A Mycobacterium tuberculosis Specific IgG3 Signature of Recurrent Tuberculosis

South Africa has the highest prevalence of HIV and tuberculosis (TB) co-infection globally. Recurrent TB, caused by relapse or reinfection, makes up the majority of TB cases in South Africa, and HIV infected individuals have a greater likelihood of developing recurrent TB. Given that TB remains a leading cause of death for HIV infected individuals, and correlates of TB recurrence protection/risk have yet to be defined, here we sought to understand the antibody associated mechanisms of recurrent TB by investigating the humoral response in a longitudinal cohort of HIV co-infected individuals previously treated for TB with and without recurrent disease during follow-up, in order to identify antibody correlates of protection between individuals who do not have recurrent TB and individuals who do. We used a high-throughput, “systems serology” approach to profile biophysical and functional characteristics of antibodies targeting antigens from Mycobacterium tuberculosis (Mtb). Differences in antibody profiles were noted between individuals with and without recurrent TB, albeit these differences were largely observed close to the time of re-diagnosis. Individuals with recurrent TB had decreased Mtb-antigen specific IgG3 titers, but not other IgG subclasses or IgA, compared to control individuals. These data point to a potential role for Mtb-specific IgG3 responses as biomarkers or direct mediators of protective immunity against Mtb recurrence.

A Prospective Cohort Study on the Prevalent and Recurrent Tuberculosis Isolates Using the MIRU-VNTR Typing

The study aims to describe the clustering characteristics of Mycobacterium tuberculosis (M.tb) strains circulating in eastern China and determine the ratio of relapse and reinfection in recurrent patients. We recruited sputum smear-positive pulmonary tuberculosis cases from five cities of Jiangsu Province, China, during August 2013 and December 2015. Patients were followed for the treatment outcomes and recurrence based on a cohort design. M.tb strains were isolated and genotyped using the 12-locus MIRU-VNTR. The Beijing family was identified by the extended Region of Difference (RD) analysis. The Hunter-Gaston Discriminatory Index (HGDI) was used to judge the resolution ability of MIRU-VNTR. The odds ratio (OR) together with 95% confidence interval (CI) were used to estimate the strength of association. We performed a cluster analysis on 2098 M.tb isolates and classified them into 545 genotypes and five categories (I, 0.19%; II, 0.43%; III, 3.34%; IV, 77.46%; V, 18.59%). After adjusting for potential confounders, the Beijing family genotype (OR = 118.63, 95% CI: 79.61–176.79, P = 0.001) was significantly related to the dominant strain infections. Patients infected with non-dominant strains had a higher risk of the pulmonary cavity (OR = 1.39, 95% CI: 1.01–1.91, P = 0.046). Among 37 paired recurrent cases, 22 (59.46%) were determined as endogenous reactivation, and 15 (40.54%) were exogenous reinfection. The type of M.tb strains prevalent in Jiangsu Province is relatively single. Beijing family strains infection is dominant in local tuberculosis cases. Endogenous reactivation appears to be a major cause of recurrent tuberculosis in Eastern China. This finding emphasizes the importance of case follow-up and monitoring after the completion of antituberculosis treatment.

