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.

Clinical characteristics and treatment outcomes of patients with pneumonia caused by Raoultella planticola.

BACKGROUND: Raoultella planticola, considered to be an environmental organism, is a rare cause of human infections. Although in recent years the frequency of R. planticola infections reported in the literature has increased, few cases of pneumonia caused by R. planticola have been described. Here, we investigate the clinical characteristics, management, and clinical outcomes of pneumonia caused by R. planticola. METHODS: Consecutive patients with pneumonia caused by R. planticola were included. The medical records of patients with R. planticola pneumonia treated at Dankook University Hospital from January 2011 to December 2017 were collected. RESULTS: A total of 11 adult patients with R. planticola pneumonia were diagnosed and treated [10 males and 1 female; median age, 70 years (range: 51-79 years)]; 5 patients had underlying malignant conditions (45.5%). Antibacterial susceptibility testing showed that all isolates of R. planticola were susceptible to cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and beta-lactams/beta-lactamase inhibitors. Chest imaging revealed consolidation (8/11, 72.7%), ground-glass opacity (5/11, 45.5%), pleural effusion (5/11, 45.5%), and micronodules (3/11, 27.3%). Four patients (36.4%) required mechanical ventilation; three survived but one died of multiple organ dysfunction syndrome (principally pneumonia and septic shock). CONCLUSIONS: R. planticola pneumonia occurred mainly in patients with underlying risk factors such as malignant disease, cerebral infarction or hemorrhage, and chronic obstructive pulmonary disease. The organism was sensitive to most antibiotics, and the clinical outcomes were favorable after empirical antibiotic therapy.

Successful treatment of acute respiratory failure in a patient with pulmonary Mycobacterium abscessus infection accompanied by organizing pneumonia.

Organizing pneumonia (OP) is an inflammatory lung disease characterized pathologically by the presence of buds of granulation tissue in the distal air spaces. There are numerous causes of OP including acute respiratory infections such as viral and bacterial infections. However, Mycobacterium abscessus (M. abscessus) has rarely been reported as a causative pathogen of OP. Here, we report a 67-year-old woman with rapidly progressive pulmonary M. abscessus infection who developed OP and acute respiratory failure (ARF). She was treated successfully with a corticosteroid and anti-mycobacterial therapy. Our observations suggest that pulmonary M. abscessus infection should be added to the list of infectious conditions associated with OP.

Extracorporeal membrane oxygenation as a rescue therapy for acute respiratory failure during chemotherapy in a patient with acute myeloid leukemia.

Acute respiratory distress syndrome (ARDS) caused by pneumonia in patients with hematologic malignancies can be life-threatening. Extracorporeal membrane oxygenation (ECMO) is the only temporary treatment for patients with ARDS who are refractory to conventional treatment. However, the immunosuppression and coagulopathies in hematological malignancies such as lymphoma and acute leukemia are relative contraindications for ECMO, due to high risks of infection and bleeding. Here, we report a 22-year-old man with acute myeloid leukemia (AML) who developed pneumonia and ARDS during induction chemotherapy; he was treated with ECMO.

Randomized Phase III Study of Docetaxel Plus Cisplatin Versus Pemetrexed Plus Cisplatin as First-line Treatment of Nonsquamous Non-Small-cell Lung Cancer: A TRAIL Trial.

INTRODUCTION: To date, no prospective phase III trials have directly compared the efficacy of pemetrexed plus cisplatin (Pem-Cis) with docetaxel plus cisplatin (Doc-Cis) in patients with nonsquamous non-small-cell lung cancer. MATERIALS AND METHODS: A total of 148 chemotherapy-naive patients lacking driver mutations were randomized into 21-day regimens of cisplatin 70 mg/m2 with either docetaxel 60 mg/m2 (n = 71) or pemetrexed 500 mg/m2 (n = 77) for ≤ 4 cycles. The primary objective was to assess the noninferiority of progression-free survival (PFS) for patients receiving the Doc-Cis regimen. The secondary endpoints were the response rates, overall survival, and toxicity profiles. RESULTS: Partial remission was observed in 24 (31.2%) and 24 (33.8%) patients in the Pem-Cis and Doc-Cis groups, respectively. The median PFS was 4.7 months (95% confidence interval [CI], 4.4-5.0) in the Pem-Cis arm and 4.4 months (95% CI, 3.7-5.1) in the Doc-Cis arm (P > .05). The median overall survival was longer in the Doc-Cis arm (13.3 months; 95% CI, 8.1-18.5) than in the Pem-Cis arm (11.7 months; 95% CI, 8.6-14.8; P > .05). Between the 2 arms, no significant difference was found in the subsequent treatments after failure of first-line treatment. The rate of grade 3 or 4 neutropenia and febrile neutropenia was greater in the Doc-Cis arm than in the Pem-Cis arm. CONCLUSION: In nonsquamous non-small-cell lung cancer patients lacking driver mutations, the PFS and response rates were similar between the 2 arms, and toxicity was tolerable, although adverse events and more severe toxicities were observed more frequently in the Doc-Cis arm.

