Doh Hyung Kim

Treatment Outcomes and Long-term Survival in Patients with Extensively Drug-resistant Tuberculosis

RATIONALE The increasing worldwide incidence of extensively drug-resistant tuberculosis (XDR-TB) has emerged as a threat to public health and tuberculosis (TB) control. Treatment outcomes have varied among studies, and data on long-term survival are still scarce. OBJECTIVES To retrospectively assess the burden, clinical characteristics, treatment outcomes, and long-term survival rate of patients with XDR-TB in a cohort of patients with HIV-negative multidrug-resistant tuberculosis (MDR-TB) in South Korea. METHODS Medical records were reviewed of patients newly diagnosed with or retreated for MDR-TB from 2000 to 2002. The cohort was monitored for 3 to 7 years after the initiation of treatment. Initial treatment outcomes and cumulative survival rates were analyzed, and predictors of treatment success and survival were defined. MEASUREMENTS AND MAIN RESULTS Of 1,407 patients with MDR-TB 75 (5.3%) had XDR-TB at treatment initiation. The default rate was high (453/1,407; 32%), and patients with XDR-TB had lower treatment success (29.3 vs. 46.2%; P = 0.004) and higher all-cause (49.3 vs. 19.4%; P < 0.001) and TB-related disease mortality (41.3 vs. 11.8%; P < 0.001) than other patients with MDR-TB. The presence of XDR-TB significantly affected treatment success (odds ratio, 0.23; 95% confidence interval [CI], 0.08-0.64; P = 0.005), all-cause mortality (hazards ratio, 3.25; 95% CI, 1.91-5.53; P < 0.001), and TB-related mortality (hazards ratio, 4.45; 95% CI, 2.48-8.00; P < 0.001) on multivariate analyses. CONCLUSIONS XDR-TB occurred in a substantial proportion of patients with MDR-TB in South Korea, and was the strongest predictor of treatment outcomes and long-term survival in patients with MDR-TB. Adequate TB control policies should be implemented to prevent the further development and spread of drug resistance.

Treatment outcomes and survival based on drug resistance patterns in multidrug-resistant tuberculosis.

RATIONALE Few large-scale studies have investigated multidrug-resistant tuberculosis (MDR-TB) treatment outcomes relative to drug-resistance patterns. OBJECTIVES To assess the impact of additional drug resistances on treatment outcomes and long-term survival in a large HIV-negative MDR-TB cohort. METHODS Treatment outcomes and long-term survival of patients with MDR-TB newly diagnosed or retreated in 2000 to 2002 were retrospectively analyzed based on drug-resistance patterns after 5-8 years of follow-up. MEASUREMENTS AND MAIN RESULTS Of 1,407 patients with MDR-TB, 75 (5.3%) had extensively drug-resistant TB (XDR-TB(re)) by the revised definition; 159 (11.3%) had ofloxacin-resistant pre-XDR-TB (pre-XDR-TB(o)); and 117 (8.3%) had second-line injectable drug (SLID)-resistant pre-XDR-TB (pre-XDR-TB(s)). Patients with XDR-TB(re) showed the lowest treatment success rate (29.3%) and the poorest long-term survival, and XDR-TB(re) was more strongly associated with long-term mortality than XDR-TB as originally defined (hazards ratio [HR], 3.15; 95% confidence interval [CI], 2.06-4.83; P < 0.001 vs. HR, 2.15; 95% CI, 1.49-3.09; P < 0.001). Patients with either form of pre-XDR-TB showed poorer cumulative survival than those with ofloxacin-susceptible/SLID-susceptible MDR-TB (P < 0.05 for each comparison). Although streptomycin susceptibility did not affect the treatment outcomes of patients with pre-XDR-TB, streptomycin-resistant pre-XDR-TB was more strongly associated with long-term mortality than ofloxacin-susceptible/SLID-susceptible MDR-TB (HR, 2.17; 95% CI, 1.22-3.84; P < 0.008 for pre-XDR-TB(o); and HR, 2.69; 95% CI, 1.40-5.16; P = 0.003 for pre-XDR-TB(s)). CONCLUSIONS The revised XDR-TB definition is appropriate for defining patients with MDR-TB with the poorest outcomes. Both pre-XDR-TB(o) and pre-XDR-TB(s) were independently associated with poor long-term survival in patients with MDR-TB. SM susceptibility was linked to better survival in patients with pre-XDR-TB.

