Compliance with new drug use and the effect of discrepant drug susceptibility testing on MDR/RR-TB treatment.

BACKGROUND: Following the WHO???s announcement in 2018, the use of new drugs was recommended for all patients with multidrug-resistant TB (MDR-TB) in Korea. This study aimed to evaluate adherence to new anti-TB drug regimens and implementation of molecular drug susceptibility testing (mDST) in Korea.METHODS: Nationwide, 560 patients were reported as having MDR-TB in 2021. The implementation of mDST and new anti-TB drug use were analysed. The discrepancy between mDST and phenotypic DST (pDST) results and their implications on the use of new anti-TB drugs were also analysed. The use of novel anti-TB drugs has been approved by the National TB Expert Committee.RESULTS: The non-adherence rate in MDR-TB patients was 14.3%. The mDST implementation rate was 96.1%. Of the 459 patients who underwent both mDST and pDST, the discordance rate for rifampicin (RIF) resistance was 22.6% (n = 104), of which 72.1% (n = 75) were resistant on mDST but susceptible on pDST. The discrepancy in mDST and pDST results related to RIF resistance was found to be the main cause of non-adherence to new drug regimen.CONCLUSION: Comprehensive training on how to interpret conflicting results between mDST and pDST could enhance the utilisation of new drugs in the treatment of MDR/RIF-resistant TB.

Lung function decline in non-tuberculous mycobacterial pulmonary disease according to disease severity.

BACKGROUND: The severity of non-tuberculous mycobacterial pulmonary disease (NTM-PD) can be classified based on an assessment of the patient´s body mass index, age, presence of cavity, erythrocyte sediment rate and sex (BACES). In this study, changes in lung function according to disease severity were analysed.METHODS: Patients with NTM-PD who underwent at least two lung function tests between 1 January 2011 and 31 December 2021, were classified according to their BACES score into mild (0-1), moderate (2-3) and severe (4-5) groups, and changes in lung function were assessed using BACES scores.RESULTS: A total of 354 patients were divided into three groups: mild (n = 108), moderate (n = 216) and severe (n = 30). As disease severity increased, the decrease in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) was greater: respectively 26.4 mL/year, 31.3 mL/year and 35.7 mL/year in case of FEV1 (P for trend = 0.002); 18.9 mL/year, 25.5 mL/year and 48.9 mL/year in case of FVC (P for trend = 0.002); and 0.7%/year, 1.3%/year and 2.5%/year for DLCO (P for trend = 0.023) in the mild, moderate and severe groups.CONCLUSION: The decrease in lung function in NTM-PD was correlated with disease severity.

Treatment outcomes of multidrug-resistant TB with selective use of new drugs.

SETTING: This was a nationwide cohort study.OBJECTIVE: To assess the treatment outcomes in patients with multidrug-resistant TB (MDR-TB) who underwent treatment guided by a national TB expert review committee in South Korea.DESIGN: We enrolled all patients with MDR-TB submitted for approval for the use of new TB drugs, including bedaquiline and delamanid, from 2016 to 2019. Patients were classified into two groups: those on new TB drugs and those not on new TB drugs. We compared the final treatment outcomes between the groups and analysed the prognostic factors.RESULTS: Of a total of 785 patients, respectively 754 (96.1%) and 31 (3.9%) were classified into the "new TB drugs" group and "no new TB drugs" group. The new TB drugs group had a higher acid-fast bacilli smear positivity rate and higher resistance rate to second-line injectable drugs or fluoroquinolones. Of all the patients, 97.8% achieved culture conversion (97.7% vs. 100%), and 80.4% achieved treatment success (80.2% vs. 86.7%); there was no difference between the two groups.CONCLUSIONS: New drugs are currently recommended for use in all MDR-TB treatment regimens, and the use of new drugs, as determined by an expert committee, in mainly quinolone-susceptible MDR-TB, did not compromise the treatment success rate.