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.

A case of advanced malignant pleural mesothelioma treatment with chemotherapy and photodynamic therapy.

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.

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.

Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs.

Unusual drug accumulation is a common mechanism underlying serious drug-induced liver injury. Polymorphisms in three drug transporter genes (ABCB1, SLCO1B1 and ABCC2) may be risk markers for hepatitis induced by the unusual accumulation of anti-tuberculosis drugs (ATDs). We therefore investigated whether polymorphisms and haplotypes of these genes are associated with ATD-induced hepatitis by comparing the frequencies and distributions of single nucleotide polymorphisms and haplotypes of these three drug transporter genes among 67 patients with ATD-induced hepatitis and 159 patients tolerant to ATDs using a multivariate logistic regression analysis. We found that the frequencies of polymorphisms and haplotypes of ABCB1, SLCO1B1 and ABCC2 were similar in patients with ATD-induced hepatitis and ATD-tolerant controls. The present results suggest that these drug transporters do not play important roles in the pathogenesis of ATD-induced hepatitis in Korean patients.

TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis.

BACKGROUND: While the mechanisms underlying the development of drug-induced liver injury are not clear, there is evidence to suggest that tumor necrosis factor-α (TNF-α) plays an important role in drug- or drug metabolite-induced immune responses. We hypothesized that polymorphisms in the TNF-α gene are associated with anti-tuberculosis drug (ATD)-induced hepatitis. METHODS: Patients who suffered from ATD-induced hepatitis were enrolled in the study. ATD-induced hepatitis was defined as an increase in liver transaminase levels that were more than three times the upper limit of normal. ATD-tolerant patients were used as a control. Patients were treated with first line ATD therapies including isoniazid, rifampicin, ethambutol, and pyrazinamide. We compared the genotype frequencies of the TNF-α polymorphism -308G/A in 77 patients with ATD-induced hepatitis and 229 ATD-tolerant patients. RESULTS: The frequency of carrying the variant allele (AG or AA) was significantly higher in patients with ATD-induced hepatitis compared with ATD-tolerant patients [26.0% vs. 15.3%, P = 0.034, OR (95% CI) = 1.94 (1.04–3.64)] and the frequency of the A allele was significantly different between the two groups [0.143 vs. 0.079, P = 0.018, OR (95% CI) = 1.95 (1.11–3.44)]. CONCLUSION: These results reveal that the TNF-α genetic polymorphism -308G/A is significantly associated with ATD-induced hepatitis. This genetic variant may be a risk factor for ATD-induced hepatitis in individuals from Korea.

NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption.