Repression of TNF-alpha-induced IL-8 expression by the glucocorticoid receptor-beta involves inhibition of histone H4 acetylation

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)β, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRα. However, recent data suggest that GRβ is not a dominant negative inhibitor of GRα in the transrepressive process and has its own functional role. We investigated the functional role of GRβ expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-α-induced IL-8 release in an airway epithelial cell line. GRβ expression was induced by treatment of epithelial cells with either dexamethasone or TNF-α. GRβ was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-α-induced IL-8 transcription was not affected by GRβ overexpression, rather GRβ had its own weak suppressive activity on TNF-α-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRβ overexpression, but TNF-α-induced histone H4 acetylation at the IL-8 promoter was decreased with GRβ overexpression. This study suggests that GRβ overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRβ induces its own histone deacetylase activity around IL-8 promoter site.

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 (ρ=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.

Endobronchial Stent Insertion to Manage Hemoptysis caused by Lung Cancer

Hemoptysis in patients with lung cancer is not uncommon and sometimes have dangerous consequences. Hemoptysis has been managed with various treatment options other than surgery and medicine, such as endobronchial tamponade, transcatheter arterial embolization and radiation therapy. However, these methods can sometimes be used only temporarily or are not suitable for a patients condition. We present a case in which uncontrollable hemoptysis caused by central lung cancer was successfully treated by inserting a covered self-expanding bronchial stent. The patient could be extubated and was able to undergo further palliative therapy. No recurrent episodes of hemoptysis occurred for the following three months. As our case, airway stenting is a considerable option for the tamponade of a bleeding lesion that cannot be successfully managed with other treatment methods and could be used to preserve airway patency in a select group of patients.

Chronic Necrotizing Bronchopulmonary Aspergillosis With Elements of Bronchocentric Granulomatosis

Chronic necrotizing pulmonary aspergillosis (CNPA) is an unusual form of pulmonary aspergillosis arising in the setting of mildly immune compromised state or altered local defense system. CNPA rarely shows histological findings mimicking bronchocentric granulomatosis (BCG), which is characterized by peribronchiolar granulomatous destruction. We describe a case representing CNPA with elements of BCG. A-64 year-old woman was admitted because of atypical pneumonia with multi-focal variable sized consolidations and cavitary lesions on high-resolution computed tomography (HRCT). The open lung biopsy specimen showed large areas of necrotizing pneumonia with some scattered aspergillus hyphae within the lung parenchyma. Some terminal bronchioles were found to be destroyed and were replaced by peribronchiolar granulomatous inflammation. There was no evidence of angioinvasion by aspergillus or aspergillous emboli. Despite vigorous antifungal agent and steroid treatment, she died of acute airway obstruction by bronchial casts on the thirty-fourth hospital day.

An Unusual Case of Superior Vena Cava Syndrome Caused by the Intravascular Invasion of an Invasive Thymoma

Superior vena cava syndrome (SVCS) is usually caused by extrinsic compression or invasion of the superior vena cava (SVC) by malignant tumors involving mediastinal structures. Although thymomas are well-known causes of SVCS, cases of SVCS caused by malignant thymomas protruding into adjacent vessels draining the SVC with thrombosis have been very rarely reported worldwide. We experienced a 39-year-old female patient with SVCS that developed after the direct invasion of the left brachiocephalic vein (LBCV) and SVC by an anterior mediastinal mass with a high maximum standardized uptake value on the chest computed tomography (CT) and positron emission tomography-CT. Based on these results, she underwent en bloc resection of the tumor, including removal of the involved vessels, and was eventually diagnosed as having a type B2 thymoma permeating into the LBCV and SVC. We present this case as a very rare form of SVCS caused by an invasive thymoma.

Paroxysmal nocturnal hemoglobinuria: Kidney biopsy and magnetic resonance imaging

