Lung Disease Diagnostic Model Through IgG Sensitization to Microbial Extracellular Vesicles

Purpose@#Recently, there has been a rise in the interest to understand the composition of indoor dust due to its association with lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Furthermore, it has been found that bacterial extracellular vesicles (EVs) within indoor dust particles can induce pulmonary inflammation, suggesting that these might play a role in lung disease. @*Methods@#We performed microbiome analysis of indoor dust EVs isolated from mattresses in apartments and hospitals. We developed diagnostic models based on the bacterial EVs antibodies detected in serum samples via enzyme-linked immunosorbent assay (ELISA) in this analysis. @*Results@#Proteobacteria was the most abundant bacterial EV taxa observed at the phylum level while Pseudomonas, Enterobacteriaceae (f) and Acinetobacter were the most prominent organisms at the genus level, followed by Staphylococcus. Based on the microbiome analysis, serum anti-bacterial EV immunoglobulin G (IgG), IgG1 and IgG4 were analyzed using ELISA with EV antibodies that targeted Staphylococcus aureus, Acinetobacter baumannii, Enterobacter cloacae and Pseudomonas aeruginosa. The levels of anti-bacterial EV antibodies were found to be significantly higher in patients with asthma, COPD and lung cancer compared to the healthy control group. We then developed a diagnostic model through logistic regression of antibodies that showed significant differences between groups with smoking history as a covariate. Four different variable selection methods were compared to construct an optimal diagnostic model with area under the curves ranging from 0.72 to 0.81. @*Conclusions@#The results of this study suggest that ELISA-based analysis of anti-bacterial EV antibodies titers can be used as a diagnostic tool for lung disease. The present findings provide insights into the pathogenesis of lung disease as well as a foundation for developing a novel diagnostic methodology that synergizes microbial EV metagenomics and immune assays.

Lung Disease Diagnostic Model Through IgG Sensitization to Microbial Extracellular Vesicles

Purpose@#Recently, there has been a rise in the interest to understand the composition of indoor dust due to its association with lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Furthermore, it has been found that bacterial extracellular vesicles (EVs) within indoor dust particles can induce pulmonary inflammation, suggesting that these might play a role in lung disease. @*Methods@#We performed microbiome analysis of indoor dust EVs isolated from mattresses in apartments and hospitals. We developed diagnostic models based on the bacterial EVs antibodies detected in serum samples via enzyme-linked immunosorbent assay (ELISA) in this analysis. @*Results@#Proteobacteria was the most abundant bacterial EV taxa observed at the phylum level while Pseudomonas, Enterobacteriaceae (f) and Acinetobacter were the most prominent organisms at the genus level, followed by Staphylococcus. Based on the microbiome analysis, serum anti-bacterial EV immunoglobulin G (IgG), IgG1 and IgG4 were analyzed using ELISA with EV antibodies that targeted Staphylococcus aureus, Acinetobacter baumannii, Enterobacter cloacae and Pseudomonas aeruginosa. The levels of anti-bacterial EV antibodies were found to be significantly higher in patients with asthma, COPD and lung cancer compared to the healthy control group. We then developed a diagnostic model through logistic regression of antibodies that showed significant differences between groups with smoking history as a covariate. Four different variable selection methods were compared to construct an optimal diagnostic model with area under the curves ranging from 0.72 to 0.81. @*Conclusions@#The results of this study suggest that ELISA-based analysis of anti-bacterial EV antibodies titers can be used as a diagnostic tool for lung disease. The present findings provide insights into the pathogenesis of lung disease as well as a foundation for developing a novel diagnostic methodology that synergizes microbial EV metagenomics and immune assays.