PURPOSE: It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE. METHODS: We enrolled 62 patients with ATD-induced MPE (mean age 47.2 ± 19.0, male 59.7%) and 159 patients without any adverse reactions to ATD (mean age 42.8 ± 17.6, male 65.4%), among patients with pulmonary tuberculosis (TB) and/or TB pleuritis and treated with first-line anti-TB medications, including isoniazid, rifampin, ethambutol, and pyrazinamide. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in four drug-metabolizing enzymes (N-acetyltransferase 2 (NAT2), cytochrome P450 (CYP) 2 C9, CYP2C19, and CYP2E1) among patients with ATD-induced MPE and patients tolerant to ATD using a multivariate logistic regression analysis. These analyses were made without identification of the responsible ATD. RESULTS: -1565 C > T of CYP2C9 showed a significant association with ATD-induced MPE (P = 0.022, OR = 0.23, 95% CI 0.07-0.78), with a lower frequency of genotypes carrying minor alleles (CT or TT) in the case group than in the controls. Additionally, W212X of CYP2C19 was significantly associated with the risk of ATD-induced MPE (P = 0.042, OR = 0.27, 95% CI 0.09-0.82). In an analysis of the CYP2C19-CYP2C9 haplotypes (-1418 C > T_W212X_-1565 C > T_-1188 C > T), ht3[T-A-T-C] showed a significant association with the development of ATD-induced MPE (P = 0.012, OR = 0.13, 95% CI 0.03-0.57). No significant associations between the other genetic polymorphisms and ATD-induced MPE were observed. CONCLUSIONS: CYP2C19 and CYP2C9 genetic polymorphisms are significantly associated with the risk of developing ATD-induced MPE, and the genetic variants in NAT2 and CYP2E1 are not closely related to the development of this adverse reaction.

GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans.

Adverse reactions induced by antituberculosis drugs (ATD) often result in serious morbidities, impeding scheduled treatment and cure. In the development of ATD-induced adverse reactions, glutathione S-transferase has been suggested to play a protective role as an intracellular scavenger by conjugating toxic reactive metabolites of ATD. This study examined the association of null mutations in GST enzyme genes (GSTT1 and GSTM1) with the development of ATD-induced hepatitis and cutaneous reactions. We compared the frequencies of GSTT1 and GSTM1 null mutations in 57 patients with hepatitis, 94 patients with cutaneous adverse reactions, and 190 ATD-tolerant controls. The frequency of null mutations in GSTT1 and GSTM1 in patients with ATD-induced hepatitis was not significantly different from that of controls (59.6% vs. 54.2% and 45.6% vs. 54.7%, respectively). Additionally, no significant difference was observed in the frequency of either null mutation in patients with ATD-induced cutaneous reactions, including maculopapular eruption, compared with controls (58.5% vs. 54.1% for GSTT1 and 59.6% vs. 54.6% for GSTM1). These findings indicate that GSTT1 and GSTM1 null mutations are not associated with the development of ATD-induced hepatitis or cutaneous reactions in this Korean population, and suggest that glutathione S-transferase enzymes do not play important roles in the pathogenesis of these conditions.

Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis.

AIMS: Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis. MATERIALS & METHODS: We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls. RESULTS: Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types. CONCLUSION: These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.

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.

Dexamethasone inhibits TRAIL- and anti-cancer drugs-induced cell death in A549 cells through inducing NF-kappaB-independent cIAP2 expression.

PURPOSE: We have examined that dexamethasone inhibits apoptotic cell death of A549 lung epithelial cells through TRAIL and anti-cancer drugs. The purpose of the study is to determine the roles of GR, cIAP and NF-kappaB in this mechanism. MATERIALS AND METHODS: In the A549 lung epithelial cell line, TRAIL, taxol, doxorubicine & gemcitabine were used to investigate cell toxicity. Cells were pretreated 12 hours in advance with dexamethasone. RU486 was pretreated 30 minutes before dexamethasone. Crystal violet assay was used for cell toxicity tests. Apoptosis assay was performed by taking morphologic surveys with fluorescent microscopy after double staining with Hoechst 33342 & propium iodide. RT-PCR was used to investigate the gene expression of cIAP1 & cIAP2 by dexamethasone. Ad-IkappaB alpha-SR transduction study was used for the role of NF-kappaB. RESULTS: TRAIL and anti-cancer drug-induced apoptosis was partially suppressed in A549 cells pretreated with dexamethasone. The inhibitory effect on cell death disappeared in A549 cells pretreated with RU486. Using RT-PCR, changes of cIAP1 and cIAP2 genes manifestation in A549 cells subsequent to pretreatment with dexamethasone were examined. The results showed an increase in cIAP2 expression during a course of time which was suppressed by RU486 pretreatment. Induction of cIAP2 expression changes by dexamethasone was uniquely observed despite the blockade of NF-kappaB by Ad-IkappaBalpha-SR transduction. CONCLUSIONS: These results suggest that dexamethasone inhibits TRAIL- and anti-cancer drug-induced apoptosis in A549 cells by inducing cIAP2 gene expression through a GR-mediated, NF-kappaB-independent pathway.