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Recurrent tuberculosis in the Netherlands – a 24-year follow-up study, 1993 to 2016
Abstract
Background
Not all treated tuberculosis (TB) patients achieve long-term recovery and reactivation rates reflect effectiveness of TB treatment.
Aim
We aimed to estimate rates and risk factors of TB reactivation and reinfection in patients treated in the Netherlands, after completed or interrupted treatment.
Methods
Retrospective cohort study of TB patients with available DNA fingerprint data, registered in the Netherlands Tuberculosis register (NTR) between 1993 and 2016. Reactivation was defined as an identical, and reinfection as a non-identical Mycobacterium tuberculosis strain in sequential episodes.
Results
Reactivation rate was 55/100,000 person-years (py) for patients who completed, and 318/100,000 py for patients who interrupted treatment. The risk of reactivation was highest in the first 5 years after treatment in both groups. The incidence rate of reactivation was 228/100,000 py in the first 2 years and 57/100,000 py 2–5 years after completed treatment. The overall rate of reinfection was 16/100,000 py. Among those who completed treatment, patients with male sex, mono or poly rifampicin-resistant TB and a previous TB episode had significantly higher risk of reactivation. Extrapulmonary TB was associated with a lower risk. Among patients who interrupted treatment, directly observed treatment (DOT) and being an undocumented migrant or people experiencing homelessness were associated with a higher risk of reactivation.
Conclusions
Both patients who completed or interrupted TB treatment should be considered as risk groups for reactivation for at least 2–5 years after treatment. They patients should be monitored and guidelines should be in place to enhance early detection of recurrent TB.
Objectives:
We describe long-term treatment outcomes in patients with multidrug-resistant/rifampicin-resistant (MDR/RR)-tuberculosis (TB) and validate established MDR/RR-TB treatment outcome definitions.
Methods:
Among patients with MDR/RR-TB admitted to a German MDR/RR-TB referral center from 01.09.2002-29.02.2020, we compared long-term treatment outcomes derived from individual patient follow-up with treatment outcomes defined by WHO-2013, WHO-2021 and TBnet-2016.
Results:
In total 163 patients (mean age 35 ± standard deviation 13 years, 14/163 [8.6%] living with HIV, 109/163 [66.9%] male, 149/163 [91.4%] migrating to Germany within five years) initiated treatment for culture confirmed MDR/RR-TB. Additional drug resistance to a fluoroquinolone or a second-line injectable agent was present in 15/163 (9.2%) of Mycobacterium tuberculosis strains; resistance against both drug classes was present in 29/163 (17.8%) of strains. Median duration of MDR/RR-TB treatment was 20 months (interquartile range [IQR] 19.3-21.6) with a medium of 5 active drugs included. Median follow-up time was 4 years (47.7 months; IQR 21.7-65.8 months). Cure was achieved in 25/163 (15.3%), 82/163 (50.3%) and 95/163 (58.3%) of patients according to WHO-2013, WHO-2021, and TBnet-2016 outcome definitions, respectively. The lost to follow-up rate was 17/163 (10.4%). Death was more likely in patients living with HIV (hazard ratio [HR]=4.28, 95% confidence interval [CI] 1.26-12.86) and older patients (HR=1.08, 95%CI 1.05-1.12, increment of one year). Overall, 101/163 (62.0%) patients experienced long-term, relapse-free cure; of those, 101/122 (82.8%) patients with a known status (not lost to-follow-up or transferred out) at follow-up.
Conclusions:
Under optimal management conditions leveraging individualized treatment regimens, long-term relapse-free cure from MDR/RR-TB is substantially higher than cure rates as defined by current treatment outcome definitions.
Background:
Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.
Methods:
We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.
Results:
From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).
Conclusions:
Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).
Background:
Patients with Mycobacterium tuberculosis isolates sharing identical DNA fingerprint patterns can be epidemiologically linked. However, municipal health services in the Netherlands are able to confirm an epidemiological link in only around 23% of the patients with isolates clustered by the conventional variable number of tandem repeat (VNTR) genotyping. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping.
Methods:
VNTR genotyping and WGS were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016. Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was ≤ 12 single nucleotide polymorphisms (SNPs). Cluster investigation was performed by municipal health services on all isolates clustered by VNTR in 2016. The proportion of epidemiological links identified among patients clustered by either method was calculated.
