The International Journal of Mycobacteriology

: 2018  |  Volume : 7  |  Issue : 1  |  Page : 1--6

Patients at high risk of tuberculosis recurrence

Mehdi Mirsaeidi1, Ruxana T Sadikot2,  
1 Department of Veterans Affair, Miami VA Medical Center; Department of Medicine, Division of Pulmonary and Critical Care, University of Miami, Miami, FL, USA
2 Department of Veterans Affairs, Atlanta VAMC, Decatur; Department of Medicine, Division of Pulmonary and Critical Care, University of Emory, Atlanta, GA, USA

Correspondence Address:
Dr Ruxana T Sadikot
Emory University School of Medicine, Atlanta, GA 30033


Recurrent tuberculosis (TB) continues to be a significant problem and is an important indicator of the effectiveness of TB control. Recurrence can occur by relapse or exogenous reinfection. Recurrence of TB is still a major problem in high-burden countries, where there is lack of resources and no special attention is being given to this issue. The rate of recurrence is highly variable and has been estimated to range from 4.9% to 47%. This variability is related to differences in regional epidemiology of recurrence and differences in the definitions used by the TB control programs. In addition to treatment failure from noncompliance, there are several key host factors that are associated with high rates of recurrence. The widely recognized host factors independent of treatment program that predispose to TB recurrence include gender differences, malnutrition; comorbidities such as diabetes, renal failure, and systemic diseases, especially immunosuppressive states such as human immunodeficiency virus; substance abuse; and environmental exposures such as silicosis. With improved understanding of the human genome, proteome, and metabolome, additional host-specific factors that predispose to recurrence are being identified. Information on temporal and geographical trends of TB cases as well as studies with whole-genome sequencing might provide further information to enable us to fully understand TB recurrence and discriminate between reactivation and new infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care. Continued improvement in diagnosis, treatment approaches, and an understanding of host-specific factors are needed to fully understand the clinical epidemiological and social determinants of TB recurrence.

How to cite this article:
Mirsaeidi M, Sadikot RT. Patients at high risk of tuberculosis recurrence.Int J Mycobacteriol 2018;7:1-6

How to cite this URL:
Mirsaeidi M, Sadikot RT. Patients at high risk of tuberculosis recurrence. Int J Mycobacteriol [serial online] 2018 [cited 2022 May 20 ];7:1-6
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Recurrence of TB can be due to a regrowth of the same strain of Mycobacterium tuberculosis (MTB) that caused the initial TB episode, known as relapse, or reinfection through a different strain. Recurrent TB poses significant threats, especially emergence of drug resistance which can pose challenges to TB control programs. The reported data suggest that recurrence rate is low in countries with a low TB incidence and mainly caused by relapse of a previously cured TB episode. In addition to incomplete treatment of the first TB episode, factors associated with recurrence have included substance use, sputum smear-positive disease, cavitary pulmonary disease, and human immunodeficiency virus (HIV) infection.[1] In a low-incidence settings such as the United States and Western Europe, most recurrence has been attributed to reactivation, or incomplete cure of the initial TB infection, rather than a new TB exposure resulting in reinfection. Poor adherence to anti-TB treatment is a well-known risk factor for recurrence of disease. While there are few published data on recurrence rates, it is considered probable that drug resistance increases with recurrence.[2]

Recurrence after successful treatment for multidrug-resistant TB (MDR-TB) is challenging because of limited treatment options.[3] A number of studies have indicated that recurrence after successful treatment of MDR-TB is not uncommon. Variation in case definition and differences in treatment protocols whether directly observed or self-directed therapy may contribute to low recurrence. However, the host factors that predispose to recurrence and its causes, particularly in the era of epidemic HIV, have not been well established.