Multidrug-resistant tuberculosis in South Korea: a retrospective analysis of national registry data in 2011-2015.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a threat to public health as a result of high treatment costs and unsatisfactory outcomes.OBJECTIVE: To elucidate trend, demographic and clinical characteristics and treatment outcomes of patients with MDR-TB between 2011 and 2015 in South Korea.METHOD: Data of patients with MDR-TB diagnosed between 1 January 2011 and 31 December 2015 were retrieved from the nationwide Internet-based TB notification system and analysed retrospectively.RESULTS: During the study period, 5192 MDR-TB patients were notified. We identified an increasing number of MDR-TB patients among foreign populations (from 1.3% to 7.7%), decreasing resistance rates to other anti-TB drugs (e.g., resistance to pyrazinamide, from 40.9% to 28.2%), a decreasing interval from treatment initiation to negative conversion of sputum culture (from 165.7 to 103.7 days) and shortening of treatment duration (719.7 to 613.2 days). However, treatment success rates did not change, and had an average of 65.7%.CONCLUSION: Despite decreasing resistance rates to other drugs and faster treatment responses, treatment outcomes did not improve during the study period. Strict management of MDR-TB patients on treatment should be adopted to improve treatment outcomes.

Radiological features and progression of incipient active pulmonary tuberculosis according to risk factors.

To examine the radiological features of incipient active pulmonary tuberculosis (PTB) in humans and evaluate radiological progression according to risk factors. We retrospectively included 66 non-human immunodeficiency virus patients with bacteriologically proven PTB who had diagnostic and incidental pre-diagnostic computed tomography (CT) scans. CT scans were reviewed using a scoring system that included typical and atypical abnormalities associated with PTB. Risk factors for progression were assessed and, based on these, the CT features and progression of TB were compared using regression analyses. The most prevalent CT finding in incipient PTB was a well-defined solid nodule in upper lobes and lower lobe superior segments. The non-risk and at-risk groups did not differ in terms of the proportion of individuals with nodules and segmental location. The at-risk group had a higher incidence of progression (adjusted odds ratio 8.59), greater increment in the CT score (adjusted regression coefficient [aRC] 9.19) and a higher proportion of atypical CT abnormalities on diagnostic CT scans (aRC 13.15). Incipient active PTB primarily manifested as a small nodule in humans regardless of risk factors. With risk factors, it progressed more frequently and rapidly into active disease, with a higher prevalence of atypical radiological manifestations. .

Multidrug-resistant tuberculosis over 20 years at a referral hospital in South Korea: trends and outcomes.

SETTING: A referral centre in South Korea. OBJECTIVE: To investigate trends in drug resistance, treatment modalities and outcomes, and adverse events of multidrug-resistant tuberculosis (MDR-TB) over two decades. DESIGN: MDR-TB patients treated at Seoul National Hospital University between 1996 and 2015 were divided into four 5-year cohorts according to the date of initial diagnosis. Changes in demographic characteristics, drug resistance, drugs used, treatment outcomes and adverse events over time were elucidated. RESULTS: Between 1996 and 2015, 418 patients were treated for MDR-TB: 86 patients between 1996 and 2000, 125 between 2001 and 2005, 123 between 2006 and 2010, and 84 between 2011 and 2015. The proportion of patients with positive acid-fast bacilli sputum (60.5-29.7%, P < 0.001) or cavities on chest radiographs (86.0-40.5%, P < 0.001) decreased over time. Resistance to pyrazinamide, fluoroquinolones, cycloserine and p-aminosalicylic acid decreased. Later-generation fluoroquinolones (77.9-90.5%) and linezolid (0-26.2%) became more frequently prescribed. The treatment success rate increased (45.3-88.1%, P < 0.001); neurological adverse events, including peripheral neuropathy also increased (4.7-13.1%, P = 0.027). CONCLUSION: MDR-TB patients presented with less severe disease and better resistance profiles over time in South Korea, with treatment outcomes improving continuously.

Evaluation of Xpert(®) MTB/RIF assay: diagnosis and treatment outcomes in rifampicin-resistant tuberculosis.

SETTING: The Xpert(®) MTB/RIF assay is endorsed by the World Health Organization for the detection of rifampicin (RMP) resistant tuberculosis (TB). OBJECTIVE: To evaluate Xpert for its diagnostic accuracy in detecting RMP-resistant TB and its impact on treatment outcomes. DESIGN: Patients with available phenotypic drug susceptibility testing (DST) results and those in whom RMP-resistant pulmonary TB was diagnosed using Xpert were evaluated. The accuracy and turnaround time (TAT) of Xpert for determining RMP-resistant TB was calculated. The TATs for treatment between patients diagnosed with RMP-resistant TB using Xpert and those diagnosed without the assay (phenotypic DST group) were compared. RESULTS: In 321 patients, when phenotypic DST was used as the gold standard, Xpert sensitivity and specificity for RMP resistance diagnosis was respectively 100% and 98.7%; the positive and negative predictive values were respectively 86.2% and 100%. The Xpert group had a much shorter interval from initial evaluation to commencing second-line anti-tuberculosis treatment (64 vs. 2 days, P < 0.001), and negative conversion of mycobacterial cultures (197 vs. 62.5 days, P < 0.001) than the phenotypic DST group. CONCLUSION: Xpert was accurate at diagnosing RMP resistance in this setting with an intermediate TB burden and a low level of RMP resistance. Xpert might reduce disease transmission by reducing the sputum culture conversion times for patients with RMP-resistant TB.

