Yousang Ko

Rapid Diagnosis of Tuberculosis and Multidrug Resistance Using a MGIT 960 System

Background The purpose of this study was to compare the turnaround time for liquid culturing and primary anti-tuberculous drug susceptibility testing (DST) performed using the mycobacteria growth indicator tube (MGIT) 960 system (Becton Dickinson, USA) with that for conventional culturing and DST (by the absolute concentration method) performed using solid culture medium and to determine the concordance rates of DST results obtained using these 2 methods. Methods In this retrospective study, we compared the turnaround times from receiving the request for mycobacterial culture to reporting the DST results before and after the introduction of the MGIT 960 system. Further, we determined the concordance between DST results for isoniazid and rifampin for Mycobacterium tuberculosis isolates obtained using the MGIT 960 system and the absolute concentration method, which was conducted at the Korean Institute of Tuberculosis. Results The overall turnaround time for mycobacterial culturing and DST was 27 days for liquid culturing and DST using the MGIT 960 system versus approximately 70 days for culturing on solid medium and DST with the absolute concentration method (P<0.001). There was a good concordance between findings of DST obtained with the 2 methods (97.2%, kappa coefficient=0.855 for rifampin; and 95.6%, kappa coefficient=0.864 for isoniazid), for 1,083 clinical isolates. Conclusions The automated MGIT 960 system for culturing and DST of M. tuberculosis was successfully introduced in a hospital laboratory setting in Korea with significant shortening of the turnaround time.

When do we need central nervous system prophylaxis in patients with extranodal NK/T-cell lymphoma, nasal type?

BACKGROUND The incidence and risk factors of central nervous system (CNS) invasion is still unclear in extranodal natural killer (NK)/T-cell lymphoma, nasal type. PATIENTS AND METHODS We analyzed 208 patients to study the clinical features and outcomes of CNS disease in extranodal NK/T-cell lymphoma. RESULTS Twelve patients (5.76%, 12/208) experienced CNS disease during treatment or follow-up period (median 11.62 months, range 0.2-123.2 months). The clinical variables associated with CNS disease were Ann Arbor stage III/IV (15.87%, P <0.001), regional lymph node involvement (10.41%, P = 0.006), group III/IV of NK/T-cell lymphoma prognostic index (NKPI; 10.20%, P = 0.003), high/high-intermediate international prognostic index (9.30%, P = 0.072) and extra-upper aerodigestive primary sites (9.75%, P = 0.008). In multivariate analysis, NKPI retained the strongest statistical power to predict CNS disease (P = 0.007, relative risk 9.289, 95% confidence interval 1.828-47.212) in extranodal NK/T-cell lymphoma. CONCLUSIONS Despite extranodal NK/T-cell lymphoma frequently involves paranasal sinus, a routine CNS evaluation and prophylaxis do not seem to be necessary in NKPI group I or II patients due to a very low incidence. Nevertheless, CNS prophylaxis should be considered in NKPI groups III and IV.

Outcomes of Pneumocystis pneumonia with respiratory failure in HIV-negative patients.

PURPOSE The outcomes and predictors of mortality from Pneumocystis pneumonia (PCP) in HIV-negative patients requiring mechanical ventilation (MV) for respiratory failure were evaluated. MATERIALS AND METHODS This retrospective observational study enrolled 48 patients with PCP requiring MV in the medical intensive care unit (ICU). Multiple logistic regression analysis was used to identify independent predictors of in-hospital mortality. RESULTS The main conditions underlying the PCP were malignancies (60%) or post solid organ transplant (35%). Excluding four patients whose initial treatment was changed due to adverse reactions, 21 (44%) of 44 patients did not respond to the initial treatment. During the ICU stay, additional complications developed: shock in 22 (46%), ventilator-associated pneumonia in 16 (33%), and acute kidney injury in 15 (31%). Ultimately, 31 (65%) patients died while hospitalised. In multivariate analysis, hospital mortality was independently associated with severity of illness on ICU admission, failure of initial antimicrobial treatment for PCP, and newly developed shock during ICU stay. CONCLUSIONS PCP in HIV-negative patients requiring MV for respiratory failure remains a serious illness with high mortality. Failure of the initial antimicrobial treatment for PCP as well as severity of illness was independent predictors of poor outcomes.

