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Purpose: Nontuberculous mycobacteria (NTM) is ubiquitous in the environment, but NTM lung disease (NTM-LD) is uncommon. Since exposure to NTM is inevitable, patients who develop NTM-LD are likely to have specific susceptibility factors, such as primary ciliary dyskinesia (PCD). PCD is a genetically heterogeneous disorder of motile cilia and is characterized by chronic respiratory tract infection, organ laterality defect, and infertility. In this study, we performed whole exome sequencing (WES) and investigated the genetic characteristics of adult NTM patients with suspected PCD., Materials and Methods: WES was performed in 13 NTM-LD patients who were suspected of having PCD by clinical symptoms and/or ultrastructural ciliary defect observed by transmission electron microscopy. A total of 45 PCD-causing genes, 23 PCD-candidate genes, and 990 ciliome genes were analyzed., Results: Four patients were found to have biallelic loss-of-function (LoF) variants in the following PCD-causing genes: CCDC114 , DNAH5 , HYDIN , and NME5 . In four other patients, only one LoF variant was identified, while the remaining five patients did not have any LoF variants., Conclusion: At least 30.8% of NTM-LD patients who were suspected of having PCD had biallelic LoF variants, and an additional 30.8% of patients had one LoF variant. Therefore, PCD should be considered in patients with NTM-LD with symptoms or signs suspicious of PCD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2021.) more...

The prevalence and incidence of nontuberculous mycobacterial (NTM) infections increased in South Korea from 2007 to 2016. Annual prevalence of NTM infection increased to 39.6 cases/100,000 population in 2016 and annual incidence to 19.0 cases/100,000 population. Overall prevalence for the study period was higher in the elderly, in females, and in cities. more...

Background: Mycobacterium kansasii is a major pathogen associated with nontuberculous mycobacterial pulmonary disease. For treatment of M. kansasii pulmonary disease, daily therapy with isoniazid, rifampin, and ethambutol is traditionally recommended. Although a regimen containing a macrolide, instead of isoniazid, has been recently recommended, supporting data are limited. We compared the treatment outcomes of a macrolide-containing regimen (macrolide group) and an isoniazid-containing regimen (isoniazid group) on patients with M. kansasii pulmonary disease., Methods: A total of 49 patients were identified between January 2002 and December 2016. Treatment outcomes for the isoniazid group (n = 24) and the macrolide group (n = 25) were compared., Results: Baseline characteristics of the isoniazid and macrolide groups were similar. Favorable outcomes did not differ between the isoniazid group (79%, n = 19) and macrolide group (88%, n = 22, P = 0.463). Total treatment duration (median 17.9 months vs. 15.4 months; P = 0.712) and time to culture conversion (median 2.0 months vs. 1.2 months; P = 0.838) were also similar between the isoniazid and macrolide groups. Five patients who completed three-times-weekly intermittent treatment containing a macrolide for non-cavitary M. kansasii pulmonary disease achieved negative sputum culture conversion within 12 months of treatment. Only one patient experienced recurrence of M. kansasii pulmonary disease in the isoniazid group., Conclusions: A macrolide-containing regimen appears to be as effective as an isoniazid-containing regimen for treatment of M. kansasii pulmonary disease. Additionally, intermittent therapy containing a macrolide could be an alternative treatment option for non-cavitary M. kansasii pulmonary disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.) more...

In this study, we aimed to retrospectively investigate and compare the drug susceptibility patterns of two major Mycobacterium abscessus complex (MABC) species; M. abscessus and M. massiliense. A total of 546 MABC respiratory isolates (277 M. abscessus and 269 M. massiliense) from 2011 to 2016 were analyzed in this study. We estimated minimum inhibitory concentrations (MICs) using the broth microdilution method, and we calculated MIC 50 and MIC 90 values from the MIC distribution. Both M. abscessus and M. massiliense were highly susceptible to amikacin and linezolid. For M. abscessus, the proportions of inducible and acquired resistance to clarithromycin were 68.6% and 12.3%, respectively. Only 15.2% of M. abscessus remained susceptible at day 14. On the other hand, none of the M. massiliense showed inducible resistance and 6.3% showed acquired resistance to clarithromycin. A total of 92.6% of the M. massiliense remained susceptible at day 14. The resistance rate of M. abscessus to moxifloxacin (90.3%) was significantly higher than that of M. massiliense (83.3%; p = 0.016). These susceptibility differences may explain the divergent treatment outcomes between patients with pulmonary disease caused by these two species., (Copyright © 2018 Elsevier Inc. All rights reserved.) more...

Background: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes., Methods: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/( 0.50 × 0.95), resulting in 102 persons per group (204 in total)., Discussion: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB., Trial Registration: ClincalTrials.gov, NCT02619994 . Registered on 2 December 2015. more...

Rationale: Patients with refractory Mycobacterium avium complex lung disease (MAC-LD) undergo long-term macrolide therapy, but macrolide resistance develops infrequently., Objectives: The aim of this study was to determine whether reinfection was a factor in the low incidence of macrolide resistance in patients with refractory MAC-LD., Methods: Among 481 patients with treatment-naive MAC-LD who started antibiotic treatment between January 2002 and December 2013, we identified 72 patients with refractory disease, characterized by persistently positive sputum cultures despite ≥12 months of treatment. Molecular analyses of the 23S ribosomal RNA gene responsible for macrolide resistance and serial mycobacterial genotyping were performed using stored MAC isolates., Measurements and Main Results: The median duration of treatment was 32 months (interquartile range, 24-41 mo) in 72 patients. After treatment for a median of 33 months (interquartile range, 21-44 mo), macrolide resistance developed in 16 (22%) patients. Molecular analysis of isolates from 15 patients revealed that 80% (12 of 15) had a point mutation at position 2,058 or 2,059 of the 23S ribosomal RNA gene. Of the 49 patients who had stored pre- and post-treatment isolates, mycobacterial genotyping revealed that reinfection by new MAC strains occurred in 36 (73%) patients. New MAC strains were found in 24 (49%) patients, and mixed infections with original and new strains occurred in 12 (24%) patients. Only 13 (27%) patients had persistent infections with their original MAC strains., Conclusions: Refractory MAC-LD is commonly caused by reinfection with new strains rather than persistence of the original strain, which may explain the infrequent development of macrolide resistance in refractory MAC-LD. Clinical trial registered with www.clinicaltrials.gov (NCT00970801). more...

