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.

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.

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.

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.

Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis.

The proper interval for repeating an interferon-γ release assay (IGRA) among tuberculosis contacts with initially negative results is unknown. The interval for IGRA conversion after exposure to patients with active pulmonary tuberculosis in an outbreak setting was evaluated. In a platoon of 32 soldiers, four active pulmonary tuberculosis patients, in addition to one index patient, were diagnosed during a contact investigation. For the other 27 contacts, a tuberculin skin test (TST) and QuantiFERON® TB-Gold In-Tube (QFT-GIT) assay were performed. For soldiers with a negative result on the initial QFT-GIT assay, the test was repeated at 2, 4, 8, 14, 18 and 30 weeks until positive conversion occurred. When conversion was identified, the subject was treated for latent tuberculosis infection. Initially, 17 (63.0%) soldiers gave positive QFT-GIT results, whereas 21 (77.8%) showed positive TST results. Among 10 participants with initially negative QFT-GIT results, three showed conversion at 2 weeks, three at 4 weeks and three at 14 weeks. Conversion did not occur during the 30-week observation period in one contact. Based on the tuberculosis exposure time-points among the contacts, IGRA conversion generally occurred 4-7 weeks after exposure, although it could occur as late as 14-22 weeks after exposure.

Impact of resistance to first-line and injectable drugs on treatment outcomes in MDR-TB.

Recently, resistance to additional first-line and injectable drugs was reported to be an independent risk factor for adverse outcomes in multidrug-resistant (MDR) tuberculosis (TB) patients. The aim of the present study was to confirm these observations in MDR-TB patients without HIV infection. MDR-TB patients treated at a tertiary referral hospital in South Korea between January 1996 and December 2005 were included. The unadjusted and adjusted odds ratios of adverse treatment outcome were calculated for resistance to each drug and combination of drugs using simple or multiple logistic regressions. None of the resistance to additional first-line or injectable drugs was associated with higher odds for adverse treatment outcome in 155 MDR but nonextensively drug-resistant (non-XDR) TB patients. However, streptomycin resistance was associated with 12 times the odds for adverse treatment outcome in 42 extensively drug-resistant (XDR) TB patients. Neither combinations of first-line drugs nor those of injectable drugs were associated with increased odds for adverse treatment outcomes in non-XDR MDR-TB patients or XDR-TB patients. Only streptomycin resistance among the first-line or injectable drugs was associated with adverse treatment outcomes in extensively drug-resistant tuberculosis patients without HIV infection.

Mechanism of suppression in Drosophila: control of sepiapterin synthase at the purple locus.

The amounts of sepiapterin and red pteridine eye pigments (drosopterins) in Drosophila melanogaster are known to be reduced in the purple mutant and restored to normal by a suppressor mutation. We show here that sepiapterin synthase activity is 30 percent of normal in pr and prbw, two naturally occurring alleles of purple, and is restored to nearly normal levels by the suppressor su(s)2. A heterozygote of two newly induced alleles of pr has even lower enzyme activity (less than 10 percent). The sepiapterin synthase activity is proportional to the number of wild-type pr alleles in flies when one and two copies of the allele are present and is higher in three-than in two-dose flies. We hypothesize that the purple locus may be a structural gene for sepiapterin synthase in Drosophila.

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.

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.

Decreased phosphorylation of STAT-1, STAT-4 and cytokine release in MDR-TB patients with primary resistance.