and pneumonia. She had a history of unknown cause of recurrent red colored urine for 8 years despite undergoing renal biopsy in a previous hospital (Fig. 1). Initial laboratory findings showed mild anemia and moderate anisocytosis. Urinalysis showed protein (3+) and occult blood (4+). Serum creatinine had increased from 3.5 to 9.1 mg/dL in the four days after admission to our hospital. Serum immunoglobulin and complements were within normal range, and antineutrophil cytoplasmic antibody was absent. Haptoglobin level was 5 (reference range, 30-200) mg/dL, and plasma hemoglobin level was 23 (reference range, 0-5) mg/dL. Her history and laboratory findings were consistent with intravascular hemolysis. Therefore, we suspected paroxysmal nocturnal hemoglobinuria (PNH) and performed magnetic resonance imaging (MRI) of the abdomen to check for characteristic findings of PNH kidney and to rule out structural causes of acute kidney injury (AKI). MRI revealed unique findings of PNH with reversal of the renal cortico-medullary pattern in T1-weighted images (Fig. 2A) and markedly reduced signal intensity of the cortex in T2-weighted images (Fig. 2B). Flow cytometry of erythrocytes showed reduced levels of CD55 and CD59, confirming the diagnosis of PNH. PNH is a rare hematologic disorder caused by mutation of the PIGA gene to result in complement-induced intravascular hemolysis. The most consistent finding of renal biopsy in patients with PNH is hemosiderin deposition in the renal tubular cells. The characteristic MRI findings of the kidneys include reversed renal cortex-medulla differentiation on T1-weighted images and low signal intensity Paroxysmal nocturnal hemoglobinuria: Kidney biopsy and magnetic resonance imaging Changhyun Park, So Mi Kim, Doh Hyung Kim, Eun Kyoung Lee Division of Nephrology, Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea Images in Practice

Is Omalizumab a Problem-Solving Remedy in Severe Asthma?

http://e-aair.org 95 Severe asthma has been a serious health burden worldwide, although its pathophysiology has been explored during several decades. In most of the asthmatic patients, inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) ameliorate clinical symptoms, enhance pulmonary function, and reduce the frequency of acute exacerbation. However, severe uncontrolled asthma still remains problematic in clinical practice. Even though the prevalence of severe asthma is low (3%-10% of all asthmatics), the socioeconomic burden of severe asthma is very huge and the overall cost for severe asthmatic patients is assumed to be more than 60% of the whole cost associated with all asthmatic patients. Therefore, the development of appropriate therapeutic strategies to manage patients with severe uncontrolled asthma is becoming more important and urgent. Many clinical trials have recently been performed on severe asthmatic patients to evaluate the effectiveness of add-on therapies, such as long-acting muscarinic antagonist (LAMA), including tiotropium bromide, and bronchial thermoplasty, molecular-targeted agents, such as anti-immunoglobulin E (antiIgE, omalizumab) and anti-interleukin-5 (mepolizumab and reslizumab). Nevertheless, effectiveness of these approaches has not yet been fully validated and clinical responses are variable among patients. Thus, tailored management based on individual phenotypic or endotypic characteristics of asthma should be considered especially in severe asthmatic patients who are refractory to standard treatment. Among novel targeted agents, omalizumab is the first anti-IgE monoclonal antibody approved as a phenotype-guided add-on therapy in severe asthmatic patients. The current 2017 GINA guidelines recommend the use of omalizumab for patients aged ≥6 years with moderate to severe allergic asthma which is uncontrolled on step 4 treatment with evidence A. In this issue of the AAIR journal, Lee et al. have confirmed the real-world effectiveness of omalizumab in Korean patients with severe asthma for the first time. In contrast to previous realworld studies, their outcomes were compared between patients treated with omalizumab for 6 months (OT group) and control patients treated with standard treatment alone who were defined by propensity score matching, and changes in outcomes were also compared between the baseline and outcome periods within and between groups. Although 6 months of treatment might be not long enough to fully evaluate omalizumab effects, the mean reduction rate of 46% exacerbation and the responder proportion of 68%, which were similar to those of previous real-world studies, were observed in the OT group. Omalizumab effectively reduced the number of asthma exacerbations, hospitalization, hospitalized days, the mean daily requirement of systemic corticosteroid (SCS) per person, and sputum eosinophil without obvious adverse events in Korean patients. The results of real-world study are useful in that patients with severe asthma often have multiple comorbidities and different socioeconomic statuses which can affect outcomes of omalizumab treatment. The real-world effectiveness would differ from those of prospective randomized controlled clinical trials. Thus, the results presented in the work of Lee et al. provide us practically valuable information on omalizumab treatment in Korean patients with severe asthma regardless of baseline clinical and socioeconomic characteristics. Basically, omalizumab has been recommended for allergic asthma and most commonly used for patients showing increased serum IgE level or at least 1 positive aeroallergen on skin prick test or an elevated serum specific IgE level to common aeroallergens. However, reports supporting the extended role of omalizumab in nonatopic asthmatic patients have been increasing. A Spanish multicenter registry study demonstrated that significant improvement in the clinical status of nonatopic asthmatics as measured by global evaluation of treatment effectiveness (GETE) and by the asthma control test. Another report showed a significant reduction in FcεRI expression on Is Omalizumab a Problem-Solving Remedy in Severe Asthma?

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.