Epstein–Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin

BACKGROUND Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). PATIENTS AND METHODS We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity. RESULTS A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study. CONCLUSIONS Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.

Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis

Rationale: Neutrophils are key effectors in the hosts immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community‐acquired pneumonia. Methods: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12‐myristate 13‐acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Measurements and Main Results: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET‐dependent mechanism. Conclusions: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium lentiflavum in a Patient with Bronchiectasis

We report a rare case of lung disease caused by Mycobacterium lentiflavum in a previously healthy woman. A 54-year-old woman was referred to our hospital due to chronic cough and sputum. A computed tomography scan of the chest revealed bilateral bronchiectasis with bronchiolitis in the right middle lobe and the lingular division of the left upper lobe. Nontuberculous mycobacteria were isolated twice from three expectorated sputum specimens. All isolates were identified as M. lentiflavum by multilocus sequence analysis based on rpoB, hsp65, and 16S rRNA fragments. To the best of our knowledge, this is the first documented case of M. lentiflavum lung disease in an immunocompetent adult in Korea.

Clinical significance of a single isolation of pathogenic nontuberculous mycobacteria from sputum specimens.

A single sputum culture positive for nontuberculous mycobacteria (NTM) could be an early sign of NTM lung disease. We found that 14% of patients with a single sputum culture positive for pathogenic NTM were diagnosed with NTM lung disease during the median follow-up period of 16 months.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease

Background Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. Patients and methods We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. Results After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. Conclusions Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

A Case of Pleural Paragonimiasis Confused with Tuberculous Pleurisy

Here, we report a case of pleural paragonimiasis that was confused with tuberculous pleurisy. A 38-year-old man complained of a mild febrile sensation and pleuritic chest pain. Radiologic findings showed right pleural effusion with pleural thickening and subpleural consolidation. Adenosine deaminase (ADA) activity in the pleural effusion was elevated (85.3 IU/L), whereas other examinations for tuberculosis were negative. At this time, the patient started empirical anti-tuberculous treatment. Despite 2 months of treatment, the pleural effusion persisted, and video-assisted thoracoscopic surgery was performed. Finally, the patient was diagnosed with pleural paragonimiasis based on the pathologic findings of chronic granulomatous inflammation containing Paragonimus eggs. This case suggested that pleural paragonimiasis should be considered when pleural effusion and elevated ADA levels are observed.

Does repeated pleural culture increase the diagnostic yield of Mycobacterium tuberculosis from tuberculous pleural effusion in HIV-negative individuals?

Background Despite recent advances in methods for culturing Mycobacterium tuberculosis (MTB), the diagnostic yield of tuberculous pleural effusion (TBPE) remains unsatisfactory. However, unlike repeated sputum cultures of pulmonary tuberculosis, little is known about the role of repeated pleural cultures. We examined whether repeated pleural cultures are associated with increased MTB yield from TBPE. Methods A multicenter, retrospective cohort study was performed from January 2012 to December 2015 in South Korea. Patients were categorized into two groups: single- or repeated-culture groups. The diagnostic yield of MTB and clinical, radiological, and pleural fluid characteristics were evaluated. Results Among the 329 patients with TBPE, 77 (23.4%) had repeated cultures and 252 (76.5%) had a single culture. Pleural culture was performed twice in all 77 patients in the repeated-culture group at a 1-day interval (inter-quartile range, 1.0–2.0). In the repeated-culture group, the yield of MTB from the first culture was 31.2%, which was similar to that in the single-culture group (31.2% vs. 29.8%, P = 0.887). However, the yield of MTB from the second culture (10/77, 13.0%) was more than that from the first. These results may be attributable to the insufficient immune clearance for MTB invasion into the pleural space between the first and second cultures. Over time, the yield of the second cultures decreased from 17.4% to 6.7% and then 6.3%. Finally, the overall yield of MTB in the repeated- and single-culture groups was 44.2% and 29.8% respectively (P < 0.001). Conclusions The results showed that repeated pleural cultures increased MTB yield from TBPE in human immunodeficiency virus-negative individuals. Furthermore, repeated cultures may increase yield when carried out for two consecutive days.