Distinguishing Relapse From Reinfection With Whole-Genome Sequencing in Recurrent Pulmonary Tuberculosis: A Retrospective Cohort Study in Beijing, China.
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SUBMITTER: Du J
PROVIDER: S-EPMC8693897 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tuberculosis (TB) recurrence can result from either relapse of an original infection or exogenous reinfection with a new strain of Mycobacterium tuberculosis (MTB). The aim of this study was to assess the roles of relapse and reinfection among recurrent TB cases characterized by a high prevalence rate of drug-resistant TB within a hospital setting. After 58 paired recurrent TB cases were genotyped to distinguish relapse from reinfection, 37 (63.8%) were demonstrated to be relapse cases, while the remaining 21 were classified as reinfection cases. Statistical analysis revealed that male gender was a risk factor for TB reinfection, odds ratios and 95% confidence interval (OR [95% CI]: 4.188[1.012-17.392], P = 0.049). Of MTB isolates obtained from the 37 relapse cases, 11 exhibited conversion from susceptible to resistance to at least one antibiotic, with the most frequent emergence of drug resistance observed to be levofloxacin. For reinfection cases, reemergence of rifampicin-resistant isolates harboring double gene mutations, of codon 531 of rpoB and codon 306 of embB, were observed. In conclusion, our data demonstrate that relapse is a major mechanism leading to TB recurrence in Beijing Chest Hospital, a national hospital specialized in TB treatment. Moreover, male patients are at higher risk for reinfection. The extremely high rate of multidrug-resistant tuberculosis (MDR-TB) among reinfection cases reflects more successful transmission of MDR-TB strains versus non-resistant strains overall.
| S-EPMC6102324 | biostudies-literature
Project description:BackgroundTuberculosis may reoccur due to reinfection or relapse after initially successful treatment. Distinguishing the cause of TB recurrence is crucial to guide TB control and treatment. This study aimed to investigate the source of TB recurrence and risk factors related to relapse in Hunan province, a high TB burden region in southern China.MethodsA population-based retrospective study was conducted on all culture-positive TB cases in Hunan province, China from 2013 to 2020. Phenotypic drug susceptibility testing and whole-genome sequencing were used to detect drug resistance and distinguish between relapse and reinfection. Pearson chi-square test and Fisher exact test were applied to compare differences in categorical variables between relapse and reinfection. The Kaplan-Meier curve was generated in R studio (4.0.4) to describe and compare the time to recurrence between different groups. p < 0.05 was considered statistically significant.ResultsOf 36 recurrent events, 27 (75.0%, 27/36) paired isolates were caused by relapse, and reinfection accounted for 25.0% (9/36) of recurrent cases. No significant difference in characteristics was observed between relapse and reinfection (all p > 0.05). In addition, TB relapse occurs earlier in patients of Tu ethnicity compared to patients of Han ethnicity (p < 0.0001), whereas no significant differences in the time interval to relapse were noted in other groups. Moreover, 83.3% (30/36) of TB recurrence occurred within 3 years. Overall, these recurrent TB isolates were predominantly pan-susceptible strains (71.0%, 49/69), followed by DR-TB (17.4%, 12/69) and MDR-TB (11.6%, 8/69), with mutations mainly in codon 450 of the rpoB gene and codon 315 of the katG gene. 11.1% (3/27) of relapse cases had acquired new resistance during treatment, with fluoroquinolone resistance occurring most frequently (7.4%, 2/27), both with mutations in codon 94 of gyrA.ConclusionEndogenous relapse is the main mechanism leading to TB recurrences in Hunan province. Given that TB recurrences can occur more than 4 years after treatment completion, it is necessary to extend the post-treatment follow-up period to achieve better management of TB patients. Moreover, the relatively high frequency of fluoroquinolone resistance in the second episode of relapse suggests that fluoroquinolones should be used with caution when treating TB cases with relapse, preferably guided by DST results.
| S-EPMC9981662 | biostudies-literature
Project description:Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01-8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30-59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting.
| S-EPMC5638046 | biostudies-literature
Project description:BackgroundSince leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin.MethodologyDNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico.Principal findingsIn all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable.Conclusions/significanceThis is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission.
| S-EPMC5498066 | biostudies-literature
Project description:BackgroundRIFAQUIN was a tuberculosis chemotherapy trial in southern Africa including regimens with high-dose rifapentine with moxifloxacin. Here, the application of whole-genome sequencing (WGS) is evaluated within RIFAQUIN for identifying new infections in treated patients as either relapses or reinfections. WGS is further compared with mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) typing. This is the first report of WGS being used to evaluate new infections in a completed clinical trial for which all treatment and epidemiological data are available for analysis.MethodsDNA from 36 paired samples of Mycobacterium tuberculosis cultured from patients before and after treatment was typed using 24-loci MIRU-VNTR, in silico spoligotyping and WGS. Following WGS, the sequences were mapped against the reference strain H37Rv, the single-nucleotide polymorphism (SNP) differences between pairs were identified, and a phylogenetic reconstruction was performed.ResultsWGS indicated that 32 of the paired samples had a very low number of SNP differences (0-5; likely relapses). One pair had an intermediate number of SNP differences, and was likely the result of a mixed infection with a pre-treatment minor genotype that was highly related to the post-treatment genotype; this was reclassified as a relapse, in contrast to the MIRU-VNTR result. The remaining three pairs had very high SNP differences (>750; likely reinfections).ConclusionsWGS and MIRU-VNTR both similarly differentiated relapses and reinfections, but WGS provided significant extra information. The low proportion of reinfections seen suggests that in standard chemotherapy trials with up to 24 months of follow-up, typing the strains brings little benefit to an analysis of the trial outcome in terms of differentiating relapse and reinfection. However, there is a benefit to using WGS as compared to MIRU-VNTR in terms of the additional genotype information obtained, in particular for defining the presence of mixed infections and the potential to identify known and novel drug-resistance markers.