Methazolamide-induced toxic epidermal necrolysis confirmed by lymphocyte activation test

Among various dermatological entities, toxic epidermal necrolysis (TEN) is a rare but potentially fatal delayed hypersensitivity reaction to numerous medications. A 38-year-old male presented with systemic hypersensitivity reaction, such as high fever, pain in the eyes, and diffuse pruritic erythematous maculopapular eruptions with multiple targetoid plaques that became vesicular and bullous. Oral mucosa and conjunctivae were involved. The first sign appeared about 1 week after taking methazolamide (50 mg twice a day) for the management of glaucomatous eyes. Although methazolamide was discontinued, blistering and skin denudation progressed to affect up to 80% of the body surface area and a positive Nikolsky sign was noted. High fever also persisted. Skin lesions started to improve after 2 weeks of management and fever subsided. Cutaneous lesions improved with minimal permanent sequele 2 months later. HLA-B*5901 was found by high-resolution genotyping. The lymphocyte activation test performed 6 months after remission showed a positive response to methazolamide challenge. This is the first case of methazolamide-induced TEN in which methazolamide was confirmed as a culprit drug by the lymphocyte activation test.

IgG Sensitization to Extracellular Vesicles in Indoor Dust Is Closely Associated With the Prevalence of Non-Eosinophilic Asthma, COPD, and Lung Cancer

PURPOSE: Recent experimental evidence shows that extracellular vesicles (EVs) in indoor dust induce neurtrophilic pulmonary inflammation, which is a characteristic pathology in patients with severe asthma and chronic obstructive pulmonary disease (COPD). In addition, COPD is known to be an important risk factor for lung cancer, irrespective of cigarette smoking. Here, we evaluated whether sensitization to indoor dust EVs is a risk for the development of asthma, COPD, or lung cancer. METHODS: Serum IgG antibodies against dust EVs were measured in 90 healthy control subjects, 294 asthmatics, 242 COPD patients, and 325 lung cancer patients. Serum anti-dust EV IgG titers were considered high if they exceeded a 95 percentile value of the control subjects. Age-, gender-, and cigarette smoke-adjusted multiple logistic regression analyses were performed to determine odds ratios (ORs) for asthma, COPD, and lung cancer patients vs the control subjects. RESULTS: In total, 4.4%, 13.6%, 29.3%, and 54.9% of the control, asthma, COPD, and lung cancer groups, respectively, had high serum anti-dust EV IgG titers. Adjusted multiple logistic regression revealed that sensitization to dust EVs (high serum anti-dust EV IgG titer) was an independent risk factor for asthma (adjusted OR, 3.3; 95% confidence interval [CI], 1.1-10.0), COPD (adjusted OR, 8.0; 95% CI, 2.0-32.5) and lung cancer (adjusted OR, 38.7; 95% CI, 10.4-144.3). CONCLUSIONS: IgG sensitization to indoor dust EVs appears to be a major risk for the development of asthma, COPD, and lung cancer.

Experience with Elizabethkingia meningoseptica Infection in Adult Patients at a Tertiary Hospital / 대한구급학회지

BACKGROUND: Few reports have documented the clinical characteristics and treatment outcomes of adult patients with Elizabethkingia meningoseptica infection. METHODS: Medical records of patients over 18 years of age and suspected of having an E. meningoseptica infection from March 1, 2006 to February 28, 2013 were reviewed retrospectively. Their clinical characteristics, antimicrobial susceptibility results, and treatment outcomes were analyzed. RESULTS: E. meningoseptica was isolated from 30 patients. Median age was 68.5 years, and infections were more frequent in males (17, 56.7%). The most common isolation source was sputum (23, 76.7%), and pneumonia was the most common condition (21, 70%) after excluding two cases of colonization. This bacterium was most susceptible to minocycline (27, 90%) and fluoroquinolones, including levofloxacin (20, 66.7%) and ciprofloxacin (18, 60%). The mortality rate due directly to E. meningoseptica infection was 20% (6/30), and uncontrolled pneumonia was the only cause of death. After isolating E. meningoseptica, the numbers of patients with pneumonia (9/9, 100% vs. 12/21, 57.1%), history of hemodialysis (5/9, 55.6% vs. 3/21, 14.3%), tracheostomy (8/9, 88.9 vs. 10/21, 47.6%), and median Charlson comorbidity index score (6 [range, 3-9] vs. 4 [range, 0-9]) were significantly higher in non-survivors than those in survivors (p < 0.05, for each). However, only 12 (40%) patients received appropriate antibiotics. CONCLUSIONS: E. meningoseptica infection most commonly presented as pneumonia in adults with severe underlying diseases. Despite the high mortality rate, the rate of appropriate antibiotic use was notably low.