QuantiFERON-TB Gold Plus (QFT-Plus) is a new-generation QuantiFERON-TB Gold In-Tube (QFT-GIT) assay which has two antigen-coated tubes called TB1, which contains long peptides derived from ESAT-6 and CFP-10, and TB2, which contains the same components as TB1 and additional short peptides which potentially stimulate CD8 + T cells through the presentation of major histocompatibility complex class I. This is the first study to compare QFT-Plus and QFT-GIT for use in the diagnosis of latent tuberculosis infection (LTBI) among immunocompromised patients in the Republic of Korea. Among 317 consecutive patients who underwent screening for LTBI before solid organ or hematopoietic stem cell transplantation and tumor necrosis factor alpha inhibitor treatment, LTBI was identified in 92 (29.0%) and 88 (27.8%) patients by QFT-GIT and QFT-Plus, respectively. The rate of concordance between QFT-GIT and QFT-Plus was 93.7% (κ value, 0.860), and the indeterminate rate (3.2%) was similar between QFT-GIT and QFT-Plus. Of 20 (6.3%) samples with discordant results, 11 (55.0%) and 7 (35.0%) were positive by QFT-GIT alone and QFT-Plus alone, respectively, and 2 (15.0%) were indeterminate by each assay. The interferon gamma level in samples with discordant results ranged from 0.39 to 1.10 IU/ml, except for one sample, in which the gamma interferon level was 2.97 IU/ml only in TB2. Conclusively, there was a high degree of agreement between the results of QFT-GIT and QFT-Plus for the screening of immunocompromised patients for LTBI. The reactivity in TB2 contributed substantially to the difference between QFT-GIT and QFT-Plus, particularly in solid organ transplant candidates. The significance of the discrete responses in TB1 and TB2 of QFT-Plus needs to be explored further by means of an immunological and clinical approach in different patient groups and clinical settings., (Copyright © 2018 American Society for Microbiology.) more...

This study investigated the changes in the major etiologic organisms and clinical phenotypes of nontuberculous mycobacterial lung disease (NTM-LD) over a recent 15-year period in Korea. The increase of number of patients with NTM-LD was primarily due to an increase of Mycobacterium avium complex (MAC) lung disease (LD). Among MAC cases, the proportion of M. avium increased compared with M. intracellulare, whereas the incidence of M. abscessus complex and M. kansasii LD remained relatively stable. The proportion of cases of the nodular bronchiectatic form increased compared with the fibrocavitary form of NTM-LD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2018 The Korean Academy of Medical Sciences.) more...

Objectives: Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB., Methods: We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea., Results: A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5-81) using solid medium and 57 days (range = 8-96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms., Conclusions: The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) more...

The effect of the clinical phenotype of Mycobacterium avium complex (MAC) lung disease on treatment outcome and redevelopment of nontuberculous mycobacterial (NTM) lung disease after treatment completion has not been studied systematically.We evaluated 481 treatment-naïve patients with MAC lung disease who underwent antibiotic treatment for ≥12 months between January 2002 and December 2013.Out of 481 patients, 278 (58%) had noncavitary nodular bronchiectatic (NB) disease, 80 (17%) had cavitary NB disease and 123 (25%) had fibrocavitary disease. Favourable outcome was higher in patients with noncavitary disease (88%) than in patients with cavitary disease (76% for fibrocavitary and 78% for cavitary NB disease; p<0.05). Cavitary disease was independently associated with unfavourable outcomes (p<0.05). Out of 402 patients with favourable outcomes, 118 (29%) experienced redevelopment of NTM lung disease, with the same MAC species recurring in 65 (55%) patients. The NB form was an independent risk factor for redevelopment of NTM lung disease (p<0.05). In patients with recurrent MAC lung disease due to the same species, bacterial genotyping revealed that 74% of cases were attributable to reinfection and 26% to relapse.Treatment outcomes and redevelopment of NTM lung disease after treatment completion differed by clinical phenotype of MAC lung disease., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.) more...

Setting: Tertiary referral centre, Samsung Medical Center, South Korea., Objective: To evaluate the pharmacokinetic parameters and toxicities of once-daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus., Design: A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015., Results: With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 μg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047)., Conclusion: Our results suggest that once-daily AMK for 4 weeks with a target Cmax of 55-65 μg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity. more...

Background: Little information is available regarding vitamin D-associated factors in patients with non-tuberculous mycobacteria (NTM) lung disease., Objective: To determine the association between vitamin D-related factors and susceptibility to NTM lung disease., Design: The relative gene expression levels of cathelicidin (CAMP), defensin (DEFB4), vitamin D receptor (VDR) and 1-hydroxylase (CYP27B1), as well as the serum levels of 25-hydroxyvitamin D (25[OH]D), cathelicidin (LL-37), defensin (hBD-2) and vitamin D-binding protein (DBP) from 82 patients with NTM lung disease and 28 control subjects were analysed., Results: Gene expression of CAMP and DEFB4 was significantly higher, and gene expression of VDR and CYP27B1 was significantly lower, in NTM patients than controls. Serum LL-37 and hBD-2 levels were not significantly different between NTM patients and controls; however, the serum DBP level was higher in NTM patients than controls. The serum vitamin D status of patients did not correlate with serum LL-37, hBD-2, or DBP concentration or gene expression of CAMP, DEFB4, VDR or CYP27B1., Conclusion: A higher level of gene expression for antimicrobial peptide is more likely to be associated with NTM lung disease than serum vitamin D status. more...