 Epidemiology and Social Factors That Predict Recurrence

Among the studies conducted in different parts of the world, variable recurrence rates have been reported from 4.9% to 47%. In general, the risk of recurrence is lower in countries with lower prevalence of TB, mainly from North America, West Europe, Australia, New Zealand, and a few Asian countries such as Japan and Taiwan. The lower recurrence is attributed to social factors, better access to health care and effective TB control programs. Panjabi et al. reviewed 32 studies to determine recurrence of TB. They found that among controlled trials, the overall recurrence rates (per 100,000 person-years) were 3010 (95% confidence interval [CI] 2230-3970) and 2290 (95% CI 1730–2940) at 6 and 12 months after treatment completion, respectively.[4]

A recent study from Australia showed that individually tailored adherence support for self-administered daily anti-TB treatment when provided was effective. Interestingly, directly observed treatment (DOT) was very rarely used. The low rate of relapse in this study was attributed to an individually tailored support to encourage adherence to self-administered anti-TB treatment and showed that using this approach, the outcomes can be excellent.[5]

In a large national study in the United States, Kim et al. found interesting differences in the US-born and foreign-born individuals. In general, social risk factors were associated with recurrent TB among US-born patients, whereas clinical characteristics appeared to play a greater role among foreign-born patients. Among US-born patients, recurrence was associated with ages 25–44 years, substance use, and treatment managed by a health department during the initial TB episode. Among foreign-born patients, initial episode factors associated with recurrence were ages 45–64 years, HIV infection, and smear-positive disease.[6]

In a study carried out by Crofts et al. in England and Wales, the recurrence incidence was reported to be 4.1 in 1000 person-years.[7] The rate of TB recurrence in Barcelona was also low and most episodes occurred within the first 3 years. In this study, patients who were coinfected with HIV and those living in neighborhoods with high TB incidence were at higher risk of recurrence. In cases where genotyping results were available, they were helpful to determine whether the recurrence was due to reinfection or relapse.[8] In a study from Russia, Gelmanova et al. found that individualized regimens that were designed according to the current global standard of care achieved low rates of MDR-TB recurrence among non-HIV-infected persons.[9]

Vieira et al. conducted a study of TB recurrence in Brazil and stratified patients by temporal classification (early or late TB recurrence) to identify possible predictors of recurrence. The found that there were statistically significant differences between the early and late TB recurrence groups. These were related to level of education (≤3 vs. >3 years of schooling; P < 0.004) and weight gain at completion of the initial treatment (1.78 kg vs. 5.31 kg; P < 0.045). A low level of education might translate to poor treatment compliance. This can impede the clearance of bacteria and facilitate their survival in a latent state, making it appear as if the treatment was effective. Their study suggests that minimal or no weight gain after completion of the initial treatment might be a reliable biomarker that may indicate treatment success.[10] In general, countries with less resources in vulnerable regions are more predisposed to recurrence.[11]

There are more robust data available from Asian countries on recurrence. In a study from Vietnam, Vree et al. showed that 21 out of 244 (8.6%) patients experienced a recurrence of the disease in 1–2 years after successful treatment.[12] A study in Southern Ethiopia reported that 15 out of 368 (4.1%) smear-positive TB patients experienced a recurrence of the disease after successful treatment.[13] Shen et al. conducted a retrospective cohort study on all bacteriologically confirmed TB cases who were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of TB cases and a low prevalence of HIV infection. 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, >18 times the rate of TB in the general population. Patients who were male, aged 30–59 years, retreatment cases, had cavitation, diabetes, drug-resistant or MDR TB in their initial episode of TB were at high risk for a recurrence.[14]