A Case of Advanced Malignant Pleural Mesothelioma Treatment with Chemotherapy and Photodynamic Therapy / 결핵및호흡기질환

Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant, and generally fatal disease. A 68-year-old male who was diagnosed with MPM at another hospital came to our hospital with dyspnea. We advised him to take combination chemotherapy but he refused to take the treatment. That was because he had already received chemotherapy with supportive care at another hospital but his condition worsened. Thus, we recommended photodynamic therapy (PDT) to deal with the dyspnea and MPM. After PDT, the dyspnea improved and the patient then decided to take the combination chemotherapy. Our patient received chemotherapy using pemetrexed/cisplatin. Afterwards, he received a single PDT treatment and then later took chemotherapy using gemcitabine/cisplatin. The patient showed a survival time of 27 months, which is longer than median survival time in advanced MPM patients. Further research and clinical trials are needed to demonstrate any synergistic effect between the combination chemotherapy and PDT.

Experience with Elizabethkingia meningoseptica Infection in Adult Patients at a Tertiary Hospital / 대한중환자의학회지

BACKGROUND: Few reports have documented the clinical characteristics and treatment outcomes of adult patients with Elizabethkingia meningoseptica infection. METHODS: Medical records of patients over 18 years of age and suspected of having an E. meningoseptica infection from March 1, 2006 to February 28, 2013 were reviewed retrospectively. Their clinical characteristics, antimicrobial susceptibility results, and treatment outcomes were analyzed. RESULTS: E. meningoseptica was isolated from 30 patients. Median age was 68.5 years, and infections were more frequent in males (17, 56.7%). The most common isolation source was sputum (23, 76.7%), and pneumonia was the most common condition (21, 70%) after excluding two cases of colonization. This bacterium was most susceptible to minocycline (27, 90%) and fluoroquinolones, including levofloxacin (20, 66.7%) and ciprofloxacin (18, 60%). The mortality rate due directly to E. meningoseptica infection was 20% (6/30), and uncontrolled pneumonia was the only cause of death. After isolating E. meningoseptica, the numbers of patients with pneumonia (9/9, 100% vs. 12/21, 57.1%), history of hemodialysis (5/9, 55.6% vs. 3/21, 14.3%), tracheostomy (8/9, 88.9 vs. 10/21, 47.6%), and median Charlson comorbidity index score (6 [range, 3-9] vs. 4 [range, 0-9]) were significantly higher in non-survivors than those in survivors (p < 0.05, for each). However, only 12 (40%) patients received appropriate antibiotics. CONCLUSIONS: E. meningoseptica infection most commonly presented as pneumonia in adults with severe underlying diseases. Despite the high mortality rate, the rate of appropriate antibiotic use was notably low.

A Case of Bronchial Artery Aneurysm in Cavitary Pulmonary Tuberculosis / 대한내과학회지

A bronchial artery (BA) aneurysm is a rare, life-threatening disease when it ruptures. Recently, we experienced a case of massive hemoptysis due to a BA aneurysm rupture in a pulmonary tuberculosis cavity, treated with BA embolization followed by surgical resection of the cavitary lesion. To our knowledge, this is the first case of a BA aneurysm associated with cavitary pulmonary tuberculosis.

A Case of Bronchial Artery Aneurysm in Cavitary Pulmonary Tuberculosis / 대한내과학회지

A bronchial artery (BA) aneurysm is a rare, life-threatening disease when it ruptures. Recently, we experienced a case of massive hemoptysis due to a BA aneurysm rupture in a pulmonary tuberculosis cavity, treated with BA embolization followed by surgical resection of the cavitary lesion. To our knowledge, this is the first case of a BA aneurysm associated with cavitary pulmonary tuberculosis.