The aim of this study was to genetically characterize clinical isolates from patients diagnosed with Mycobacterium avium lung disease and to investigate the clinical significance. Multi-locus sequencing analysis (MLSA) and pattern of insertion sequence analysis of M. avium isolates from 92 Korean patients revealed that all isolates were M. avium subspecies hominissuis. In hsp65 sequevar analysis, codes 2, 15, and 16 were most frequently found (88/92) with similar proportions among cases additionally two isolates belonging to code N2 and an unreported code were identified, respectively. In insertion element analysis, all isolates were IS1311 positive and IS900 negative. Four of the M. avium subsp. hominissuis isolates did not harbor IS1245 and 1 of the M. avium isolates intriguingly harbored DT1, which is thought to be a M. intracellulare-specific element. M. avium subsp. hominissuis harboring ISMav6 is prevalent in Korea. No significant association between clinical manifestation and treatment response has been found in patients with the hsp65 code type and ISMav6, indicating that no specific strain/genotype among M. avium subsp. hominissuis organisms was a major source of M. avium lung disease. Interestingly, the presence of ISMav6 was correlated with greater resistance to moxifloxacin. Conclusively, the genotype of Korean M. avium subsp. hominissuis isolates is not a disease determinant responsible for lung disease and specific virulent factors of M. avium subsp. hominissuis need to be investigated further. more...

The clinical significance of Mycobacterium kansasii respiratory isolates is uncertain. The aims of this study were to determine the clinical relevance of M. kansasii isolates and to identify the clinical features and outcomes of M. kansasii lung disease. We reviewed the medical records of 104 patients from whom at least one respiratory M. kansasii isolate was obtained from January 2003 to July 2014 at Samsung Medical Center, South Korea. Of these 104 patients, 54 (52%) met the diagnostic criteria for nontuberculous mycobacterial lung disease; among them, 41 (76%) patients received antibiotic treatment for a median time of 15.0 months (interquartile range [IQR], 7.0-18.0 months). The remaining 13 (24%) without overt disease progression were observed for a median period of 24.0 months (IQR, 5.0-34.5 months). Patients with M. kansasii lung disease exhibited various radiographic findings of lung disease, including the fibrocavitary form (n = 24, 44%), the nodular bronchiectatic form (n = 17, 32%), and an unclassifiable form (n = 13, 24%). The fibrocavitary form was more common in patients who received treatment (n = 23, 56%), while the nodular bronchiectatic form was more common in patients with M. kansasii lung disease who did not receive treatment (n = 9, 70%). None of the patients with a single sputum isolate (n = 18) developed M. kansasii disease over a median follow-up period of 12.0 months (IQR, 4.0-26.5 months). In total, 52% of all patients with M. kansasii respiratory isolates exhibited clinically significant disease. Moreover, patients with M. kansasii lung disease displayed diverse radiographic findings in addition to the fibrocavitary form. The nodular bronchiectatic form was more common in patients with M. kansasii lung disease with an indolent clinical course. Thus, since the clinical significance of a single M. kansasii respiratory isolate is not definite, strict adherence to recommended diagnostic criteria is advised. more...

Deficiencies in essential trace elements are associated with impaired immunity in tuberculosis infection. However, the trace element concentrations in the serum of Korean patients with tuberculosis have not yet been investigated. This study aimed to compare the serum trace element concentrations of Korean adult patients with tuberculosis with noninfected controls and to assess the impact of serum trace element concentration on clinical outcome after antituberculosis treatment. The serum concentrations of four trace elements in 141 consecutively recruited patients with tuberculosis and 79 controls were analyzed by inductively coupled plasma-mass spectrometry. Demographic characteristics were also analyzed. Serum cobalt and copper concentrations were significantly higher in patients with tuberculosis compared with controls, while zinc and selenium concentrations were significantly lower (p < 0.01). Moreover, serum selenium and zinc concentrations were positively correlated (ρ = 0.41, p < 0.05). A high serum copper concentration was associated with a worse clinical outcome, as assessed after one month of antituberculosis therapy. Specifically, culture-positive patients had higher serum copper concentrations than culture-negative patients (p < 0.05). Patients with tuberculosis had altered serum trace element concentrations. Further research is needed to elucidate the roles of individual trace elements and to determine their clinical impact on patients with tuberculosis. more...

Rationale: Although intermittent, three-times-weekly therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic Mycobacterium avium complex (MAC) lung disease, supporting data are limited., Objectives: To evaluate the clinical efficacy of intermittent therapy compared with daily therapy for nodular bronchiectatic MAC lung disease., Methods: A retrospective cohort study of 217 patients with treatment-naive noncavitary nodular bronchiectatic MAC lung disease. All patients received either daily (n = 99) or intermittent therapy (n = 118) that included clarithromycin or azithromycin, rifampin, and ethambutol., Measurements and Main Results: Modification of the initial antibiotic therapy occurred more frequently in the daily therapy group than in the intermittent therapy group (46 vs. 21%; P < 0.001); in particular, ethambutol was more frequently discontinued in the daily therapy group than in the intermittent therapy group (24 vs. 1%; P ≤ 0.001). However, the rates of symptomatic improvement, radiographic improvement, and sputum culture conversion were not different between the two groups (daily therapy vs. intermittent therapy: 75 vs. 82%, P = 0.181; 68 vs. 73%, P = 0.402; 76 vs. 67%, P = 0.154, respectively). In addition, the adjusted proportion of sputum culture conversion was similar between the daily therapy (71.3%; 95% confidence interval, 59.1-81.1%) and the intermittent therapy groups (73.6%; 95% confidence interval, 62.9-82.2%; P = 0.785)., Conclusions: These results suggest that intermittent three-times-weekly therapy with a macrolide, rifampin, and ethambutol is a reasonable initial treatment regimen for patients with noncavitary nodular bronchiectatic MAC lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00970801). more...