Results:
In total, 535 isolates were genotyped, of which 25% (134/535) were clustered by VNTR and 14% (76/535) by WGS; the concordance between both typing methods was 86%. The proportion of epidemiological links among WGS clustered cases (57%) was twice as common than among VNTR clustered cases (31%).
Conclusion:
When WGS was applied, the number of clustered isolates was halved, while all epidemiologically linked cases remained clustered. WGS is therefore a more reliable tool to predict epidemiological links between tuberculosis cases than VNTR genotyping and will allow more efficient transmission tracing, as epidemiological investigations based on false clustering can be avoided.
Background
We investigated the epidemiology and prevalence of potential risk factors of tuberculosis (TB) recurrence in a population-based registry cohort of 8084 TB cases between 1995 and 2013. Methods
An episode of recurrent TB was defined as a case re-registered in the National Infectious Disease Register at least 360 days from the date of the initial registration. A regression model was used to estimate risk factors for recurrence in the national cohort. To describe the presence of known risk factors for recurrence, patient records of the recurrent cases were reviewed for TB diagnosis confirmation, potential factors affecting the risk of recurrence, the treatment regimens given and the outcomes of the TB episodes preceding the recurrence. ResultsTB registry data included 84 patients, for whom more than 1 TB episode had been registered. After a careful clinical review, 50 recurrent TB cases (0.6%) were identified. The overall incidence of recurrence was 113 cases per 100,000 person-years over a median follow up of 6.1 years. For the first 2 years, the incidence of recurrence was over 200/100000. In multivariate analysis of the national cohort, younger age remained an independent risk factor at all time points, and male gender and pulmonary TB at 18 years of follow-up. Among the 50 recurrent cases, 35 patients (70%) had received adequate treatment for the first episode; in 12 cases (24%) the treating physician and in two cases (4%) the patient had discontinued treatment prematurely. In one case (2%) the treatment outcome could not be assessed. Conclusions
In Finland, the rate of recurrent TB was low despite no systematic directly observed therapy. The first 2 years after a TB episode had the highest risk for recurrence. Among the recurrent cases, the observed premature discontinuation of treatment in the first episode in nearly one fourth of the recurrent cases calls for improved training of the physicians.
Background
In Uzbekistan, despite stable and relatively high tuberculosis treatment success rates, relatively high rates of recurrent tuberculosis have recently been reported. Recurrent tuberculosis is when a patient who was treated for pulmonary tuberculosis and cured, later develops the disease again. This requires closer analysis to identify possible causes and recommend interventions to improve the situation. Using countrywide data, this study aimed to analyse trends in recurrent tuberculosis cases and describe their associations with socio-demographic and clinical factors.
Method
Countrywide retrospective cohort study comparing recurrent tuberculosis patients with all new tuberculosis patients registered within the NTP between January 2006 and December 2010 using routinely collected data. Determinants studied were baseline characteristics and treatment outcomes.
Results
Of 107,380 registered patients during the period January 2006 and December 2010, 9358 (8.7%) were recurrent cases. Between 2006 and 2008, the number of recurrent cases per annum increased from 1530 to 2081, then fell slightly thereafter from 2081 to 1888 cases. The proportion of all notified cases during this period increased from 6.5% to 9.9%. Factors associated with recurrent tuberculosis included age (35–55 years old), having smear positive pulmonary tuberculosis, residing in certain areas of Uzbekistan, having particular co-morbidities (including chronic obstructive pulmonary disease and HIV), and being unemployed, a pensioner or disabled. Recurrent tuberculosis patients also had a higher likelihood of having an unfavourable treatment outcome
Conclusion
Despite signs of declining national tuberculosis notifications between 2006 and 2010, the relative proportion of recurrent cases appears to have increased. These findings, together with the identification of possible risk factors associated with recurrent tuberculosis, highlight various areas where Uzbekistan needs to focus its tuberculosis control efforts, particularly in light of the country’s rapidly emerging multi drug resistant tuberculosis epidemic.
Abstract
SETTING:
Even among persons who have completed a course of treatment for their first tuberculosis (TB) episode, patients with a history of TB are at higher risk for having TB.
OBJECTIVE:
To describe factors from the initial TB episode associated with recurrent TB among patients who completed treatment and remained free of TB for at least 12 months.
DESIGN:
During 1993-2006, US TB cases stratified by birth origin were examined. Cox proportional hazards regression was used to assess the association of factors during the initial episode with recurrence at least 12 months after treatment completion.