The safety and efficacy of recombinant fibroblast growth factor 2 in human asthmatics: A pilot study

PURPOSE: Fibroblast growth factor 2 (FGF2) has been shown to inhibit airway inflammation, mucus production, and airway hyperresponsiveness in mouse model of asthma. The aim of this study was to evaluate the safety and efficacy of inhaled recombinant FGF2 in asthmatic patients. METHODS: Eight asthmatics were eligible for the study. All patients were admitted to a hospital, and recombinant FGF2 was administered using a nebulizer at a concentration of 4.5 ng/mL three times a day for one week. Pulmonary function test, methacholine bronchial provocation test, induced sputum analysis, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were performed at the beginning of wash-out period, before and after the treatment, and at the end of study. And all these parameters were compared before and after FGF2 treatment. RESULTS: There were no serious adverse events associated with recombinant FGF2 during five-week study period. Daytime and nocturnal symptoms improved after the treatment (P=0.028 and P=0.012, respectively). AQLQ and ACT also improved after the treatment (P=0.017 and P=0.011, respectively). However, lung function, airway hyperresponsiveness, and airway inflammation showed no significant difference before and after the treatment. CONCLUSION: Inhaled recombinant FGF2 was safely used to eight asthmatics without any serious adverse events, and improved daytime and nocturnal symptoms, and quality of life in adult asthmatics. FGF2 may be a potential drug in the treatment of asthma.

ERRATUM: Author's Name Correction. The safety and efficacy of recombinant fibroblast growth factor 2 in human asthmatics: A pilot study

The fourth author's name was misprinted.

ABCC2 Haplotype is Associated With Antituberculosis Drug-Induced Maculopapular Eruption

Genetic variants in ATP-binding cassette (ABC) transporter genes are associated with increased susceptibility to adverse drug reactions. We hypothesized that genetic variant ABC transporters (ABCB1 and ABCC2) may be candidate markers for predicting maculopapular eruption (MPE) induced by antituberculosis therapy. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in the ABCB1 and ABCC2 genes between 62 antituberculosis drug (ATD)-induced MPE cases and 159 ATD-tolerant controls using multivariate logistic regression analysis. There was no significant association between genetic polymorphisms in ABCB1 and ATD-induced MPE (P>0.05). Among seven selected SNPs of ABCC2, IVS3-49C>T in intron and I1324I were associated with ATD-induced MPE (P=0.029 and 0.036, respectively). In an analysis of the ABCC2 haplotypes (ht; -1549G>A_-24C>T_IVS3-49C>T_V417I), ht1[G-C-C-G] was significantly associated with ATD-induced MPE (P=0.032, OR=0.35, 95% CI: 0.16-0.95). No significant association between the other haplotypes and ATD-induced MPE was observed. An ABCC2 haplotype is associated with the presence of ATD-induced MPE in patients with tuberculosis and may be a genetic risk factor for the development of MPE induced by ATD.

A Case of Recurrent Kimura Disease in the Groin Area / 대한내과학회지

Kimura disease is a rare chronic inflammatory disorder of unknown etiology, suggestive of an allergic or autoimmune mechanism, which presents mainly as soft tissue masses in the head and neck area in young Asian males. Blood tests show eosinophilia and an elevated immunoglobulin E; the typical pathologic findings are lymphoid follicular hyperplasia, interfollicular eosinophilic infiltration, and vascular hyperplasia. There is no standard treatment; surgical resection is preferred and systemic steroid or radiotherapy is used to treat disease relapses. Kimura disease in unusual sites has been reported, but there are few cases with long-term observations because of its benign nature. Here, we present the case of a female with recurrent Kimura disease; we follow her progress for about 5 years after surgical resection of masses in the right groin area, an unusual site, with a brief review of the literature.

A Case of Hypersensitivity Pneumonitis Following Placenta Extract Injection / 결핵및호흡기질환

Human placenta contains various kinds of nutritional elements essential for embryonic development. Currently, human placenta extracts are widely overused in Korea to improve certain health conditions (postmenopausal syndrome, liver function, and cosmetic purposes) without scientific evidence that they actually work. The use of placenta extracts should be restricted, due to a lack of systematic research on the therapeutic effectiveness and adverse results from these treatments. While the common adverse effects that have been reported are fever, rash, itching, nausea, vomiting, breast pain, and rare cases of anaphylactic shock, there have been no reports of pulmonary complications such as hypersensitivity pneumonitis. Recently, we experienced a patient with hypersensitivity pneumonitis following a placenta extract injection. To our knowledge, this is the first case of hypersensitivity pneumonitis associated with placenta extract use.