Changes in treatment outcomes of multidrug-resistant tuberculosis.

SETTING: After several changes in treatment modalities, it is time to re-evaluate treatment outcomes of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVE: To evaluate treatment outcomes, elucidate changes in outcomes over time and identify predictors of treatment success for MDR-TB. DESIGN: Patients diagnosed with MDR-TB at a tertiary referral centre in South Korea between January 2006 and December 2010 were included. Treatment modalities and outcomes were assessed. Predictors of treatment success were analysed using multiple logistic regression. The treatment modalities and outcomes of these patients were compared with those of MDR-TB patients between January 1996 and December 2005. RESULTS: Of the 123 MDR-TB patients diagnosed during the later study period, treatment was successful in 103 (83.7%). Extensive drug resistance (OR 0.31, P = 0.044) and additional resistance to fluoroquinolones (OR 0.23, P = 0.039) were inversely associated with treatment success. The treatment success rate improved from 53.5% in 1996-2000 to 68.8% in 2001-2005 and 83.7% in 2006-2010 (P < 0.001). Improved outcomes were accompanied with more frequent use of later-generation fluoroquinolones and linezolid and less frequent surgical resection. CONCLUSION: Treatment outcomes for MDR-TB improved at a tertiary referral centre in South Korea. The improvement was associated with more frequent use of later-generation fluoroquinolones and linezolid.

Accuracy of the Xpert® MTB/RIF assay for the diagnosis of extra-pulmonary tuberculosis in South Korea.

SETTING: The Xpert(®) MTB/RIF assay has been endorsed by the World Health Organization for the detection of pulmonary and extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To determine the accuracy of the Xpert assay in diagnosing EPTB in South Korea, a country with an intermediate TB burden. DESIGN: We retrospectively reviewed the medical records of 1429 patients in whom the Xpert assay using EPTB specimens was requested between 1 January 2011 and 31 October 2013 in a tertiary referral hospital in South Korea. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of EPTB and detection of rifampicin (RMP) resistance were calculated. RESULTS: Using culture as gold standard, the sensitivity, specificity, PPV and NPV of the assay were respectively 67.7%, 98.1%, 60% and 98.6%. Using a composite reference standard, the sensitivity, specificity, PPV and NPV were respectively 49.3%, 100%, 100% and 95.1%. The sensitivity, specificity, PPV and NPV for the detection of RMP resistance among specimens with positive results for Mycobacterium tuberculosis were respectively 80%, 100%, 100% and 97.7%. CONCLUSION: The Xpert assay showed acceptable sensitivity in certain groups and excellent specificity in diagnosing EPTB and detecting RMP resistance in an intermediate TB burden country.

The effects of statin use on the development of tuberculosis among patients with diabetes mellitus.

OBJECTIVE: To evaluate whether statin use affects the development of tuberculosis (TB) among patients with diabetes mellitus (DM). METHODS: This is a retrospective cohort study of patients with newly diagnosed type 2 DM based on the South Korean nationwide claims database. The participants were type 2 DM patients aged 20-99 years who were newly treated with anti-diabetic drugs between 1 January 2007 and 31 December 2010. Patients who had statin prescriptions before a diagnosis of diabetes or were diagnosed with TB before diabetes were excluded. RESULTS: Of 840,899 newly diagnosed type 2 DM patients, 281,842 (33.5%) patients were statin users and 559,057 (66.5%) were non-users. During the study period, 4075 [corrected] individuals were diagnosed with TB; the estimated incidence of TB in our cohort was 251/100,000 patient-years (95%CI 243-258). In comparison to non-TB patients, statin users were less frequent among TB patients (19.2% vs. 33.6%). After adjustment for potential baseline confounders, statin use was not associated with the development of TB in DM patients (aHR 0.98; 95%CI 0.89-1.07). CONCLUSIONS: TB development among newly diagnosed type 2 DM was considerable, and statin use among these diabetics was not associated with a protective effect on TB incidence.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.