SETTING: We recently showed that treatment failure rate was higher among multidrug-resistant tuberculosis (MDR-TB) patients without a previous history of tuberculosis (TB) treatment, or so-called 'primary resistance'. OBJECTIVE: To investigate the phosphorylation levels of signal transducers and activators of transcription-1 (STAT-1) and STAT-4 and the subsequent cytokine release as a possible cause of a poor prognosis in MDR-TB patients with primary resistance. DESIGN: Ten patients with successfully treated pulmonary TB without resistance, 12 MDR-TB patients with acquired resistance and 10 MDR-TB patients with primary resistance were enrolled. After 24 h stimulation of peripheral blood mononuclear cells (PBMC) with interferon-gamma (IFN-gamma), interleukin-12 (IL-12), purified protein derivative (PPD), or lysate of Mycobacterium tuberculosis, flow cytometric analysis of intracellular pSTAT-1 and pSTAT-4 were performed and secretion of IFN-gamma, IL-12p40 and tumour necrosis factor-alpha (TNF-alpha) was measured in culture supernatant. RESULTS: The mean fluorescent intensities of pSTAT-1 and pSTAT-4 in PBMC of MDR-TB patients with primary resistance decreased on stimulation of IFN-gamma, PPD or lysate of M. tuberculosis when compared with patients with acquired resistance. In addition, secretion of IFN-gamma, IL-12p40 and TNF-alpha in these patients decreased on various stimuli. CONCLUSION: Decreased phosphorylation of STAT-1, STAT-4, and of subsequent cytokine release, might be associated with a poor prognosis in MDR-TB patients with primary resistance.

Predictors of persistent airway stenosis in patients with endobronchial tuberculosis.

SETTING: The university and municipal hospitals in Seoul, Korea. OBJECTIVE: To evaluate the predictors of persistent airway stenosis following anti-tuberculosis chemotherapy in patients with endobronchial tuberculosis (TB). DESIGN: Diagnosis of TB was confirmed by microbiology or histopathology. Bronchoscopic examinations revealed that patients had endobronchial lesions compatible with endobronchial TB. Study subjects had at least one follow-up bronchoscopy to evaluate their treatment response. Treatment response was determined by changes in the degree or extent of airway stenosis between the first and last bronchoscopic examinations. RESULTS: Sixty-seven subjects were recruited retrospectively from Seoul National University Hospital and Seoul National University Boramae Hospital. Persistent bronchostenosis occurred in 41.8% of the patients. In multivariate regression analysis, age >45 years (OR 3.65), pure or combined fibrostenotic subtype (OR 5.54) and duration from onset of chief complaint to the initiation of anti-tuberculosis chemotherapy >90 days (OR 5.98) were identified as independent predictors of persistent airway stenosis. Oral corticosteroids (prednisolone equivalent >or=30 mg/d) did not reduce the frequency of persistent airway stenosis. CONCLUSION: Early diagnosis and early administration of anti-tuberculosis chemotherapy before involvement of the deeper airways is important to prevent the development of unwanted sequelae of bronchostenosis.

Role of the C-reactive protein for the diagnosis of TB among military personnel in South Korea.

Clinicians are frequently faced with the task of differentiating between pulmonary tuberculosis (PTB) and pneumonia. We evaluated the role of the C-reactive protein test (CRP) for differentiating between TB and pneumonia among military personnel in South Korea. Only immunocompetent males were eligible. Forty-six patients with PTB and 67 with pneumonia were enrolled prospectively. Median CRP concentration was lower in patients with TB than in patients with non-tuberculous pneumonia (3.2 mg/dl [range 0.1-15.7 mg/dl] vs. 8.3 mg/dl [range 0.2-33.7 mg/dl], P < 0.001). The sensitivity and specificity for TB of a low CRP concentration (< 11.2 mg/dl) in serum was 93.3% and 40.9%, respectively. CRP concentration measurement might be useful for eliminating the diagnosis of TB.

Aetiologies and predictors of pulmonary cavities in South Korea.

OBJECTIVE: To identify the aetiologies of pulmonary cavities and the clinical predictors of cavities of mycobacterial origin. SETTING: A tertiary referral hospital in South Korea, where the prevalence of tuberculosis (TB) is intermediate. DESIGN: A retrospective review of clinical records and radiographic examinations of patients presenting pulmonary cavities on simple chest radiograph between January and December 2005. RESULTS: Of 131 patients enrolled with pulmonary cavities, 66 (50.4%) had cavities of mycobacterial origin. Age <50 years (P = 0.04) and largest cavity located in the upper lobes (P = 0.04) increased the likelihood that the cavities were of mycobacterial origin. Conversely, history of malignancy (P = 0.02), lesions confined to one lobe (P = 0.02) and multiple enlarged mediastinal lymph nodes (P = 0.03) suggested a non-mycobacterial cause. CONCLUSION: Mycobacterial infection accounted for half of the cavitary lesions identified in this study. In older patients with a history of malignancy, non-nodular infiltration, lesions confined to one lobe and with multiple lymphadenopathy, diseases not caused by mycobacteria should be considered.