Recurrent tuberculosis disease in Singapore

Background Previously treated ie. recurrent tuberculosis (TB) cases account for ~7-8% of incident TB globally and in Singapore. Molecular fingerprinting has enabled the differentiation of these patients into relapsed or re-infection cases. Methods Patient demographics, disease characteristics and treatment information were obtained from the national TB notification registry and TB Control Unit. We performed a retrospective, case-control study to evaluate factors associated with recurrent TB disease in Singapore citizens and Permanent Residents with culture-positive TB from 2006 to 2013 and who developed a second episode of culture-positive TB up to 2016 using multivariable logistic regression analyses. Results 91 cases with culture-positive first and recurrent TB disease episodes were identified. Recurrent TB was associated with age ≥60 years (adjusted odds ratio [aOR] 1.98, 95% confidence interval [CI] 1.09-3.61), male gender (aOR 2.29, 95% CI 1.22–4.51), having concomitant pulmonary and extrapulmonary TB (aOR 3.10, 95% CI 1.59–6.10) and extrapulmonary TB alone (aOR 3.82, 95% CI 1.12-13.31); and was less likely in non-Malays (aOR 0.52, 95% CI 0.27–0.99). DNA fingerprinting results for both episodes in 49 cases differentiated these into 28 relapsed and 21 re-infection cases. Relapse was associated with having concomitant pulmonary and extrapulmonary TB (aOR 9.24, 95% CI 2.50–42.42), and positive sputum acid fast bacilli smear (aOR 3.95, 95% CI 1.36–13.10). Conclusion Relapse and re-infection contributed to 57% and 43% respectively of recurrent TB in Singapore. Our study highlights the under-appreciated association of concomitant pulmonary and extrapulmonary TB as a significant risk factor for disease relapse.

Relapse or Re-Infection, the Situation of Recurrent Tuberculosis in Eastern China

PurposeRecurrent tuberculosis (TB) is defined by more than one TB episode per patient and is caused by re-infection with a new Mycobacterium tuberculosis (Mtb) strain or relapse with the previous strain. Recurrence of TB is one important obstacle for End TB strategy in the world and elucidating the triggers of recurrence is important for the current TB control strategy in China. This study aimed to analyze the sources of recurrent TB by the molecular genotyping method.MethodA population-based surveillance was undertaking on all culture-positive TB cases in Jiangsu province, China from 2013 to 2019. Phenotypic drug susceptibility test (DST) by proportion method and mycobacterial interspersed repetitive units-variable number of tandem repeat (MIRU-VNTR) were adopted for drug resistance and genotype detection.ResultsA total of 1451 culture-positive TB patients were collected and 30 (2.06%, 30/1451) TB cases had recurrent TB episodes. Except 7 isolates were failed during subculture, 23 paired isolates were assessed. After genotyping by MIRU-VNTR, 12 (52.17%, 12/23) paired recurrence TB were demonstrated as relapse and 11 (47.83%,11/23) paired cases were identified as re-infection. The average interval time for recurrence was 24.04 (95%CI: 19.37-28.71) months, and there was no significant difference between relapse and re-infection. For the relapsed cases, two paired isolates exhibited drug resistance shifting, while four paired isolates revealed inconsistent drug resistance among the re-infection group including two multidrug-resistant tuberculosis (MDR-TB) at the second episode.ConclusionRelapse and re-infection contributed equally to the current situation of recurrence TB in Jiangsu, China. Besides, more efficient treatment assessment, specific and vigorous interventions are urgently needed for MDR-TB patients, considering obvious performance among re-infection cases.

Risk factors for recurrent tuberculosis after successful treatment in a high burden setting: a cohort study

Background People successfully completing treatment for tuberculosis remain at elevated risk for recurrent disease, either from relapse or reinfection. Identifying risk factors for recurrent tuberculosis may help target post-tuberculosis screening and care. Methods We enrolled 500 patients with smear-positive pulmonary tuberculosis in South Africa and collected baseline data on demographics, clinical presentation and sputum mycobacterial cultures for 24-loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. We used routinely-collected administrative data to identify recurrent episodes of tuberculosis occurring over a median of six years after successful treatment completion. Results Of 500 patients initially enrolled, 333 (79%) successfully completed treatment for tuberculosis. During the follow-up period 35 patients with successful treatment (11%) experienced a bacteriologically confirmed tuberculosis recurrence. In our Cox proportional hazards model, a 3+ AFB sputum smear grade was significantly associated with recurrent tuberculosis with a hazard ratio of 3.33 (95% CI 1.44–7.7). The presence of polyclonal M. tuberculosis infection at baseline had a hazard ratio for recurrence of 1.96 (95% CI 0.86–4.48). Conclusion Our results indicate that AFB smear grade is independently associated with tuberculosis recurrence after successful treatment for an initial episode while the association between polyclonal M. tuberculosis infection and increased risk of recurrence appears possible.