The Effects of On-site Measured Ozone Concentration on Pulmonary Function and Symptoms of Asthmatics

Most studies on the effects of ambient ozone on asthmatics have been based on ozone concentration measurements taken by air monitors in downtown areas. Using a passive ozone sampler, we investigated the effects of on-site ozone concentrations on the pulmonary function and symptoms of asthmatics. Twenty moderate to severe asthmatics who had been managed for at least 2 months without changes of their medication were enrolled from 3 June to 18 July 2005. Respiratory, nasal and ocular symptoms, peak expiratory flow (PEF), which was measured twice a day, and medication use were recorded on a daily basis during the study period. Data for 17 subjects were analyzed. The average ozone exposure level was 28.2+/-23.6 ppb (3.4-315.3 ppb). There was no significant correlation between PEF and ozone concentration (p>0.05) on the same day or 1-, 2-, or 3-day lags. Interestingly, the degree of asthma symptoms was influenced by the ozone concentration (rho=0.303, p<0.001), even at concentrations less than 80 ppb (p=0.298, p<0.001), but the correlation between ozone exposure and the frequency of reliever medication use was not statistically significant (p=0.99). Our results suggest that exposure to relatively low concentrations of ozone influences the symptoms of moderate to severe asthmatics regardless of changes in pulmonary function or medication use.

A Case of Primary Pulmonary Artery Sarcoma Mimicking Pulmonary Embolism: Role of PET/CT for Differential Diagnosis / 결핵및호흡기질환

Primary pulmonary artery sarcoma is a rare malignant tumor arising from the pulmonary artery. Diagnosis of primary pulmonary artery sarcoma is quite difficult and the conditon is often misdiagnosed as a more common disease, such as a pulmonary embolism. PET can help in diagnosing a pulmonary artery sarcoma due to the increased uptake of 18F-FDG in the area of the tumor. However, the poor anatomic resolution of PET has limited its clinical applications in pulmonary vascular disease. The recently developed PET/CT is the fusion of PET and CT that improves the anatomical resolution of PET. We report a case of a primary pulmonary artery sarcoma mimicking a pulmonary embolism that was diagnosed with PET/CT and confirmed with a surgical resection.

Paraquat-Induced Apoptotic Cell Death in Lung Epithelial Cells / 결핵및호흡기질환

BACKGROUND: Paraquat is extremely toxic chemical material, which generates reactive oxygen species (ROS), causing multiple organ failure. In particular, paraquat leads to irreversible progressive pulmonary fibrosis. Exaggerated cell deaths exceeding the normal repair of type II pneumocytes leads to mesenchymal cells proliferation and fibrosis. This study examined the followings; i) whether or not paraquat induces cell death in lung epithelial cells; ii) whether or not paraquat-induced cell deaths are apoptosis or necrosis; and iii) the effects of N-acetylcysteine, dexamethasone, and bcl-2 on paraquat-induced cell deaths. METHODS: A549 and BEAS-2B lung epithelial cell lines were used. The cell viability and apoptosis were evalluated using a MTT assay, Annexin V staining was monitored by fluorescence microscopy, The level of bcl-2 inhibition was examined by establishing stable A549 pcDNA3-bcl-2 cell lines throung the transfection of pcDNA3-bcl-2 with the mock. RESULTS: Paraquat decreased the cell viability in A549 and BEAS-2B cells in a dose and time dependent manner. The Annexin V assay showed that apoptosis was the type of paraquat-induced cell death. Paraquat-induced cell deaths was significantly inhibited by N-acetylcysteine, dexamethasone, and bcl-2 overexpression. The cell viability of A549 cells treated with N-acetylcysteine, and dexamethasone on the paraquat-induced cell deaths were increased significantly by 10 ~ 20%, particularly at high doses. In addition, the cell viability of A549 pcDNA3-bcl-2 cells overexpressing bcl-2 was significantly higher than the untransfected A549 cells. CONCLUSION: Paraquat induces apoptotic cell deaths in lung epithelial cells in a dose and time dependent manner. The paraquat-induced apoptosis of lung epithelial cells might occur through the mitochondrial pathway.