Determinants of diagnostic bronchial washing in peripheral lung cancers.

OBJECTIVE: To establish clinical determinants affecting the diagnostic yield of bronchial washing. SETTING: We performed bronchial washing in 241 consecutive patients with bronchoscopically invisible lung tumours. Of these, 150 patients known to have lung cancer were enrolled for the final analysis. DESIGN: A multi-centre study. RESULTS: Bronchial washing provided a diagnosis of lung cancer in 30 of the 150 patients (20%). Tumour size > or = 3 cm (P = 0.005), the location of the tumour within 8 cm of the carina (P = 0.003), and exposed type bronchus sign of tumour (P < 0.001) were factors affecting diagnostic bronchial washing for bronchoscopically invisible lung cancers. However, multivariate logistic regression revealed that exposed type bronchus sign was the sole determinant (OR 19.22, 95% CI 4.23-87.46, P < 0.001). CONCLUSION: Bronchial washing is a useful procedure for the diagnosis of bronchoscopically invisible lung cancers. As the tumour-bronchus relationship is the most important determinant of a diagnostic yield, the routine use of bronchial washing should be considered for tumours with exposed type bronchus sign.

Alternate use of divergent forms of an ancient exon in the fructose-1,6-bisphosphate aldolase gene of Drosophila melanogaster.

The fructose-1,6-bisphosphate aldolase gene of Drosophila melanogaster contains three divergent copies of an evolutionarily conserved 3' exon. Two mRNAs encoding aldolase contain three exons and differ only in the poly(A) site. The first exon is small and noncoding. The second encodes the first 332 amino acids, which form the catalytic domain, and is homologous to exons 2 through 8 of vertebrates. The third exon encodes the last 29 amino acids, thought to control substrate specificity, and is homologous to vertebrate exon 9. A third mRNA substitutes a different 3' exon (4a) for exon 3 and encodes a protein very similar to aldolase. A fourth mRNA begins at a different promoter and shares the second exon with the aldolase messages. However, two exons, 3a and 4a, together substitute for exon 3. Like exon 4a, exon 3a is homologous to terminal aldolase exons. The exon 3a-4a junction is such that exon 4a would be translated in a frame different from that which would produce a protein with similarity to aldolase. The putative proteins encoded by the third and fourth mRNAs are likely to be aldolases with altered substrate specificities, illustrating alternate use of duplicated and diverged exons as an evolutionary mechanism for adaptation of enzymatic activities.

The role of TST in the diagnosis of latent tuberculosis infection among military personnel in South Korea.

BACKGROUND: The rapid and accurate diagnosis of latent tuberculosis infection (LTBI) is crucial in military settings because military personnel live in crowded circumstances and are of an age group with a high incidence of tuberculosis (TB). We tried to elucidate whether the tuberculin skin test (TST) accurately reflects the risk of TB infection among military personnel, in a setting of intermediate TB prevalence and where bacille Calmette-Guérin (BCG) vaccination is mandatory. METHODS: A multi-stage cluster survey was conducted among military personnel in South Korea. Participants were grouped according to their risk of TB infection: Group 1, no identifiable risk of TB; Groups 2 and 3, recent casual (Group 2) or close (Group 3) contact with smear-positive TB patients. RESULTS: Of 1045 participants, 857 (82.0%) had been BCG-vaccinated. The odds ratio (OR) of a positive TST (10 mm cut-off) for Group 2 (n = 184) and Group 3 (n = 83) compared with Group 1 (n = 778) were 0.95 (95%CI 0.67-1.38) and 1.7 (95%CI 1.06-2.70), respectively (P value for trend 0.16). CONCLUSIONS: The TST does not accurately reflect the risk of LTBI among young military personnel in a setting where there is intermediate TB prevalence and extensive BCG coverage.

Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans.

OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.