incheon, Korea for an evaluation of a lung mass and underwent blood, sputum, and tissue tests, 23patients (18 NSCLC, 5 pulmonary inflammation) were enrolled in this study. DNA was extracted from each sample and the level of p16(INK4a) methylation was determined using methylation-specific polymerase chain reaction. RESULTS: p16(INK4a) methylation of the blood was observed in 88.9% (16 of 18) and 20.0% (1 of 5) of NSCLC and from pulmonary inflammation samples, respectively (P=0.008). Methylation of the sputum was observed in 83.3% (10 of 12) 80.0% (4 of 5) of NSCLC and pulmonary inflammation samples, respectively (P=1.00). Among the 8 NSCLC tissue samples, methylation changes were detected in 75.0% of samples (6 cases). Four out of seven tissue samples (57.1%) showed concordance, being methylated in both the blood and sputum. CONCLUSIONS: There was a higher level of p16(INK4a) methylation of the blood from NSCLC patients than from pulmonary inflammation. The tissue showed a high concordance with the blood in the NSCLC samples. These findings suggest that p16(INK4a) promoter hypermethylation of the blood can used to discriminate between NSCLC and pulmonary inflammation.

Analysis of Sleep Questionnaires of Patients who Performed Overnight Polysomnography at the University Hospital / 결핵및호흡기질환

BACKGROUND: The objective of this study was to understand sleep-related problems, and to determine whether the sleep questionnaires is a clinically useful method in patients who need polysomnography. METHODS: Subjects were patients who performed polysomnography and who asked to answer a sleep questionnaires at the Sleep Disorders Clinic of St. Paul's Hospital, Catholic University of Korea. Baseline characteristics, past medical illness, behaviors during sleep-wake cycle, snoring, sleep-disordered breathing and symptoms of daytime sleepiness were analyzed to compare with data of polysomnography. RESULTS: The study population included 1081 patients(849 men, 232 female), and their mean age was 44.2+/-12.8 years. Among these patients, 38.9% had an apnea-hypopnea index(AHI) < 5, 27.9% had 5 < or = AHI < 20, 13.2% had 20 < or = AHI < 40, and 20.0% had 40 < or = AHI. The main problems for visiting our clinic were snoring(91.7%), sleep apnea(74.5%), excessive daytime sleepiness(8.0%), insomnia(4.3%), bruxism(1.1%) and attention deficit(0.5%). The mean value of frequency of interruptions of sleep was 1.6 and the most common reason was urination(46.3%). Epworth Sleepiness Scale(ESS) had a weak correlation with AHI(r=0.209, p<0.01). When we performed analysis of sleep questionnaires, there were significant differences in the mean values of AHI according to the severity of symptoms including snoring, daytime sleepiness, taking a nap and arousal state after wake(p<0.05). CONCLUSION: On the basis of statistical analysis of sleep questionnaires, the severity of subjective symptoms such as ESS, snoring, daytime sleepiness and arousal state after wake correlated with the AHI significantly. Therefore the sleep questionnaires can be useful instruments for prediction of the severity of sleep disorder, especially sleep-disordered breathing.

Analysis of Sleep Questionnaires of Patients who Performed Overnight Polysomnography at the University Hospital / 결핵및호흡기질환

BACKGROUND: The objective of this study was to understand sleep-related problems, and to determine whether the sleep questionnaires is a clinically useful method in patients who need polysomnography. METHODS: Subjects were patients who performed polysomnography and who asked to answer a sleep questionnaires at the Sleep Disorders Clinic of St. Paul's Hospital, Catholic University of Korea. Baseline characteristics, past medical illness, behaviors during sleep-wake cycle, snoring, sleep-disordered breathing and symptoms of daytime sleepiness were analyzed to compare with data of polysomnography. RESULTS: The study population included 1081 patients(849 men, 232 female), and their mean age was 44.2+/-12.8 years. Among these patients, 38.9% had an apnea-hypopnea index(AHI) < 5, 27.9% had 5 < or = AHI < 20, 13.2% had 20 < or = AHI < 40, and 20.0% had 40 < or = AHI. The main problems for visiting our clinic were snoring(91.7%), sleep apnea(74.5%), excessive daytime sleepiness(8.0%), insomnia(4.3%), bruxism(1.1%) and attention deficit(0.5%). The mean value of frequency of interruptions of sleep was 1.6 and the most common reason was urination(46.3%). Epworth Sleepiness Scale(ESS) had a weak correlation with AHI(r=0.209, p<0.01). When we performed analysis of sleep questionnaires, there were significant differences in the mean values of AHI according to the severity of symptoms including snoring, daytime sleepiness, taking a nap and arousal state after wake(p<0.05). CONCLUSION: On the basis of statistical analysis of sleep questionnaires, the severity of subjective symptoms such as ESS, snoring, daytime sleepiness and arousal state after wake correlated with the AHI significantly. Therefore the sleep questionnaires can be useful instruments for prediction of the severity of sleep disorder, especially sleep-disordered breathing.