Background: Mycobacterium abscessus group belongs to a group of rapidly growing mycobacteria (RGM) and, following Mycobacterium avium complex, is the second most common pathogen responsible for lung disease caused by nontuberculous mycobacteria (NTM). Clarithromycin is known to be the key drug in the treatment of M. abscessus group disease, but a high failure rate of treatment response is reported due to clarithromycin inducible resistance., Methods: Using the results from a clarithromycin susceptibility test we examined the proportion of clarithromycin inducible resistant M. abscessus (sensu stricto; hereafter referred to as M. abscessus) clinical strains. Also, we attempted to detect the clarithromycin resistant strains, using the amplification refractory mutation system-PCR (ARMS-PCR) and real-time PCR methods for rapid detection of single-nucleotide polymorphisms (SNPs) at position 28 (T or C) of the erm(41) gene of M. abscessus leading to resistance to clarithromycin., Results: Of the 157 M. abscessus clinical strains, clarithromycin susceptible, resistant, and inducible resistant strains accounted for 10.83% (n = 17), 22.29% (n = 35), and 66.88% (n = 105), respectively. Clarithromycin resistant strains were able to separate from clarithromycin susceptible strains by ARMS-PCR and real-time PCR identical to DNA sequence analysis., Conclusion: Most M. abscessus clinical strains in Korea are resistant to clarithromycin, and ARMS-PCR and real-time PCR are useful tools for the rapid detection of single-nucleotide polymorphisms (SNPs) at position 28 of the erm(41) gene., (© 2014 Wiley Periodicals, Inc.) more...

The data regarding risk factors for death during tuberculosis (TB) treatment are inconsistent, and few studies examined this issue in Korea. The purpose of this study was to evaluate baseline prognostic factors for death during treatment of adult patients with pulmonary TB in Korea. A multicenter retrospective cohort study of 2,481 patients who received TB treatment at eight hospitals from January 2009 to December 2010 was performed. Successful treatment included cure (1,129, 45.5%) and treatment completion (1,204, 48.5%) in 2,333 patients (94.0%). Unsuccessful treatment included death (85, 3.4%) and treatment failure (63, 2.5%) occurred in 148 patients (6.0%). In multivariate analysis, male sex, anemia, dyspnea, chronic heart disease, malignancy, and intensive care unit (ICU) admission were significant risk factors for death during TB treatment. Therefore, male sex, anemia, dyspnea, chronic heart disease, malignancy, and ICU admission could be baseline prognostic factors for death during treatment of adult patients with pulmonary TB in Korea. more...

Background: We compared the demographic characteristics and outcomes of patients with severe healthcare-associated pneumonia (HCAP) to those with severe community-acquired pneumonia (CAP)., Methods: This was a retrospective study of prospectively collected data from all consecutive patients with severe pneumonia who were admitted to the hospital through the emergency department between January 2008 and December 2010., Results: During the study period, 247 patients had severe pneumonia; of these, 107 had severe CAP and 140 had severe HCAP. There was no significant difference in demographic characteristics between the two groups, except for comorbidities. Although the incidence of potentially drug-resistant pathogens was higher in patients with severe HCAP than in those with severe CAP (34 vs. 6 %, P = 0.004), there was no statistically significant difference in the rate of inappropriate antibiotic treatment (16 vs. 3 %, P = 0.143). Finally, clinical outcomes, such as intensive care unit admission, length of hospital stay, and in-hospital mortality, were not different between the two groups. In a multiple logistic regression analysis, a higher PSI score (adjusted OR 1.01; 95 % CI 1.00-1.02; P = 0.024) and the need for mechanical ventilation (adjusted OR 2.62; 95 % CI 1.37-5.00; P = 0.004) were independently associated with in-hospital mortality. However, the type of pneumonia was not associated with in-hospital mortality after adjusting for potential confounding factors., Conclusions: The severity of illness rather than the type of pneumonia might be associated with in-hospital mortality in patients with severe pneumonia. more...

Species identification of nontuberculous mycobacteria (NTM) is challenging due to the increasing number of identified NTM species and the lack of standardized testing strategies. The objectives of this study were to investigate the distribution of NTM species recovered from respiratory specimens by multigene sequence-based typing and to evaluate the clinical significance of identified species. Two hundred thirty-two consecutive clinical NTM isolates were subjected to sequencing of multiple genes, including hsp65, rpoB, and 16S-23S rRNA internal transcribed spacer (ITS) sequence. In addition, clinical data from all patients whose specimens had NTM isolates were analyzed to examine clinical virulence and treatment history. Eighteen strains from 227 isolates from 169 patients were successfully identified at the species level by multigene sequence-based typing. Mycobacterium avium complex and M. abscessus complex made up the majority of isolated NTM (88%; 199/227), followed by M. fortuitum complex (4%; 10/227). The pathogenic potential of NTM differs enormously by species, and M. avium complex and M. abscessus complex revealed especially high levels of virulence compared with findings for other NTM species. The results from our work support M. avium complex and M. abscessus complex being the most common NTM species with highly pathogenic potential isolated from clinical respiratory specimens and could be a good resource for molecular epidemiology of NTM species in South Korea. more...

