If You Had Tb Once Can You Get It Again

• Research article
• Open Access
• Published: 23 October 2020

Risk factors for recurrent tuberculosis after successful handling in a loftier burden setting: a cohort study

• Douglas Wilson² &
• Ted Cohen³

BMC Infectious Diseases volume 20, Article number:789 (2020) Cite this article

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Abstract

Groundwork

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 mail-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. Nosotros used routinely-nerveless administrative data to identify recurrent episodes of tuberculosis occurring over a median of vi years afterward successful treatment completion.

Results

Of 500 patients initially enrolled, 333 (79%) successfully completed treatment for tuberculosis. During the follow-up menstruation 35 patients with successful handling (eleven%) experienced a bacteriologically confirmed tuberculosis recurrence. In our Cox proportional hazards model, a three+ AFB sputum smear grade was significantly associated with recurrent tuberculosis with a run a risk ratio of 3.33 (95% CI i.44–7.7). The presence of polyclonal Chiliad. tuberculosis infection at baseline had a chance ratio for recurrence of i.96 (95% CI 0.86–iv.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.

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Introduction

Patients who take recently completed handling for tuberculosis (TB) are at elevated take chances of recurrent TB affliction, either equally a result of relapse or reinfection [1, two]. When individuals are diagnosed with recurrent TB, they are less likely to complete treatment and suffer higher bloodshed than those with first episodes of TB [3]. While in that location is a growing appreciation of the risks associated with recurrent TB, a clearer moving-picture show of which covariates place individuals at greater risk of recurrent illness tin can inform more targeted mail-tuberculosis intendance and monitoring.

Several covariates have been found to be associated with recurrence of TB subsequently completion of handling. Drug-resistance [4], smoking [5], HIV infection with depression CD4 lymphocyte counts [half dozen], substance utilise [7], chronic lung disease [eight], sputum smear-positive disease [9], and cavitary pulmonary illness [10] have each been found to exist associated with increased risk of recurrent tuberculosis. These factors may increase hazard of recurrence because they make it more likely for some modest numbers of mycobacteria to persist beyond treatment or because they are associated with allowed incompetence that places individuals at greater risk of illness following reinfection [11].

Over the last few years, molecular genetic tools have provided a new view on the extent of within-host genotypic heterogeneity of Mycobacterium tuberculosis infections. These "mixed-strain" or "heterogeneous" infections arise either through sporadic mutation (clonal heterogeneity) or host conquering of more than one strain of Grand. tuberculosis (polyclonal heterogeneity), either at the fourth dimension of infection or through series re-infection [12]. While detection of mixed-strain infection is limited by the biological samples collected equally well equally the laboratory processes and sensitivity of sequencing, the frequency at which clonal heterogeneity and polyclonal heterogeneity are reported is nearly xx% in some settings [xiii]. While several studies take institute that within-host heterogeneity, especially polyclonal infections, are associated with poorer treatment response [14], the effects on risk of recurrence are less clear [thirteen].

Studies of recurrent TB are challenging to acquit considering the gamble of recurrent TB can remain elevated for up to 10 years [2]. In this analysis, nosotros combined a inquiry database with electronic notification records to study the long term hazard of recurrent tuberculosis amidst a cohort of ambulatory pulmonary TB patients with a high prevalence of HIV co-infection afterwards successful completion of anti-tubercular therapy.

Methods

Setting

The Umgungundlovu health district, in KwaZulu-Natal (KZN), South Africa had a tuberculosis notification rate of 880 cases per 100,000 during the initial study catamenia of 2011. Local HIV prevalence was xvi.9% and approximately lxx% of people with active tuberculosis were co-infected with HIV [xv].

Participants

All adults with newly diagnosed pulmonary tuberculosis and sputum smear-positive for acrid-fast bacilli (AFB) from five principal health care clinics in the Umgungundlovu wellness commune were eligible for the study. Between June 2011 and November 2012 we enrolled 500 participants and collected two spot pre-treatment sputum samples. Immediately afterwards enrollment, participants were initiated on antitubercular therapy according to South African Department of Health guidelines. Further details of written report blueprint are available in a previous publication [xvi].

Laboratory

Pre-treatment sputum samples were cultured and those positive for M. tuberculosis were genotyped with 24-loci mycobacterial interspersed repetitive unit of measurement-variable number tandem echo (MIRU-VNTR) typing at Genoscreen (Institute Pasteur, Lille, France) [17]. Details of the laboratory procedures have been published previously [sixteen]. For samples with multiple repeats at any MIRU-VNTR loci, indicating more than than genotype, the ClassTR algorithm [18] was used to distinguish clonal M. tuberculosis infection from polyclonal 1000. tuberculosis infection.

Follow-up

Later completion of antitubercular therapy, nosotros tracked outcomes by using routinely nerveless electronic handling annals (ETR) [nineteen] data. The Umgungundlovu health district ETR data includes l clinics serving a population of over one,000,000 people, and also encompasses the original v sites from which participants were recruited [20]. Each facility in the district records tuberculosis case data, including final treatment outcome, in a standardized newspaper tuberculosis register. The health district collects local facility tuberculosis registers and enters them into a commune-wide ETR.