RESULTS:
Among 632 US-born patients, TB recurrence was associated with age 25-44 years (adjusted hazard ratio [aHR] 1.77, 99% confidence interval [CI] 1.02-3.09, attributable fraction [AF] 1-34%), substance use (aHR 1.57, 99%CI 1.23-2.02, AF 8-22%), and treatment supervised by health departments (aHR 1.42, 99%CI 1.03-1.97, AF 2-28%). Among 211 foreign-born patients, recurrence was associated with human immunodeficiency virus infection (aHR 2.24, 99%CI 1.27-3.98, AF 2-9%) and smear-positive TB (aHR 1.56, 99%CI 1.06-2.30, AF 3-33%).
CONCLUSION:
Factors associated with recurrence differed by origin of birth, and might be useful for anticipating greater risk for recurrent TB among certain patients with a history of TB.
During the last decade, remarkable progress has been made in the diagnostics of pulmonary tuberculosis; however, diagnostic challenges
in extra-pulmonary tuberculosis (EPTB) remain to be addressed. Diagnosis of EPTB is difficult due to the pauci-bacillary nature of disease,
the variable clinical presentation, and need for invasive procedures to secure appropriate sample, and lack of laboratory facilities in the
resource-limited settings. A more accurate test to diagnose various forms of EPTB, which can easily be incorporated in the routine TB
control programme, would contribute significantly towards improving EPTB case-detection and thus reducing the morbidity and mortality.
In this overview, we describe the status of current conventional and newer methods available for laboratory diagnosis of EPTB and discuss
the challenges in their implementation in the resource-limited settings, and suggestion for better EPTB diagnostic algorithms, which can be
incorporated in the routine TB control programmes.
Recurrence of tuberculosis (TB) can be the consequence of relapse or exogenous reinfection. The study aimed to assess the factors associated with exogenous TB reinfection.
Prospective cohort study based on the TB database, maintained at the Division of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy). Time period: 1995-2010. Inclusion criteria: (1) ≥2 episodes of culture-confirmed TB; (2) cure of the first episode of TB; (3) availability of one Mycobacterium tuberculosis isolate for each episode. Genotyping of the M. tuberculosis strains to differentiate relapse and exogenous reinfection. Logistic regression analysis was used to assess the influence of risk factors on exogenous reinfections.
Of the 4682 patients with TB, 83 were included. Of these, exogenous reinfection was diagnosed in 19 (23 %). It was independently associated with absence of multidrug resistance at the first episode [0, 10 (0.01-0.95), p = 0.045] and with prolonged interval between the first TB episode and its recurrence [7.38 (1.92-28.32) p = 0.004]. However, TB relapses occurred until 4 years after the first episode. The risk associated with being foreign born, extrapulmonary site of TB, and HIV infection was not statistically significant. In the relapse and re-infection cohort, one-third of the patients showed a worsened drug resistance profile during the recurrent TB episode.
Exogenous TB reinfections have been documented in low endemic areas, such as Italy. A causal association with HIV infection could not be confirmed. Relapses and exogenous reinfections shared an augmented risk of multidrug resistance development, frequently requiring the use of second-line anti-TB regimens.
Background. Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain.
Methods. In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008.
Results. Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004).
Conclusions. While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection.
Background:
There is increasing evidence from tuberculosis high-burden settings that exogenous reinfection contributes considerably to recurrent disease. However, large longitudinal studies of endogenous reactivation (relapse) and reinfection tuberculosis are lacking. We hypothesize a relationship between relapse vs reinfection and the time between treatment completion and recurrent disease.
Methods:
Population-based retrospective cohort study on all smear-positive tuberculosis cases successfully treated between 1996 and 2008 in a suburban setting in Cape Town, South Africa. Inverse gaussian distributions were fitted to observed annual rates of relapse and reinfection, distinguished by DNA fingerprinting of Mycobacterium tuberculosis strains recultured from diagnostic samples.
Results:
Paired DNA fingerprint data were available for 130 (64%) of 203 recurrent smear-positive tuberculosis cases in the 13-year study period. Reinfection accounted for 66 (51%) of 130 recurrent cases overall, 9 (20%) of 44 recurrent cases within the first year, and 57 (66%) of 86 thereafter (P < .001). The relapse rate peaked at 3.93% (95% confidence interval [CI], 2.35%-5.96%) per annum 0.35 (95% CI, .15-.45) years after treatment completion. The reinfection tuberculosis rate peaked at 1.58% (95% CI, .94%-2.46%) per annum 1.20 (95% CI, .55-1.70) years after completion.