Background: The concept of healthcare-associated pneumonia (HCAP) exists to identify patients infected with highly resistant pathogens who are exposed to the healthcare environment. However, many studies have included immunosuppressed patients who were excluded from the original concept., Objectives: The risk factors of potentially drug-resistant (PDR) pathogens in patients with pneumonia developed outside the hospital were reevaluated after excluding the patients who had immunosuppression., Methods: This was a retrospective study of prospectively collected data from all consecutive patients with pneumonia who were admitted to hospital via the emergency department between January 2008 and December 2011., Results: Pathogens were isolated in a total of 315 patients with pneumonia from our cohort; 33% with PDR pathogens did not meet the criteria for HCAP, but 44% without PDR pathogens did meet the criteria. Variables independently associated with PDR included nursing home residency, hospitalization in the preceding 90 days, antibiotics in the 30 days prior to pneumonia, poor function status and chronic lung disease. The new predictive scoring system based on the logistic regression model had a higher predictive power for the risk of PDR pathogens than the presence of the risk factors or the HCAP criteria., Conclusions: Functional status, pulmonary comorbidity and previous exposure to the healthcare environment were significantly associated with acquiring PDR pathogens in immunocompetent patients with pneumonia that developed out of hospital. However, a risk stratification model was more accurate than the presence of the risk factors or the HCAP criteria for assessing the probability of PDR pathogens. more...

The QuantiFERON-TB Gold In-Tube (QFT-G IT) test (Cellestis Inc., Valencia, CA) is one of the gamma interferon release assays (IGRAs) that are promising tools for diagnosing active or latent Mycobacterium tuberculosis infections. We investigated the clinical and laboratory factors that affect the rate of indeterminate QFT-G IT test results. We also suggest a workflow strategy for achieving optimized test results using the QFT-G IT test for the diagnosis of active tuberculosis (TB) or latent TB infection. We performed statistical analysis using data from a retrospective review of medical records. The first phase included 683 QFT-G IT test results from 676 patients tested between January 2008 and May 2008, and the second phase included an additional 663 QFT-G IT test results from 653 patients tested between January 2008 and December 2008 at Samsung Medical Center, a tertiary care hospital in South Korea. Immunosuppressive drug therapy, underlying diseases, bedridden status, and hypoalbuminemia were significantly associated with indeterminate QFT-G IT test results. With reduction of the incubation delay during the test procedure from an average of 9.82 h to an average of 2.70 h with changes in the workflow, the frequency of indeterminate QFT-G IT test results was significantly reduced from 11.4% to 2.7%. With >6 h of incubation delay, however, the frequency of indeterminate QFT-G IT test results was increased in a statistically significant manner. This study demonstrates that not only clinicopathological factors but also laboratory factors, such as incubation delay, significantly affect the rate of indeterminate QFT-G IT test results; therefore, optimization of the test procedure may contribute to reductions in the rate of indeterminate QFT-G IT test results, which delay the diagnosis of TB. more...

Background: Bacteria of the Mycobacterium abscessus group are the second most common pathogens responsible for lung disease caused by nontuberculous mycobacteria in Korea. There is still a lack of studies investigating the genetic mechanisms involved in M. abscessus resistance to antibiotics other than clarithromycin. This study investigated the characteristics of drug resistance exhibited by M. abscessus clinical isolates from Korea., Methods: We performed drug susceptibility testing for a total of 404 M. abscessus clinical strains. Subspecies were differentiated by molecular biological methods and examined for mutations in drug resistance-related genes., Results: Of the 404 strains examined, 202 (50.00%), 199 (49.26%), and 3 (0.74%) strains were identified as M. abscessus, M. massiliense, and M. bolletii, respectively. Of the 152 clarithromycin-resistant strains, 6 possessed rrl mutations, while 4 of the 30 amikacin-resistant strains contained rrs mutations, and 5 of the 114 quinolone-resistant strains had gyr mutations. All mutant strains had high minimal inhibitory concentration values for the antibiotics., Conclusions: Our results showed the distribution of the strains with mutations in drug resistance-related genes was low in the M. abscessus group. Furthermore, we performed drug susceptibility testing and sequence analyses to determine the characteristics of these genes in the M. abscessus group. more...

Background and Objective: Previous studies have found evidence of an association between tuberculosis and vitamin D deficiency (VDD). However, the association between VDD and infection caused by non-tuberculous mycobacteria (NTM) has never been studied. This study evaluated the prevalence and severity of VDD in NTM lung disease and attempted to identify predictive factors., Methods: Age- and sex-matched case-control study was conducted to assess the prevalence and severity of VDD in patients with NTM lung disease., Results: After adjusting for potential confounding factors, the adjusted mean serum level of 25-hydroxyvitamin D (25(OH)D) levels was lower in 104 patients with NTM lung disease (10.7 ng/mL, 95% confidence interval (CI) 4.5-16.8 ng/mL) than that of 312 controls (13.7 ng/mL, 95% CI 7.4-19.5 ng/mL) (P = 0.012). Although the prevalence of VDD defined as serum 25(OH)D level <20 ng/mL was not different, severe VDD defined as serum 25(OH)D level <10 ng/mL was more prevalent in patients (P < 0.001). In multivariate analysis, severe (but not mild) VDD was independently associated with NTM lung disease (adjusted odds ratio 3.9, 95% CI 1.9-8.5, P < 0.001)., Conclusions: Patients with NTM lung disease have a high prevalence of severe VDD and VDD was independently associated with NTM lung disease. Further studies are needed to examine causality., (© 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.) more...