Sun et al. conducted a retrospective cohort study in Henan Province, China, to measure the long-term outcomes among patients who had completed treatment under DOT short-course, with a particular focus on recurrence in MDR-TB. In their study cohort, about one-third (29.5%, 69/234) suffered recurrence after completion of treatment. The overall recurrence rate was 35/1000 patient-years (PY), with a much higher rate (65/1000 PY) among MDR-TB patients. They found that TB recurrence was strongly associated with MDR-TB infection and an annual household income that was <10,000 Yuan. The mean time for recurrence among MDR-TB patients was 5.7 years compared to 7.2 years among non-MDR-TB patients.[15] Among the recurrence group members, 61.3% died and 18.8% had failed treatments. These studies suggest that treatment outcomes reported with short follow-up time may overestimate treatment success.[15] It was shown that the recurrence rates in Henan Province were much higher compared to that in the UK (around 23/1000 PY),[4] Malawi (3.1% of all registered TB patients between July 1, 1999, and June 30, 2000),[13] and Vietnam (8.6%, 21/244 TB patients surveyed).[12] However, the recurrence rate was lower than that measured in a study conducted in Uzbekistan (36.0%, 42/118 patients followed up a median of 22 months).[2] The recurrence rate among MDR-TB patients was similar to that reported in Heilongjiang Province (61.0%, 79/129 patients surveyed over a 4-year follow-up and as reported from Malawi).[16],[17]

A study by Chen et al. from Taiwan aimed to determine the rates and predictors of MDR-TB recurrence after successful treatment. Three percent of the patients experienced MDR-TB recurrence during a median follow-up of 4.8 years. The overall recurrence rate was 0.6 cases per 1000 person-months. Cavitation on chest imaging was an independent predictor of recurrence.[18] The low recurrence rate in this study was attributed to the fact that MDR-TB patients were managed in specialized treatment facilities where patients were followed up more aggressively after treatment to ensure adherence. Interestingly, despite low prevalence of HIV in the Taiwanese population, the incidence of recurrent TB among Taiwanese was not less than that of other countries.[19]

Moosazadeh et al. characterized the risk of recurrence in a cohort of 1271 patients in Iran. They found a variable rate of recurrence from 8.3% to 85% in their cohort. The recurrence rate was significantly higher in patients who smoked, whose sputum smears were strongly positive before treatment, and those patients who continued to be smear positive for acid-fast bacilli at the end of the 2nd month of the treatment. They also found that there was a significant correlation with gender, age, or diabetes.[20] Recurrence of MDR TB is an emerging threat although the epidemiologic data are limited. In a retrospective study from India, Munje et al. found a recurrence rate of 47% with 39% treatment failure.[21] Together, these studies highlight the complexities associated with defining the epidemiology of recurrence because of regional variations in social factors and availability of health resources.

 Host Factors Predisposing to Recurrence

There are several host factors that have been identified to predispose to recurrence independent of the treatment program. These factors include gender differences, malnutrition, comorbid conditions such as diabetes, renal and liver failure, and immunosuppressive states such as HIV, substance abuse including tobacco use, and environmental exposure such as silicosis.[22],[23]

Smoking is one of the most important modifiable risk factors, which has been consistently shown to increase the incidence of recurrence in patients with TB. Leung et al. conducted a prospective study in Hong Kong from 2001 to 2003 and followed patients for treatment outcome. Patients were subsequently tracked through TB notification registry for relapse until the end of 2012. They found that smoking was associated with more extensive lung disease, lung cavitation, and positive sputum smear and culture at the baseline. Their data suggest that smoking adversely affects baseline disease severity, bacteriological response, treatment outcome, and relapse in patients with TB.[24] A recent study by Ahmed et al. conducted in Pakistan found an increased recurrence of TB in male patients who were smoking.[25] In a meta-analysis, Underner et al. reviewed 17 studies that investigated smoking and recurrence of TB. The collective data suggest that active smoking increases the risk of relapse of pulmonary and extrapulmonary TB after treatment. In addition, they found that smokers were less likely to adhere to anti-TB treatment.[26] Together, these data strongly suggest that smoking cessation should be encouraged and are likely to reduce relapse and secondary transmission. TB public health program should reinforce the need of smoking cessation as an essential component of treatment.