The Effect of a Proton-pump Inhibitor in Unexplained Chronic Cough Patients / 결핵및호흡기질환

BACKGROUND: Recent studies have suggested an association between chronic cough and gastroesophageal reflux. Our study aimed to assess the utility of a proton-pump inhibitor in unexplained chronic cough patients. METHODS: Patients with chronic cough of unknown etiology were evaluated using a chest x-ray, methacholine challenge test, and an empirical trial of postnasal drip therapy. After excluding other potential causes of the cough, forty patients were included in the study and treated for 8 weeks with a proton-pump inhibitor. RESULTS: Eleven and three patients in the first and second 4 weeks were lost to follow-up, leaving twenty-six patients finally included in the study. Of these patients, two were unimproved, eight partially responded to the proton-pump inhibitor and sixteen responded completely after the 8 week treatment. CONCLUSION: We suggest that empirical treatment with a proton pump inhibitor in all patients with persistent cough, which is not secondary to asthma or postnasal drip syndrome, represents a practical and simple approach to this ailment.

The Utility of Pleural Fluid Cell IFN-gamma Production Assay in the Diagnosis of Tuberculous Pleurisy / 결핵및호흡기질환

BACKGROUND: Diagnosis of tuberculous pleurisy is sometimes difficult using conventional diagnostic methods. We have investigated the utility of pleural fluid cell IFN-gamma production assay in the diagnosis of tuberculous pleurisy. METHODS: We prospectively performed pleural fluid cell IFN-gamma production assay in 39 patients with tuberculous pleural effusions (TPE) and in 26 patients with nontuberculous pleural effusions (NTPE) (13 malignant pleural effusions and 13 parapneumonic effusions). Pleural fluid cells were cultured in DMEM media and stimulated with purified protein derivatives (PPD), and phytohemagglutinin (PHA) for 24 hr. The amount of IFN-gamma released in the culture supernatant was quantitated by IFN-gamma ELISA assay. We have also measured adenosine deaminase (ADA) activities and IFN-gamma concentrations in the pleural fluid. RESULTS: 1) The pleural fluid levels of ADA activity and IFN-gamma concentrations were significantly higher in TPE than NTPE (p<0.01). 2) IFN-gamma production in TPE cells stimulated by PPD (755,266+/-886,636 pg/ml) was significantly higher than NTPE cells (3,509+/-6,980 pg/ml) (p<0.01). By considering the fact that IFN-gamma concentrations over 10,000 pg/ml is a criteria for the diagnosis of TBE, sensitivity and specificity of the test were 97.4 and 92.3%, respectively. 3) The ratios of IFN-gamma production by the stimulation with PPD and PHA (PPD/PHA) were significantly higher in TPE cells (59+/-85) than NTPE cells (5+/-18)(p<0.01). Considering the criteria for the diagnosis of TBE as PPD/PHA ratio over 5, sensitivity and specificity of the test were 76.9 and 92.3%, respectively. CONCLUSION: Pleural fluid cell IFN-gamma production assay may be useful for the diagnosis of tuberculous pleurisy.

A case of primary pulmonary botryomycosis by Gemella morbilium / 대한내과학회지

Botryomycosis is a chronic supprative disease with characteristic granules formation in the pus caused by bacteria and frequently is mistaken for a fungal infection. Pulmonary botryomycosis can resemble actinomycosis, tuberculosis, or invasive carcinoma by causing a mass lesion with constitutional symptoms. We report a case of pulmonary botryomycosis in a 43 years old man. He had a cavitary lesion of the right upper lobe and diagnosis was confirmed by percutaneous needle aspiration. The specimen demonstrated multiple clusters of bacteria within abscess that best were visualized by gram staining. Cultures of the biopsy materials yielded pure growth of Gemella morbilium. The patient recovered quickly after antibiotics treatment for 3 weeks.