Background: Variable number of tandem repeats (VNTR) loci were recently identified in Japanese isolates of Mycobacterium intracellulare. We hypothesised that some mycobacterial genotypes are more virulent than others, resulting in particular genotypes being associated with disease phenotype and progression., Objective: To evaluate the VNTR loci of M. intracellulare in clinical isolates from Korean patients, and investigate the association between mycobacterial genotype and disease phenotype and progression., Design: In total, 70 M. intracellulare clinical isolates were genotyped using 16 M. intracellulare VNTR loci., Results: VNTR typing showed strong discriminatory power and genetic diversity for molecular epidemiological studies of M. intracellulare. In a phylogenetic tree, the M. intracellulare clinical isolates were divided into two clusters (A and B). Cluster A was observed more frequently (77%) than Cluster B; however, there was no association between the clinical characteristics, disease progression, drug susceptibility and clusters based on VNTR genotyping., Conclusions: VNTR typing could be used for epidemiological studies of M. intracellulare lung disease; however, no association was found between the specific VNTR genotypes of M. intracellulare and the clinical characteristics of Korean patients. more...

Several lines of evidence suggest that in Caucasian populations, mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene are associated with susceptibility to lung disease caused by nontuberculous mycobacteria (NTM). However, there is little data available in Asian populations, in which the prevalence of CF is very low. Therefore, we investigated this potential relationship in a Korean population. Sixty patients who fulfilled the diagnostic criteria for NTM lung disease were screened for genetic alterations in the CFTR gene by whole-exon resequencing. For all identified CFTR gene variants, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) genotyping was performed. Genotype and haplotype data were compared between 360 patients with NTM lung disease and 446 healthy controls. Among 13 CFTR genetic variants that were found by whole-exon resequencing, Q1352H showed a significantly higher frequency in NTM patients than in controls, giving an odds ratio (OR) of 4.27 (95% confidence interval (CI), 1.43-12.78). A haplotype with Q1352H showed the strongest association with the disease, with an OR of 3.73 (95% CI, 1.50-9.25). Furthermore, all Q1352H alleles were associated with the V allele of the V470M variant. Our results suggest that CFTR gene variants may increase susceptibility to NTM lung disease in the Korean population. Q1352H appears to be strongly related to NTM lung disease susceptibility in the Korean population. more...

The aim of this study was to investigate antifactor Xa (aFXa) levels after once daily dose of 40 mg of enoxaparin and to evaluate factors influencing aFXa levels among Korean intensive care unit (ICU) patients. This prospective observational study was conducted between August and December 2011 in medical ICUs at Samsung Medical Center. AFXa levels between 0.1 and 0.3 U/mL were considered to be effective for antithrombotic activity. Fifty-five patients were included. The median aFXa levels were 0.22 (IQR 0.17-0.26) at 4 hr, 0.06 (IQR 0.02-0.1) at 12 hr, and 0 U/mL (IQR 0-0.03) at 24 hr. The numbers of patients showing effective antithrombotic aFXa levels were 48 (87.3%), 18 (32.7%), and 0 (0%) at 4, 12 and 24 hr, respectively. At 12 hr, higher sequential organ failure assessment (SOFA) scores and hyperbilirubinemia were significantly associated with low aFXa levels (OR, 0.58; 95% CI, 0.36-0.93; P = 0.02 and 0.06; 0.003-0.87; 0.04, respectively). Once daily dose of 40 mg of enoxaparin is inadequate for maintaining effective antithrombotic aFXa levels, and the inadequacy is more salient for patients with high SOFA scores and hyperbilirubinemia. more...

Background: Few studies have investigated the impact of diabetes mellitus (DM), a globally increasing metabolic disease, on treatment outcomes and long-term survival in patients with multidrug-resistant forms of tuberculosis (MDR-TB)., Objectives: We analyzed outcomes in a large cohort to assess the impact of DM on treatment outcomes of patients with MDR-TB., Methods: MDR-TB patients newly diagnosed or retreated between 2000 and 2002 and followed for 8-11 years were retrospectively analyzed with respect to the effect of DM as a comorbidity on their treatment outcome and long-term survival., Results: Of 1,407 patients with MDR-TB, 239 (17.0%) had coexisting DM. The mean age and body mass index were higher in MDR-TB patients with DM [MDR-TBDM(+)] than in those without DM [MDR-TBDM(-)]. Patients with MDR-TB and a comorbidity of DM had a significantly lower treatment success rate than those without a history of DM (36.0 vs. 47.2%, p = 0.002). In addition, DM was the negative predictor for MDR-TB treatment success in multivariate analyses [odds ratio 0.51, 95% confidence interval (CI) 0.26-0.99]. Mean survival times were also lower in MDR-TBDM(+) than in MDR-TBDM(-) patients (102 vs. 114 months, p = 0.001), with DM as a significant predictor of poor long-term survival in multivariate analyses (hazard ratio 1.59, 95% CI 1.01-2.50)., Conclusions: Among MDR-TB patients, DM was a relatively common comorbidity. In patients undergoing treatment for MDR-TB and followed for 8-11 years, it was found to be independently associated with an increased risk of both treatment failure and death., (Copyright © 2013 S. Karger AG, Basel.) more...