Individuals with HIV infection have a higher risk of recurrent TB disease.[27],[28],[29] TB remains a major cause of global morbidity and mortality, in the context of HIV coinfection because, despite anti-viral therapy, immunity is not completely restored.[30] A study by Punjabi et al. found that TB recurrence (%) was higher among HIV-infected (6.7, 95% CI 5.9–7.6) than non-HIV-infected individuals (3.3, 95% CI 2.8–3.9). Among those patients with HIV infection, recurrent TB was associated with a low initial CD4 count and those who received <37 weeks of anti-TB treatment.[4] It is important to identify additional factors associated with recurrent TB in the HIV-infected population to aid in the development of efficient risk-reduction interventions. In a systematic review of published literature describing factors associated with TB recurrence in people living with HIV in Africa, Moodley et al. identified several factors that predisposed to recurrence of TB in patients with HIV. Baseline CD4 count and HIV viral load, a positive tuberculin skin test, prior active TB disease, cutaneous hypersensitivity reaction to treatment, extensive TB involving > 3 lung zones, prior TB disease, and anemia were associated with recurrent TB in patients infected with HIV. Interestingly, age and antiretroviral status were not identified as risk factors for recurrence.[29]

In a small study by Thobakgale et al. in patients with HIV, the production of interleukin 1 beta (IL-1β) by innate immune cells following Toll-like receptor (TLR) and Bacillus Calmette–Guérin (BCG) stimulations was shown to correlate with TB recurrence. Those patients who showed an elevated production of IL-1β from monocytes following TLR-2, TLR-4, and TLR-7/8 stimulation showed reduced rates of TB recurrence. In contrast, production of IL-1β from both monocytes and dendritic cells following BCG stimulation was associated with increased odds of TB recurrence (risk of recurrence increased by 30% in monocytes and 42% in dendritic cells). Their study highlights differences in host response to TB.[31]

Mannose-binding lectin (MBL) is an acute-phase serum protein that belongs to the collectin family, a key molecule of the innate immune system that recognizes a pathogen by its carbohydrate recognition domain. The impact of MBL gene polymorphism and the susceptibility to TB have been reported before though the findings are inconsistent between studies. A meta-analysis of 17 clinical studies by Denholm et al. showed no significant correlation between TB and genetic polymorphisms in MBL gene.[32] However, a recent study by Guo et al. that investigated if MBL2 polymorphisms or MBL levels are associated with the development of pulmonary TB in China showed that polymorphisms of MBL gene may be associated with susceptibility to TB and the recurrence of TB. Interestingly, they also found that YA/YA association occurred more commonly in healthy controls and may be a protective single nucleotide polymorphism (SNP) against TB.[33]

Although it is known that diabetes mellitus (DM) increases the risk of TB and adversely affect outcomes following TB treatment, the risk of recurrence has not been well studied. Diabetes is an emerging epidemic in developing countries where the prevalence of TB is high. It is imperative that public health programs emphasize glycemic control for patients with DM, especially during treatment for TB.[34] Use of newer biologics has also been associated with reactivation of TB, in particular tumor-necrosis-factor blockers. A recent report described reinfection of TB in a patient receiving programmed death-1 (PD-1) blocker for Hodgkin's lymphoma.[35] The risk of reactivation of TB with the use of PD-1 inhibitors may be under-reported in the current literature due to limited long-term follow-up data and mainly use in developed countries with low prevalence of latent infection. Incorporation of appropriate TB screening for patients who receive biologics including PD-1 is essential. There is also a concern of increased occurrence of TB in patients on newer therapies such as pirfenidone[36] although the risk of recurrence will need to be studied further.