Conclusions:
To our knowledge, this is the first study of sufficient size and duration using DNA fingerprinting to investigate tuberculosis relapse and reinfection over a lengthy period. Relapse occurred early after treatment completion, whereas reinfection dominated after 1 year and accounted for at least half of recurrent disease. This temporal relationship may explain the high variability in reinfection observed across smaller studies. We speculate that follow-up time in antituberculosis drug trials should take reinfection into account.
Tuberculosis (TB) recurrence can be due to reinfection or relapse. The contribution of each to TB incidence and the factors associated with recurrence are not well known. Effectiveness of TB control programs is assessed in part by recurrence rates. The aim of this study was to establish the recurrence rate of TB in Barcelona, the associated risk factors and the role of reinfection.
A population-based retrospective longitudinal study was performed in Barcelona, Spain. TB patients with positive culture results who completed treatment between Jan 1(st), 2003 and Dec 31(st), 2006 were followed-up until December 31st, 2009 by the TB Control Program. The incidence rate of recurrence was calculated per person-year of follow-up (py). Kaplan-Meier and Cox regression methods were used for the survival analysis by calculating the hazard ratio (HR) with 95% confidence intervals (CI).
Of the 1,823 TB cases identified, 971 fulfilled the inclusion criteria and 13 (1.3%) had recurrent TB. The recurrence rate was 341 cases per 100,000 py, 13 times higher than the TB incidence of the general population. Likelihood of TB recurrence at the 1st, 3rd and 5th year of follow-up was 0.1%, 1.4% and 1.6%, respectively. Factors associated with recurrence were HIV infection (HR: 4.7, CI: 1.4-15.7), living in the inner city district (HR: 3.9, CI: 1.3-11.8) and history of TB treatment (HR: 5.2, CI: 1.7-16.2). Genotyping results of recurrent cases were available for 6 patients (3 reinfections and 3 relapses).
The rate of TB recurrence in Barcelona is low and most episodes occur within the first three years. Patients at higher risk of recurrence are co-infected with HIV, living in neighborhoods with high TB incidence or with a history of TB treatment. When available, genotyping results help determine whether the recurrence is due to reinfection or relapse.
Patients with tuberculosis require retreatment if they fail or default from initial treatment or if they relapse following initial treatment success. Outcomes among patients receiving a standard World Health Organization Category II retreatment regimen are suboptimal, resulting in increased risk of morbidity, drug resistance, and transmission.. In this study, we evaluated the risk factors for initial treatment failure, default, or early relapse leading to the need for tuberculosis retreatment in Morocco. We also assessed retreatment outcomes and drug susceptibility testing use for retreatment patients in urban centers in Morocco, where tuberculosis incidence is stubbornly high.
Patients with smear- or culture-positive pulmonary tuberculosis presenting for retreatment were identified using clinic registries in nine urban public clinics in Morocco. Demographic and outcomes data were collected from clinical charts and reference laboratories. To identify factors that had put these individuals at risk for failure, default, or early relapse in the first place, initial treatment records were also abstracted (if retreatment began within two years of initial treatment), and patient characteristics were compared with controls who successfully completed initial treatment without early relapse.
291 patients presenting for retreatment were included; 93% received a standard Category II regimen. Retreatment was successful in 74% of relapse patients, 48% of failure patients, and 41% of default patients. 25% of retreatment patients defaulted, higher than previous estimates. Retreatment failure was most common among patients who had failed initial treatment (24%), and default from retreatment was most frequent among patients with initial treatment default (57%). Drug susceptibility testing was performed in only 10% of retreatment patients. Independent risk factors for failure, default, or early relapse after initial treatment included male gender (aOR = 2.29, 95% CI 1.10-4.77), positive sputum smear after 3 months of treatment (OR 7.14, 95% CI 4.04-13.2), and hospitalization (OR 2.09, 95% CI 1.01-4.34). Higher weight at treatment initiation was protective. Male sex, substance use, missed doses, and hospitalization appeared to be risk factors for default, but subgroup analyses were limited by small numbers.
Outcomes of retreatment with a Category II regimen are suboptimal and vary by subgroup. Default among patients receiving tuberculosis retreatment is unacceptably high in urban areas in Morocco, and patients who fail initial tuberculosis treatment are at especially high risk of retreatment failure. Strategies to address risk factors for initial treatment default and to identify patients at risk for failure (including expanded use of drug susceptibility testing) are important given suboptimal retreatment outcomes in these groups.