| S-EPMC5371199 | biostudies-literature
Project description:ImportanceDespite posing a significant challenge to global tuberculosis (TB) elimination efforts, recurrent TB remains understudied due to the challenges of long-term observation.ObjectiveTo investigate the burden of recurrent TB using data from patients with pulmonary TB (PTB) in China.Design, setting, and participantsThis retrospective cohort study included all bacteriologically confirmed or clinically diagnosed PTB cases reported to the Tuberculosis Information Management System with completed or successful treatment outcomes from January 1, 2005, to December 31, 2021. Data were analyzed from July 15, 2022, to October 28, 2023.ExposuresNewly diagnosed PTB was classified into primary, hematogenous disseminated, or secondary PTB.Main outcomes and measuresThe primary outcome was the annual recurrence rate, stratified by disease classification, over the 17-year observation period. The recurrence rate for year n was calculated by dividing the number of patients with recurrent TB in year n by observed person-years in year n. The secondary outcome was the annual proportion of recurrent TB among reported cases and associated risk factors.ResultsOf 13 833 249 patients with TB reported to the Tuberculosis Information Management System, 10 482 271 with PTB met the inclusion criteria. Of these, 68.9% were male, 22.3% were 65 years or older, 89.6% were of Han ethnicity, and 68.4% were agricultural workers. A total of 413 936 patients experienced a recurrent TB episode after successful treatment, resulting in an overall recurrence rate of 0.47 (95% CI, 0.47-0.48) per 100 person-years. The recurrence rate for patients with primary PTB was 0.24 (95% CI, 0.22-0.26) per 100 person-years; for hematogenous disseminated PTB, 0.37 (95% CI, 0.36-0.38) per 100 person-years; and for secondary PTB, 0.48 (95% CI, 0.47-0.48) per 100 person-years. The cumulative proportion of recurrences within the first 2 years accounted for 48.9% of all recurrent cases. The proportion of recurrent cases among notified incident cases increased 1.9-fold from 4.7% in 2015 to 8.8% in 2021. Among other factors, ages 45 to 64 years (adjusted hazard ratio, 1.77 [95% CI, 1.65-1.89]) and having completed treatment (adjusted hazard ratio, 1.16 [95% CI, 1.14-1.18]) were identified as associated with recurrence.Conclusions and relevanceIn this retrospective cohort study, the PTB recurrence rate was substantially higher than the incidence, and the proportion of recurrent cases increased. Almost half of the recurrence occurred within the first 2 years, suggesting that routine posttreatment follow-up may represent an important strategy for accelerating TB elimination.
| S-EPMC11320166 | biostudies-literature
Project description:Relapse and Reinfection in Tuberculosis
| PRJEB2777 | ENA
Project description:Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (± 2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (± 6.4) days for relapses and 14.7 (± 6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates.
| S-EPMC3388025 | biostudies-literature
Project description:BackgroundRecurrence of tuberculosis after treatment makes management difficult and is a key factor for determining treatment efficacy. Two processes can cause recurrence: relapse of the primary infection or re-infection with an exogenous strain. Although re-infection can and does occur, its importance to tuberculosis epidemiology and its biological basis is still debated. We used whole-genome sequencing-which is more accurate than conventional typing used to date-to assess the frequency of recurrence and to gain insight into the biological basis of re-infection.MethodsWe assessed patients from the REMoxTB trial-a randomised controlled trial of tuberculosis treatment that enrolled previously untreated participants with Mycobacterium tuberculosis infection from Malaysia, South Africa, and Thailand. We did whole-genome sequencing and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing of pairs of isolates taken by sputum sampling: one from before treatment and another from either the end of failed treatment at 17 weeks or later or from a recurrent infection. We compared the number and location of SNPs between isolates collected at baseline and recurrence.FindingsWe assessed 47 pairs of isolates. Whole-genome sequencing identified 33 cases with little genetic distance (0-6 SNPs) between strains, deemed relapses, and three cases for which the genetic distance ranged from 1306 to 1419 SNPs, deemed re-infections. Six cases of relapse and six cases of mixed infection were classified differently by whole-genome sequencing and MIRU-VNTR. We detected five single positive isolates (positive culture followed by at least two negative cultures) without clinical evidence of disease.InterpretationWhole-genome sequencing enables the differentiation of relapse and re-infection cases with greater resolution than do genotyping methods used at present, such as MIRU-VNTR, and provides insights into the biology of recurrence. The additional clarity provided by whole-genome sequencing might have a role in defining endpoints for clinical trials.FundingWellcome Trust, European Union, Medical Research Council, Global Alliance for TB Drug Development, European and Developing Country Clinical Trials Partnership.
| S-EPMC3861685 | biostudies-literature
Project description:In a 2-year prospective study of tuberculosis (TB) patients in China, the prevalences of non-Beijing strains of Mycobacterium tuberculosis varied between Shandong Province (20.6%), Shanghai (27.6%), and Sichuan Province (45.9%) (P < 0.005). These differences may be due to factors such as human migration, transmission, or diversification and adaptation of the mycobacteria to different hosts.
| S-EPMC3020470 | biostudies-literature