 Duration of Treatment and Recurrence

Although the most effective treatment regimen for reducing the likelihood of relapse in patients at high risk of relapse has not been determined by clinical trials, recent observational studies have demonstrated that prolonged treatment reduced the rate of relapse.[37] Quin et al. investigated the characteristics of culture-confirmed pulmonary TB patients reported to the California TB Registry during 2004–2009. In this study, patients who had cavities on initial chest imaging and patients who had delayed culture conversion (>70 days) were considered at “high risk of relapse.” Those patients who received anti-TB treatment for > 270 days were considered as “extended treatment.” They found that of the 5680 patients with TB, 483 (8.5%) were at high risk of relapse: 372 (77%) received extended treatment, but 111 (23%) did not. Their data suggest that almost a quarter of the patients did not receive extended treatment which might have predisposed to recurrence.[38]

In a retrospective cohort study of adult patients with MDR-TB, Ahmad et al. found that patients who were on long and aggressive treatment regimen had a lower rate of recurrence. Patients were classified as having received “aggressive regimens” if their intensive phase consisted of five effective drugs used for at least 6 months postculture conversion and their continuation phase included at least four effective drugs.[39] These data suggest that long aggressive regimens for MDR-TB treatment may be associated with lower risk of disease recurrence. The study by Wang et al. found that the risk of recurrence of TB in patients with HIV can be reduced by extending anti-TB treatment duration to 9–12.5 months.[40]

 Bacterial Factors and Recurrence

In the pregenomic era, all posttreatment infections were attributed to relapses. A potential confounder in differentiating relapse from reinfection is the presence of mixed infections. Whole-genome sequencing (WGS) studies have identified multiple coinfecting TB strains. The occurrence of recurrent TB was associated with a higher prevalence of mixed-strain infections, but this difference has not been reported to be significant.[41] Recent studies have used WGS to evaluate paired samples, comparing SNP differences between the original and new infection following treatment; however, the results are variable results.[42],[43],[44],[45] While the capacity to generate WGS data has grown substantially, over the last few years, our understanding of how best to use these data is still not clear.[46],[47]

In a recent study by RIFAQUIN investigators, WGS was evaluated for identifying new infections in treated patients as either relapses or reinfections and compared with mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) typing. These investigators found that both WGS and MIRU-VNTR differentiated relapses and reinfections to the same extent; however, WGS provided significant extra information. This was particularly useful for defining the presence of mixed infections and the potential to identify novel drug-resistance markers.[48] Their study illustrated the merits of WGS which should be preferred. Velayati et al. showed that continual polymerase chain reaction positivity, even when the culture is negative may reflect treatment failure in MDR-TB in otherwise clinically nonsuspicious cases of treatment failure.[49] Huyen et al. showed that in a cohort of Vietnamese population recurrence was significantly associated with MTB Beijing genotype infections.[50]

 Summary and Conclusions

Recurrent TB is caused by an endogenous reactivation of the same strain of MTB (relapse) or exogenous infection with a new strain (reinfection). WGS provides scientifically valuable data and with improved technology will become of greater value. As more genome sequence data become available and information about the genotype–phenotype correlation emerges, their impact on disease and transmission will be better defined. Elucidating factors associated with recurrence may help TB control programs and clinical providers recognize those patients with a history of TB who have a greater risk for recurrence so that they can explore ways of minimizing the risk. For clinical and social reasons, drug users, individuals with mental health issues, those living with the HIV, and marginalized and vulnerable populations may have a higher risk of recurrence related to default from treatment which favors emergence of MDR TB. Currently, there are no immune biomarkers that can predict the risk for TB recurrence; however, in the future, development of such immune markers could help in the design of host-directed therapies and clinical management. A key question facing Phase III trials in both drug-susceptible and MDR TB is the optimum duration of treatment that is required to yield an acceptable risk of recurrence. Researchers, epidemiologists, and public health teams should combine clinical, epidemiological, and WGS data to strengthen investigations of transmission. While rapid diagnosis and treatment remain the mainstay of TB control, being able to recognize those patients who are at the highest risk of recurrence might lead to better integration with associations such as mental health, substance abuse, and optimal management of HIV infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care.[51] Most importantly, information on temporal and geographical trends of TB cases and genotyping will be critical to fully understand TB recurrence and discriminate between reactivation and new infection.

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Conflicts of interest

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