Information on recurrent tuberculosis can provide an indication of the effectiveness of tuberculosis services and identify patients who are most vulnerable. The objective of this study was to estimate the incidence of, and investigate risk factors for, recurrent episodes of tuberculosis in England and Wales.
Episodes of recurrent tuberculosis were identified among prospectively collected records of tuberculosis cases reported to the Health Protection Agency between 1998 and 2005. An episode of recurrent tuberculosis was defined as a re-notified case in the same patient after at least 12 months from the date of the initial notification. To estimate incidence, follow-up time was calculated for all cases until re-notification or censure. Multivariable Cox proportionate hazard models were used to determine hazard ratios (HR) for recurrence of tuberculosis and investigate the risk associated with clinical, demographic and microbiological factors.
Five hundred and eighty-eight recurrent tuberculosis events were identified among 53 214 cases reported between 1998 and 2005, a rate of 4.1 (95% CI 3.8 to 4.5) episodes per 1000 person years of follow-up. Factors independently associated with a greater risk of recurrent tuberculosis were HIV co-infection (HR 1.64, 95% CI 1.13 to 2.38) and belonging to a South Asian ethnic group (HR 1.54, 95% CI 1.23 to 1.93).
Tuberculosis recurrence is uncommon in England and Wales despite the absence of a universal directly observed treatment policy. The identification of HIV co-infection as a risk factor for recurrent tuberculosis is consistent with findings elsewhere. The higher risk among South Asians, however, requires further investigation.
Denmark, a country with a low-incidence of tuberculosis (TB).
To analyse the proportion of relapse vs. re-infection and to compare selected characteristics between the two subgroups.
A population-based cohort study. All 4154 Mycobacterium tuberculosis isolates from patients in Denmark genotyped by insertion sequence 6110 restriction fragment length polymorphism were followed for recurrent TB over 13.5 years. Recurrent cases were classified as relapse or re-infection by genotype patterns in initial and serial disease episodes.
Recurrent TB was found in 73 (1.8%) cases. Identical M. tuberculosis genotypes in initial and serial episodes were found in 54 (1.3%), indicating relapse, whereas different genotypes, representing re-infection, were found in 19 (0.5%) cases. Cavitary TB in the initial episode was significantly associated with relapse (OR 4.6, 95%CI 1.1-26.9) compared to re-infection.
The rate of recurrent TB is low in Denmark. Comparing selected characteristics between the relapse and re-infection subgroups revealed that only the presence of cavitary disease was associated with relapse. Although recurrent TB was rarely due to re-infection, the risk of re-infection increased with time.
Recurrence of active tuberculosis following treatment of an initial disease episode can occur due to endogenous re-activation or exogenous re-infection. Cases of recurrent tuberculosis in the Australian state of New South Wales between 1994 and 2006 were identified by data linkage analysis with confirmatory review of case notes. Patients with more than one culture-positive disease episode during that time period who had completed treatment for the initial disease episode were included. Genotyping of Mycobacterium tuberculosis was used to determine whether recurrence was likely to be due to re-activation or re-infection. There were 5,723 tuberculosis notifications between 1994 and 2006, 3,731 of which were culture-positive. Fifteen (0.4%) patients had recurrent culture-positive disease over a mean 5.7 yrs of follow-up (crude annual incidence 71 per 100,000 population). Recurrent tuberculosis was attributable to re-activation (indistinguishable strains) in 11 (73%) cases and to re-infection (different strains) in four (27%). In a low-incidence setting of tuberculosis, a control programme incorporating directly observed therapy for active disease resulted in a very low rate of recurrent tuberculosis over a long period of follow-up. Re-infection is less likely than re-activation, but still contributes significantly to the number of cases with recurrent disease.
Incidence rates of pulmonary tuberculosis among immigrants from high incidence countries remain high for at least a decade after immigration into the Netherlands. Possible explanations are reactivation of old infections and infection transmitted after immigration. Control policies should be determined on the basis of the as-yet unknown main causes of the persistent high incidence.