Nosotros matched study participants with commune data in ETR past exact matching of identifiers (e.g. proper noun, gender, date of birth, treatment start date). Every bit there is no unique patient identifier in South Africa and there are several opportunities during administrative data collection for transcription errors, we conducted fuzzy matching for study participants not located by exact matching. We allowed for substitutions of numerical variables and used Jaro-Winkler [21] altitude for matching string variables. A study writer (PC) reviewed all potential matches. We recorded the concluding treatment consequence for each participant. For participants who the ETR listed as lost to follow-up or who transferred their care during treatment, further exact and fuzzy searches were made to endeavor to link intendance episodes and establish a final treatment event.

For report participants with documented treatment success (by Earth Wellness Organization defined [22] cure or handling completion) of their initial episode of tuberculosis, a search for secondary episodes of tuberculosis was then made in the electronic register during the period from initial study enrollment though March 30, 2019. For any secondary tuberculosis episodes found in the electronic register, nosotros recorded the time to recurrence from the initial diagnosis as well as the method of tuberculosis diagnosis (empiric, smear microscopy, Gene Xpert MTB/Rif, or civilisation), and treating dispensary.

Nosotros constructed Cox proportional hazards models with an outcome of recurrent tuberculosis. Participants were censored on the date the ETR search was made. For a multivariable model, nosotros included covariates for inside-host M. tuberculosis heterogeneity (uncomplicated, clonal, and polyclonal) as this was the focus of the written report besides every bit HIV status, given its potent clan with recurrent tuberculosis, and a gaussian frailty random furnishings term for the health center to adjust for clustering. In addition, covariates with a p-value of < 0.20 (age, instruction, marital status, and AFB sputum smear grade) in univariable models were included.

Statistical analysis

R statistical software was used to perform statistical analyses [23]. Cox proportional adventure models were constructed using the packages survival [24] version 2.42–six, survminer [25] version 0.4.3, and prodlim [26] version 2018.04.18 to assess whether any factors were associated with recurrent tuberculosis afterward treatment completion for the initial episode. Proportionality was assessed with correlations between Schoenfeld residuals and log (time) for each covariate and the global model. Multicollinearity was assessed using variance inflation factor.

Results

During the study enrollment and follow-upward period, 110,859 cases of tuberculosis were recorded in the Umgungundlovu Health District ETR. Of the 500 patients initially enrolled, nosotros matched 478 (96%) within the ETR (Fig. 1). 135 (28%) had a handling outcome of "not evaluated" due to clinic transfer or loss to follow-upward. Further searches allowed discovery of the treating clinic of 89 of these 135 (66%) to make up one's mind a final handling effect. 421 (88%) of the matched participants had a positive baseline mycobacterial culture with successful MIRU-VNTR genotyping.

Fig. 1

Participant flow diagram

Total size epitome

333 (79%) of the original written report participants with a MIRU-VNTR genotype were recorded as achieving treatment completion or cure for their initial tuberculosis episode (Table 1). Those with a successful treatment outcome were less likely to exist living with HIV (65.8 vs 79%) and less likely to have sputum negative for AFB (40.8% vs 56.3%) (Supplemental Tabular array 1). In this cohort, median age was 35 years, and 57% were men. 228 (69%) were HIV positive and 77 (23%) had bear witness of heterogeneous K. tuberculosis infection by MIRU-VNTR genotyping. When utilizing the ClassTR algorithm to interpret MIRU-VNTR results, 30 (9%) had clonally heterogeneous M. tuberculosis illness, and 47 (fourteen%) had polyclonal heterogeneous K. tuberculosis disease. 59 (18%) had a history of tuberculosis prior to enrollment. 7 (2%) had multidrug-resistant TB (MDR-TB).

Table one Baseline characteristics

Full size table

The time from initial tuberculosis diagnosis to searching in the District ETR was a median of 2125 days (interquartile range 2032 to 2271 days). Fourty-v participants (14%) were diagnosed with recurrent tuberculosis, of which 35 participants (eleven%) had bacteriologically proven tuberculosis, by either sputum smear, Cistron Xpert, or culture, later on a median of 504 days. Kaplan-Meier curves for bacteriologically proven recurrent tuberculosis later treatment for either simple, clonal or polyclonal M. tuberculosis tuberculosis infection were not statistically significantly different by log-rank test (Fig. 2).

Fig. 2

Kaplan Meier estimates for freedom from recurrent tuberculosis after completion or cure

Total size image

In univariable analysis with Cox proportional hazards models, younger age was significantly associated with increased chance of bacteriologically proven tuberculosis recurrence with a hazard ratio of 0.94 (95% confidence interval (CI) 0.91–0.98) for every additional year of age (Table ii). In our multivariable model, a 3+ AFB sputum smear grade was significantly associated with recurrent tuberculosis with a hazard ratio of 3.33 (95% CI ane.44–seven.vii, p = 0.005) (Fig. 3). The presence of clonally heterogeneous M. tuberculosis infection at baseline had a gamble ratio for recurrence of 0.92 (95% CI 0.27–3.ane), while polyclonal heterogeneous M. tuberculosis infection at baseline had a hazard ratio for recurrence of 1.96 (95% CI 0.86–4.5). None of those with recurrent tuberculosis had MDR-TB at baseline, which fabricated inclusion of MDR-TB in our models impossible.