Antiplatelet or anticoagulant therapy might not increase the risk of haemoptysis in patients with bronchiectasis.

The aim of this study was to assess whether the use of antiplatelets and anticoagulants increased haemoptysis in patients with bronchiectasis. Cases (n = 242) with a history of haemoptysis were compared with controls (n = 242) without a history of haemoptysis. Of the 242 case patients, 16.5% took antiplatelets compared with 19.8% of controls (P = 0.346). The proportion of warfarin users did not differ between cases and controls (3.3% vs. 2.5%, P = 0.588). The use of these agents might not be associated with increased risk of haemoptysis in patients with bronchiectasis.

Diagnostic accuracy of Xpert® MTB/RIF on bronchoscopy specimens in patients with suspected pulmonary tuberculosis.

OBJECTIVE: To determine the diagnostic accuracy of the Xpert® MTB/RIF assay using samples obtained through bronchoscopy in patients with suspected pulmonary tuberculosis (PTB). DESIGN: We retrospectively reviewed the records of patients with suspected PTB for whom the Xpert MTB/RIF assay was performed on bronchoscopy specimens. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of active PTB were calculated for acid-fast bacilli (AFB) smear microscopy and the Xpert assay using culture of Mycobacterium tuberculosis from sputum or bronchoscopy specimens as a reference standard. RESULTS: A total of 132 patients were included in the final analysis. Of these, 38 had culture-confirmed PTB. The sensitivity of the Xpert assay using bronchial washing or bronchoalveolar lavage (BAL) fluid for the diagnosis of PTB was 81.6%, and specificity was 100%. The PPV and NPV were 100% and 92.1%, respectively. The sensitivity and specificity of AFB smear microscopy were respectively 13.2% and 98.8%. CONCLUSION: The Xpert assay on bronchoscopy specimens provided an accurate diagnosis of PTB in patients who had a negative AFB smear or who could not produce sputum.

Serial interferon-gamma release assays after chemoprophylaxis in a tuberculosis outbreak cohort.

PURPOSE: Interferon-gamma release assay (IGRA) results have been suggested as a surrogate marker of treatment response in latent tuberculosis infection (LTBI). However, data have not been consistent, and most previous studies focused on participants taking isoniazid prophylaxis. The aim of this study was to elucidate the changes in the IGRA results in patients who underwent chemoprophylaxis with isoniazid and rifampicin daily for 3 months. METHODS: In a TB outbreak cohort, 26 asymptomatic close contacts with normal chest radiographs and positive QuantiFERON-TB Gold In-Tube assay (QFT-GIT) results were recruited. These patients were treated with isoniazid and rifampicin daily for 3 months. The QFT-GIT was repeated at 3 and 6 months following treatment initiation. RESULTS: Compared with the initial QFT-GIT results (3.59 ± 3.39 IU/mL), the interferon-gamma (IFN-γ) levels had decreased significantly at 6 months (0.84 ± 1.14 IU/mL; P = 0.005), but not at 3 months (3.58 ± 3.64 IU/mL; P = 0.98). Reversions occurred in seven (26.9 %) patients at 3 months and in an additional two participants at 6 months; a total of nine participants (34.6 %) had reversions. Recent conversion was associated with reversion of the test results (odds ratio 26.3, 95 % confidence interval 3.04-226.6). CONCLUSION: Chemoprophylaxis with isoniazid and rifampicin generally decreased IFN-γ levels among tuberculosis contacts. However, only a small portion of participants achieved reversion.

Adverse events and development of tuberculosis after 4 months of rifampicin prophylaxis in a tuberculosis outbreak.

We screened tuberculosis (TB) contacts as an outbreak investigation with tuberculin skin test (TST) and interferon-gamma release assay (IGRA). We evaluated adverse events and TB incidence in all persons screened after rifampicin (RFP) prophylaxis, and specifically assessed the new TB cases in relation to initial TST and IGRA results. The 180 contacts were divided into four groups: TST+/IGRA+ (n = 101), TST+/IGRA- (n = 22), TST-/IGRA+ (n = 16), and TST-/IGRA- (n = 41). RFP treatment (4 months) was prescribed only to the TST+/IGRA+ group. Of 87 contacts who initiated prophylaxis, adverse events occurred in 21 contacts (24.1%) including hepatotoxicity (11.5%), flu-like syndrome (5.7%), and thrombocytopenia (3.4%). TB developed in two TST+/IGRA+ subjects after completion of prophylaxis, including one multidrug-resistant (MDR)-TB case during 21.8 months of follow-up. Adverse events were frequent, and development of TB including MDR-TB occurred after RFP prophylaxis.