Molecular epidemiologic studies of tuberculosis (TB) have focused largely on utilizing molecular techniques to address short- and long-term epidemiologic questions, such as in outbreak investigations and in assessing the global dissemination of strains, respectively. This is done primarily by examining the extent of genetic diversity of clinical strains of Mycobacterium tuberculosis. When molecular methods are used in conjunction with classical epidemiology, their utility for TB control has been realized. For instance, molecular epidemiologic studies have added much-needed accuracy and precision in describing transmission dynamics, and they have facilitated investigation of previously unresolved issues, such as estimates of recent-versus-reactive disease and the extent of exogenous reinfection. In addition, there is mounting evidence to suggest that specific strains of M. tuberculosis belonging to discrete phylogenetic clusters (lineages) may differ in virulence, pathogenesis, and epidemiologic characteristics, all of which may significantly impact TB control and vaccine development strategies. Here, we review the current methods, concepts, and applications of molecular approaches used to better understand the epidemiology of TB.
The proportion of recurrent tuberculosis (TB) cases caused by re-infection has varied widely in previous studies. The aim of the present study was to determine the relative frequency of relapse and exogenous re-infection in patients with second episodes of TB, using DNA fingerprinting. A population-based retrospective longitudinal descriptive study was conducted in Madrid (Spain) during 1992-2004. The study consisted of 645 patients with culture-confirmed TB. Of these, 20 (3.1%) were retained because they presented with a second isolate of Mycobacterium tuberculosis. Finally, 12 of these cases were excluded because they did not complete the full treatment prescribed. All strains were typed by restriction fragment length polymorphism analysis and some by mycobacterial interspersed repetitive unit-variable number of tandem repeats analysis. The patients with recurrent TB were compared with those without recurrent TB. For seven out of the eight patients, the restriction fragment length polymorphism patterns of the Mycobacterium tuberculosis strains from the episodes of recurrent disease showed identical initial and final genotypes, indicating relapse; the remaining recurrent case showed different genotypes, suggesting exogenous re-infection. Re-infection is possible among people in developed countries, but the rates are lower than those occurring in high-risk areas. The risk factors for recurrent tuberculosis should be taken into account in the follow-up of treatment and tuberculosis control strategies.
Background:
Gender has a significant impact on tuberculosis (TB) diagnosis and outcomes in many settings worldwide. We explored gender differences in Victoria, Australia, a low-incidence setting.
Methods:
Retrospective cohort study: 2002-2015. Gender was included as an independent variable in multivariate statistical analyses assessing TB management.
Results:
There were 2655 (54.5%) males and 2212 (45.5%) females notified (male:female ratio = 1.2:1). Among cases with pulmonary involvement, males underwent a chest X-ray or CT scan (CXR) sooner (hazard ratio [HR] 1.2, 95%CI 1.04-1.31, P = 0.010), began treatment sooner after presentation (HR 1.2, 95%CI 1.08-1.34, P = 0.001) and were more likely to have a sputum smear sample performed (OR 1.3, 95%CI 1.01-1.55, P = 0.037). Male cases with extra-pulmonary TB sought health care sooner after symptom onset (HR 1.3, 95%CI 1.03-1.58, P = 0.024) and were more likely to have an abnormal CXR (OR 1.9, 95%CI 1.54-2.32, P < 0.001). Males were more likely to die before or during treatment (OR 1.5, 95%CI 1.06-2.11, P = 0.024).
Conclusions:
Women experienced small delays in management compared with men, with no obvious detriment to assessment results or treatment outcomes. Differences were consistent with the hypothesis that males manifest more severe disease at presentation, which could be related to a range of biological and social factors.
Setting:
Victoria, Australia, is an industrialised setting with low tuberculosis (TB) incidence and universal health care. Individually tailored adherence support for self-administered daily anti-tuberculosis treatment is provided. Directly observed treatment (DOT) is very rarely used.
Objective:
To review the rate of recurrent TB in Victoria between 2002 and 2014.
Design:
This was a retrospective cohort study. All recurrent episodes of TB were reviewed and 24-locus MIRU-VNTR (mycobacterial interspersed repetitive units-variable number of tandem repeats) molecular typing was used where possible to determine the likelihood of relapse or reinfection.
Results:
Of 4766 notifications, 32 (0.7%) were recurrent episodes. Of 20 episodes that occurred in patients who had previously completed treatment, 11 were culture-positive (0.4% of 3012 culture-positive episodes): 9 were likely relapses (distinguishable at no more than one of 24 loci) and two were likely reinfections, giving a TB relapse rate among culture-positive episodes of 52.5/100 000 person-years (mean time to study end per patient of 5.7 years). The median time until relapse was 18 months (interquartile range 12-30).
Conclusions:
The low rate of relapse in our setting demonstrates that individually tailored adherence support for self-administered anti-tuberculosis treatment can achieve excellent treatment outcomes.