This study was designed to investigate the incidence, causes, and outcomes of new-onset thrombocytopenia (NOT) in Korean intensive care units (ICUs). A prospective cohort study was conducted in medical ICUs of Samsung Medical Center between August 2010 and February 2011. All newly admitted patients were included if they stayed in the ICU for more than 48 hr and did not have thrombocytopenia upon admission. A total of 186 patients were included. NOT developed in 37.1%. Most common cause of NOT was sepsis with disseminated intravascular coagulation (66.7%), followed by drug-induced thrombocytopenia (18.8%), and heparin-induced thrombocytopenia (2.9%). IgG-specific antibody to platelet factor 4/heparin was positive in 2.4% among patients treated with heparin, and thrombosis occurred in two patients. Twenty eight-day mortality was higher in patients that developed NOT compared to those that did not develop NOT (39.1% vs 12%, P < 0.001). NOT increased the odds ratio of 28-day mortality and was an independent risk factor for mortality (OR 3.52; 95% CI 1.32-9.38; P = 0.012). In conclusion, NOT is common and is an independent risk factor for mortality in Korean ICU patients. Therefore, clinicians should make every effort to correct the causes of NOT. more...

Rationale: Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections., Objectives: To compare the activity of CLR and AZM in experimental models., Methods: We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erythromycin ribosome methyltransferase gene (erm)(41) expression in experimental models of M. abscessus and M. massiliense infections., Measurements and Main Results: In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration [MIC] on Day 3 versus Day 14; P < 0.001). Whereas the AZM MIC increased on Day 14 (P < 0.01 versus Day 3), the level was significantly lower than the CLR MIC on Day 14 (P < 0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared with CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P < 0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher after exposure to CLR than after exposure to AZM (P < 0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance., Conclusions: CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense. more...

Rationale: Little is known regarding the application of therapeutic drug monitoring for treatment of Mycobacterium avium complex (MAC) lung disease., Objectives: To evaluate drug interactions of multidrug regimens and clinical usefulness of therapeutic drug monitoring in the management of MAC lung disease., Methods: A total of 130 patients with MAC lung disease and 60 patients with Mycobacterium abscessus complex lung disease were enrolled in this study. All of the MAC patients were treated with multidrug regimens that included clarithromycin (CLR), rifampin (RIF) or rifabutin (RFB), and ethambutol (EMB), and the plasma drug concentrations of CLR, RIF, and EMB were measured., Measurements and Main Results: Peak plasma CLR concentrations were lower in patients with MAC lung disease who received daily (median, 0.3 μg/ml) or intermittent (median, 0.2 μg/ml) therapy with CLR in conjunction with RIF in both groups, compared with those diagnosed with M. abscessus complex lung disease who received CLR without RIF (median, 3.8 μg/ml; P < 0.05). The proportion of patients with MAC lung disease who received daily therapy and whose plasma CLR levels were below the target range of 2 μg/ml was 97% (96 of 99), and this rate was 100% (21 of 21) among patients with MAC lung disease who received intermittent therapy. The peak plasma drug concentrations and the peak plasma drug concentration/minimal inhibitory concentration ratios of CLR, RIF, and EMB did not differ between patients with unfavorable treatment outcomes and those with favorable outcomes., Conclusions: Low plasma CLR concentrations were common in patients treated for MAC lung disease. However, there was no association between low plasma CLR concentrations and treatment outcomes. Therefore, therapeutic drug monitoring may not be beneficial in managing the therapy of patients with MAC lung disease. more...

Setting: A recent study in Japan found that mycobacterial genotyping was associated with disease progression and susceptibility to certain drugs in Mycobacterium avium lung disease. However, it is not known whether this association is true in other populations., Objective: To investigate the association between mycobacterial genotype, clinical characteristics and the progression of M. avium lung disease in Korean patients., Design: A total of 102 M. avium clinical isolates were genotyped using M. avium tandem repeats-variable number of tandem repeats (MATR-VNTR)., Results: MATR-VNTR typing demonstrated a high discriminatory power and genetic diversity for molecular epidemiological studies of M. avium. In the phylogenetic tree, the M. avium clinical isolates were divided into three major clusters: A, B and C. Cluster A was observed most frequently (64/102, 63%), whereas cluster C was found in a minor proportion of the isolates (8/102, 8%). However, there was no association between the clinical characteristics, disease progression and drug susceptibility and the phylogenetic tree based on VNTR genotyping., Conclusions: MATR-VNTR genotyping may be useful for epidemiological studies of M. avium lung disease; however, no association was found between the specific VNTR genotypes of M. avium and the clinical characteristics of Korean patients. more...

The aim of this study was to evaluate the usefulness of the interferon-γ release assay (IGRA) for the diagnosis of latent tuberculosis infection (LTBI) in arthritis patients who received tumor necrosis factor (TNF) antagonist in Korea. The study involved 107 consecutive patients: 61 (57%) with ankylosing spondylitis and 46 (43%) with rheumatoid arthritis. Screening tests were performed including the tuberculin skin test (TST), the QuantiFERON-TB Gold In-Tube (QFT-IT) test, and chest radiography. A positive QFT-IT test result, regardless of TST results, was considered an indication for LTBI treatment. If the QFT-IT results were indeterminate, a positive TST was regarded as an indication for LTBI treatment. A Bacillus Calmette-Guérin (BCG) scar was found in 63 patients (59%). LTBI treatment was performed in 37 patients (35%), including 36 with positive QFT-IT results and one with indeterminate QFT-IT and positive TST results. No patients developed tuberculosis during a median of 18 months (range, 13-26 months) of TNF antagonist therapy. In 16 patients who had positive TST and negative QFT-IT results, TNF antagonists were given without LTBI treatment. Tuberculosis did not occur, even in these patients, during a median of 24.5 months (range, 15-33.5 months) of TNF antagonist therapy. IGRA may be used instead of TST for the diagnosis of LTBI in patients before starting TNF antagonists in countries where tuberculosis prevalence is intermediate and the BCG vaccination is mandatory at birth, such as in Korea. more...