The impact of combined pulmonary fibrosis and emphysema on mortality.

SETTING: The impact on patient mortality of combined pulmonary fibrosis and emphysema (CPFE) compared with emphysema alone has never been investigated. OBJECTIVE: To elucidate whether CPFE has an impact on overall mortality over that of emphysema alone. DESIGN: We screened patients who underwent chest computed tomography (CT) scans during the period from 1 January 2001 to 31 December 2005 in a tertiary referral hospital. Patients who had both emphysema and pulmonary fibrosis, thus meeting the inclusion criteria, were defined as CPFE. Controls with emphysema alone who were matched for age, sex and the date of CT scan were randomly selected. Cox proportional regression analysis was performed to verify whether CPFE is associated with increased overall mortality. RESULTS: We found 135 CPFE cases. In the multivariable Cox regression stratified by the presence of comorbid malignancy, CPFE had five times higher mortality risk (adjusted HR 5.10, 95%CI 1.75-14.9) in non-malignant cases, and showed a statistically insignificant trend for higher mortality risk (adjusted HR 1.70, 95%CI 0.94-2.51) in the malignant cases after adjusting for forced vital capacity, height and hypertension. CONCLUSION: CPFE is not rare and CPFE patients had a higher overall mortality risk than emphysema-only patients.

Impact of antibiotic prophylaxis on postbronchoscopy fever: a randomised controlled study.

BACKGROUND: Postbronchoscopy fever can develop in 5-16% of adult patients. The microbiological contribution to postbronchoscopy fever is unclear. OBJECTIVE: To elucidate the effect of prophylactic antibiotics on the development of postbronchoscopy fever and pneumonia. DESIGN: Study patients were randomised to receive no treatment or oral amoxicillin/clavulanate 30 min before flexible bronchoscopy. The primary outcome variable was the frequency of postbronchoscopy fever and pneumonia. White blood cell counts, C-reactive protein and the serum pyrogenic cytokines interleukin (IL) 1ß, IL-6 and tumour necrosis factor-alpha were measured before and after bronchoscopy. RESULTS: Of 143 subjects enrolled in the study, the final analysis was performed among 67 subjects in the prophylaxis group and 64 in the control group. The frequency of postbronchoscopy fever did not differ between the groups (25.4% for the prophylaxis group vs. 26.6% for controls, P > 0.05). Pneumonia developed in 1.5% of the prophylaxis group and 4.7% of the controls. There was no bacteraemia in either group. Serum pyrogenic cytokines did not differ between the groups. CONCLUSIONS: Prophylactic antibiotics before bronchoscopy did not reduce the frequency of postbronchoscopy fever and did not affect serum levels of pyrogenic cytokines. These findings suggest that microbiological factors may not be responsible for the development of postbronchoscopy fever.

Clinical characteristics and outcomes of H1N1-associated pneumonia among adults in South Korea.

BACKGROUND: Pneumonia has been reported to be the most life-threatening complication of influenza virus infection. OBJECTIVE: to describe clinical characteristics and determine risk factors for death among patients with H1N1-associated pneumonia. DESIGN: A retrospective cohort study included all adult patients diagnosed and treated with H1N1-associated pneumonia in 14 participating institutions between 1 May 2009 and 28 February 2010 in South Korea. Clinical outcomes were summarised and predictors for death evaluated through univariate and multivariate analysis. RESULTS: A total of 269 adult patients with H1N1-associated pneumonia were diagnosed and treated. Hospital visits or admissions peaked in November 2009, coinciding with the peak in the 2009 H1N1 epidemic in South Korea. The patients' median age was 48 years; 143 were male. Most (n = 266, 98.9%) were admitted for treatment: 97 (36.1%) required intensive care and 28 (10.4%) needed mechanical ventilation. Despite the use of antiviral and antibacterial agents, 19 patients (7.1%) died. Risk factors predictive of death included presence of malignancy (aOR 12.0, 95%CI 2.8-51.5), and pneumonia severity index (PSI) score (aOR 1.03, 95%CI 1.01-1.04). CONCLUSION: Deaths among adult patients with H1N1-associated pneumonia were not rare. Clinicians should be aware of the possibility of a poor prognosis among H1N1-associated pneumonia patients with underlying malignancy or high PSI score.