Tuberculosis (TB) disease can be characterized by genotypic and phenotypic complexity in Mycobacterium tuberculosis bacilli within a single patient. This microbiological heterogeneity has become an area of intense study due its perceived importance in drug tolerance, drug resistance and as a surrogate measure of transmission rates. This review presents a descriptive analysis of research describing the prevalence of mixed strain TB infections in geographically distinct locations. Despite significant variation in disease burden and a rampant HIV-TB co-epidemic, there was no difference in the prevalence range of mixed infections reported in African countries when compared to the rest of the world. The occurrence of recurrent TB was associated with a higher prevalence of mixed strain infections, but this difference was not reported as statistically significant. These interpretations were limited by differences in the design and overall size of the studies assessed. Factors such as sputum quality, culture media, number of repeated culture steps, molecular typing methods and HIV-infection status can affect the detection of mixed strain infection. It is recommended that future clinical studies should focus on settings with varying TB burdens, with a common sample processing protocol to gain further insight into these phenomena and develop novel transmission blocking strategies.
The etiology of recurrent tuberculosis is typically presumed to be reactivation of residual Mycobacterium tuberculosis infection, but reinfection may account for a greater proportion of recurrent tuberculosis than previously recognized.
To use M. tuberculosis genotyping to characterize the etiology of recurrent tuberculosis ≥12 months after treatment completion.
The study population for this national population-based cohort was drawn from the estimated 3,039 persons reported to the National Tuberculosis Surveillance System with 2 episodes of tuberculosis in the United States during 1993-2011; 194 had genotyping results from both the initial and subsequent episode. We analyzed the proportion of recurrent tuberculosis attributable to and the risk factors associated with reinfection.
Among 136 recurrences meeting inclusion criteria, genotypes between episodes were the same for 116 (85%) recurrences during 1996-2011; the 20 (15%) with differing genotypes were categorized as reinfection. Using exact logistic regression, factors associated with reinfection included Mexican birth with both TB episodes diagnosed in the United States within 12 years of immigration (adjusted odds ratio, 10.7; 95% confidence interval, 1.7-86.3) and exclusive use of directly observed therapy for treatment of the first episode (adjusted odds ratio, 4.5; 95% confidence interval, 1.0-29.2).
Reinfection was the cause for 15% of late recurrent tuberculosis cases in this US cohort. The proportion caused by reinfection increased to 60% in certain subpopulations, such as recent immigrants from Mexico, suggesting that despite successful treatment for TB during their first episode, they remain in a social environment where they are reexposed to M. tuberculosis. Public health interventions to prevent novel reinfection might require a broader focus on these communities.
The frequency and determinants of exogenous reinfection and of endogenous reactivation of tuberculosis in patients previously treated are poorly understood. In Gran Canaria Island, Spain, between 1991 and 1996, 962 tuberculosis cases were confirmed by culture. Drug susceptibility testing was performed on available bacterial isolates and IS6110-based RFLP genotyping was carried out. Twenty-three patients (2.4%) had two positive cultures separated by at least 12 mo, 18 of whom had bacterial DNA available for genotypic analysis. The initial and final isolates from eight (44%) were different genotypes, indicating exogenous reinfection. Six of them were retreated after cure and two retreated after default. Six were HIV seronegative and two were HIV seropositive. Endogenous reactivation was seen in the remaining 10 patients of whom eight were retreated after default and two after cure. Three of the eight (38%) being retreated after default developed multidrug resistance. One genotype was responsible for a second episode of tuberculosis in five cases, three exogenous reinfections and two endogenous reactivations. In the context of a moderate incidence of tuberculosis, exogenous reinfection is an important cause of TB recurrence, even in HIV-seronegative patients.
To determine the proportion of recurrent tuberculosis (TB) due to relapse with the patient's initial strain or reinfection with a new strain of Mycobacterium tuberculosis 1-2 years after anti-tuberculosis treatment in Uganda, a sub-Saharan TB-endemic country.
Records of patients with culture-confirmed TB who completed treatment at an urban Ugandan clinic were reviewed. Restriction fragment length polymorphism (RFLP) patterns were used to determine relapse or reinfection. Associations between human immunodeficiency virus (HIV) positivity and type of TB recurrence were determined.