Background: Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. The most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been well established among Caucasian populations. In Koreans, however, there are very few cases of genetically confirmed CF thus far, and the spectrum of mutations seems quite different from that observed in Caucasians., Methods: In the present study, we describe the cases of 2 Korean CF patients, present sequencing results identifying mutations in their CFTR gene, and summarize the results of CFTR mutational spectrum from previously reported Korean CF patients. The mutations described were identified by performing direct sequencing analysis of the complete coding regions and flanking intronic sequences of the CFTR gene, followed by multiplex ligation-dependent probe amplification (MLPA) analysis in order to detect gene deletions or duplications that could not be identified by a direct sequencing method., Results: Three CFTR mutations were identified in the 2 patients, including p.Q98R, c.2052delA, and c.579+5G>A. In an analysis of 9 Korean CF patients that included the 2 patients presented in this study, p.Q98R mutation was the only recurrently observed mutation with a frequency of 18.8% (3/16 alleles). Furthermore, only one of the mutations (c.3272-26A>G) was found among the 32 common mutations in the screening panel for Caucasians from the Cystic Fibrosis Mutation Database., Conclusions: Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for genetic analysis of Korean CF patients. more...

Background: Health care-associated pneumonia (HCAP) has been proposed as a new category of respiratory infection. ATS/IDSA guidelines state that all patients with HCAP should receive empirical therapy directed at multidrug-resistant pathogens. However, recent data from other countries have reported a different picture of HCAP., Methods: We conducted a retrospective observational study of patients with HCAP and CAP who were hospitalized through the emergency department in January-December 2008 at Samsung Medical Center, Seoul, Korea, and compared clinical characteristics, severity, distribution of pathogen, and outcomes., Results: In total, 345 patients hospitalized with pneumonia were eligible, 182 (52.8%) with HCAP and 163 (47.2%) with CAP. Patients with HCAP had greater comorbidity and higher Pneumonia Severity Index (PSI) score (P < 0.001). Although Streptococcus pneumoniae was the most frequently isolated pathogen in HCAP and CAP patients, the occurrence of potentially drug-resistant pathogens (29.3% vs. 13.0%; P = 0.044) and inappropriate initial antimicrobial treatment (24.6% vs. 8.7%; P = 0.032) were significantly higher in HCAP patients. Patients with HCAP had a longer duration of hospital stay (13 [8-18] vs. 8 [6-12] days; P < 0.001), and higher in-hospital mortality (19.2% vs. 7.4%; P = 0.001). In a multiple logistic regression analysis, however, in-hospital mortality was independently associated with higher PSI class (OR 2.82, 95% CI 1.19-6.70) and ICU admission (OR 15.37, 95% CI 3.58-66.05)., Conclusions: Severity of illness, rather than type of pneumonia, was the main predicting factor for in-hospital mortality among patients with pneumonia hospitalized through the emergency department., (Copyright © 2010 Elsevier Ltd. All rights reserved.) more...

Purpose: Little information exists regarding the association of specific cytokine levels and different subgroups of patients with critical illness-related corticosteroid insufficiency (CIRCI)., Methods: Data from a previous prospective study on adrenal function in the ICU were used in this study. CIRCI was diagnosed when either the basal cortisol was less than 10 μg/ml or the Δ cortisol was less than 9 μg/ml. The patients with CIRCI were further divided into a low basal cortisol (LBC) group (basal cortisol < 10 μg/ml), and low Δ cortisol (LDC) group (basal cortisol ≥ 10 μg/ml and Δ cortisol < 9 μg/ml). Serum cytokine levels were compared among the normal (NOM), LBC, and LDC groups., Results: The serum of 82 out of 123 (67%) patients included in the previous study was available for analysis; these patients were included in the present study. The overall incidence of CIRCI was 43.9% (36 out of 82 patients). Among patients with CIRCI, 16 (44.4%) were classified as the LBC group and 20 (55.6%) as the LDC group. The LDC group had significantly higher levels of IL-6 and IL-10 compared to both the NOM and LBC groups (p < 0.01). The LDC group also had significantly increased TNF-α (p = 0.002) compared to the LBC group. There were no significant differences in any of the cytokine levels between the NOM and LBC groups., Conclusions: Elevated cytokines were associated with adrenal dysfunction in a subset of patients meeting the criteria for CIRCI (normal or high basal cortisol and low Δ cortisol). more...

Objectives: Chronic necrotizing pulmonary aspergillosis (CNPA) is uncommon, and the optimal therapeutic regimen has not been established. In a retrospective cohort study, we investigated the clinical characteristics and treatment outcomes of patients with CNPA., Methods: We reviewed the medical records of all patients who had been diagnosed with CNPA at our institution over the last 10 years., Results: Forty-three patients were identified. Their median age was 60 years (interquartile range (IQR) 45-65 years), and 34 (79%) of the patients were men. The most common underlying lung disease was pulmonary tuberculosis (n=40, 93%). After CNPA was diagnosed, all patients were treated with antifungal drugs, including oral itraconazole (n=39, 91%) or intravenous amphotericin B (n=4, 9%). Seventeen (40%) patients discontinued therapy early (<3 months), 14 patients due to death and three to loss of follow-up. Twenty-six (60%) patients received oral itraconazole at a daily dose of 200-400mg for more than 3 months. The median treatment duration was 6 months (IQR 6-12 months). In these 26 patients, clinical improvement was observed in 15 (58%) and radiological improvement was observed in 11 (42%). Ten (38%) patients showed no improvement. Twenty-two (51%) patients died, including 18 (42%) CNPA-related deaths, during a median follow-up of 15 months (IQR 2.5-32 months). The median survival time was 62 months., Conclusions: CNPA is difficult to treat and often has a poor outcome. Further studies with more patients are needed to identify the optimal therapy for patients with CNPA., (Copyright 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.) more...