Of 1701 patients cured of their initial TB episode with a median follow-up of 1.24 years, 171 (10%) had TB recurrence (8.4 per 100 person-years). Rate and risk factors for recurrence were similar to other studies from sub-Saharan Africa. Insertion sequence (IS) 6110-based RFLP of paired isolates from 98 recurrences identified 80 relapses and 18 reinfections. Relapses among HIV-positive and -negative patients were respectively 79% and 85% of recurrences.
Relapse was more common and presented earlier than reinfection in both HIV-positive and -negative TB patients 1-2 years after completing treatment. These findings impact both the choice of retreatment drug regimen, as relapsing patients are at higher risk for acquired drug resistance, and clinical trials of new TB regimens with relapse as clinical endpoint.
The proportion of recurrent tuberculosis cases attributable to relapse or reinfection and the risk factors associated with these different mechanisms are poorly understood. We followed up a cohort of 326 South African mineworkers, who had successfully completed treatment for pulmonary tuberculosis in 1995, to determine the rate and mechanisms of recurrence.
Patients were examined 3 and 6 months after cure, and then were monitored by the routine tuberculosis surveillance system until December, 1998. IS6110 DNA fingerprints from initial and subsequent episodes of tuberculosis were compared to determine whether recurrence was due to relapse or reinfection All patients gave consent for HIV-1 testing.
During follow-up (median 25.1 months, IQR 13.2-33.4), 65 patients (20%) had a recurrent episode of tuberculosis, a recurrence rate of 10.3 episodes per 100 person-years at risk (PYAR)-16.0 per 100 pyar in HIV-1-positive patients and 6.4 per 100 pyar in HIV-1-negative patients. Paired DNA fingerprints were available in 39 of 65 recurrences: 25 pairs were identical (relapse) and 14 were different (reinfection). 93% (13/14) of recurrences within the first 6 months were attributable to relapse compared with 48% (12/25) of later recurrences. HIV-1 infection was a risk factor for recurrence (hazard ratio 2.4, 95% CI 1.5-4.0), due to its strong association with disease caused by reinfection (18.7 2.4-143), but not relapse (0.58; 0.24-1.4). Residual cavitation and increasing years of employment at the mine were risk factors for relapse.
In a setting with a high risk of tuberculous infection, HIV-1 increases the risk of recurrent tuberculosis because of an increased risk of reinfection. Interventions to prevent recurrent disease, such as lifelong chemoprophylaxis in HIV-1-positive tuberculosis patients, should be further assessed.
Surveillance data from the National Tuberculosis Register for the period 1993-1997 complemented with DNA fingerprinting results of Mycobacterium tuberculosis isolates.
To estimate the proportion of disease attributable to recent re-infection among Dutch tuberculosis patients with reported tuberculosis infection or disease before 1981.
Data from 1,547 Dutch patients diagnosed between 1994 and 1997 in the Netherlands were studied. Cases with reported tuberculosis infection or disease before 1981 were attributed to reactivation if their M. tuberculosis isolate was unclustered based on DNA fingerprinting or if they were the first case in a cluster, and to re-infection if they were clustered, but not as the first case.
In total, 183 Dutch tuberculosis patients (12%) had reported tuberculosis infection or disease before 1981. Tuberculosis in 29 of these patients (16%) was attributed to recent re-infection.
In this setting with a low tuberculosis incidence, approximately one in six new disease episodes among patients with previous tuberculosis infection or disease may be attributable to recent re-infection.
National Institute for Public Health and the Environment (RIVM). Code book Netherlands Tuberculosis Register
- J Cacho
- Pérez Meixeira
- A Cano
- I Soria
- Ramos Martos
- Sánchez Concheiro
Cacho J, Pérez Meixeira A, Cano I, Soria T, Ramos Martos A,
Sánchez Concheiro M, et al. Recurrent tuberculosis from 1992
to 2004 in a metropolitan area. Eur Respir J. 2007;30(2):333-7.
https://doi.org/10.1183/09031936.00005107 PMID: 17504801
21. National Institute for Public Health and the Environment
(RIVM). Code book Netherlands Tuberculosis Register.
Bilthoven: RIVM; 2013. [Accessed: 19 Mar 2022].
Gender differences in tuberculosis diagnosis
- K Dale
- E Tay
- J M Trauer
- P Trevan
- J Denholm
Dale K, Tay E, Trauer JM, Trevan P, Denholm J. Gender
differences in tuberculosis diagnosis, treatment and outcomes
in Victoria, Australia, 2002-2015. Int J Tuberc Lung Dis.
2017;21(12):1264-71. https://doi.org/10.5588/ijtld.17.0338
PMID: 29297447