Table 2 Unadjusted and adjusted hazard ratios for recurrent tuberculosis

Full size table

Fig. three

Adjusted hazard ratios for recurrent TB

Full size image

Discussion

Subsequently following a cohort of largely HIV-coinfected ambulatory individuals successfully treated for pulmonary tuberculosis disease in a high burden setting for a median of vi years, we found that 11% (95% CI 7.2 to 13.8%) had bacteriologically proven recurrent tuberculosis and an additional 3% (95% CI 1.2 to 4.8%) had empirically-diagnosed recurrent tuberculosis. This is consistent with other studies performed in high burden settings [2, 27].

Our finding of an clan between higher sputum AFB smear grade during the initial tuberculosis episode and recurrent episodes of tuberculosis may be due higher mycobacterial load disease and cavitary disease, leading to a higher hazard of relapse later treatment completion. The association between smear form and poor handling outcomes, including recurrent affliction, has been seen in other studies [28].

In this long-term follow-up, the point estimate for the odds of recurrence for individuals with polyclonal Chiliad. tuberculosis infection was 1.96, merely the 95% confidence interval did not exclude i. The relatively pocket-size number of outcomes recorded limits our power to make conclusive statements about whether such polyclonal infections make it more likely for patients to experience relapse after successful handling. An association of recurrent tuberculosis and heterogeneous M. tuberculosis infection is plausible equally heterogeneous infection leads to the potential for heteroresistance. Additionally, Shin and colleagues recently found an association between heterogeneous M. tuberculosis infection and treatment failure in Botswana that was independent of heteroresistance [14]. A high mycobacterial burden inside a host or repeated exposures to tuberculosis in a high TB prevalence environment could be other mechanisms for an association of heterogeneous K. tuberculosis infection and poor treatment outcomes or recurrence.

HIV co-infection was non associated with the risk of recurrence in univariable or multivariable analysis. This could reverberate rise rates of antiretroviral therapy in our setting, and that Due south African guidelines at the time of our initial study recommended placing patients living with HIV and tuberculosis co-infection on antiretrovirals. Antiretrovirals reduce the gamble of developing agile tuberculosis, only how that gamble compares to the HIV uninfected population is not currently known [6, 29, 30]. Alternatively, participants living with HIV could have suffered higher mortality rates in subsequent years that may accept biased our results given nosotros did not have access to vital statistics.

There were limitations in linking our study dataset with ETR data to identify recurrent tuberculosis episodes as there is currently no national health identifier in South Africa. Fuzzy matching of patient identifiers identified many instances of likely matches that were initially missed due to misspellings and transpositions, just we do not know if other matches were missed due to larger discrepancies and whether this introduced bias into our findings. If take chances factors of recurrence are too associated with death, lack of access to vital statistics may have biased results by not properly censoring participants who died during the follow-up period.

This limitation leads to our finding of 11% recurrence as a lower bound on the burden of recurrent tuberculosis. Additionally, even though the ETR encompasses a health district that serves over 1,000,000 people, the population of KZN is highly mobile [31] and the ETR database does not capture recurrences outside of the wellness district. 135 (28%) of the participants in this study transferred clinics or were lost to follow-up during their initial TB handling and we were able to locate 66% of them at their last treating clinic within the wellness commune. Information technology is conceivable that migration out of the health district may have introduced some bias into our study.

Another limitation is that our sampling was at one timepoint from i anatomical source (sputum). Our group's work with mail service-mortem studies in the same population as represented in this report has constitute meaning proportions of multi-organ disseminated tuberculosis with strain heterogeneity that was not captured when sampling sputum alone [32]. Genotyping with MIRU-VNTR as well has limited sensitivity for determining M. tuberculosis strain multifariousness and may have underestimated the true proportion of heterogeneous infection [12]. We also were unable to genotype M. tuberculosis strains from recurrent episodes to distinguish reinfection from relapse. In other studies with matched fingerprinting of initial and recurrent tuberculosis episodes, reinfection accounted for at least half of recurrent disease, reflecting the hyperendemic communities to which people living with tuberculosis return to after treatment completion. We suspect similarly loftier rates of reinfection occurred in our population too, merely we practice not have genotypes from recurrent tuberculosis episodes to test this hypothesis.

Conclusions

Our results indicate that AFB smear grade is independently associated with tuberculosis recurrence after successful treatment for an initial episode while the association betwixt polyclonal 1000. tuberculosis infection and increased take a chance of recurrence appears possible, but further studies are needed to meliorate establish this relationship.

Availability of data and materials

The data sets compiled and analyzed for the current study are available from the corresponding author on reasonable request.

Abbreviations

AFB:

Acrid-fast bacilli

CI:

Confidence interval

ETR:

Electronic treatment register

KZN:

KwaZulu-Natal

MDR-TB:

Multidrug-resistant tuberculosis

MIRU-VNTR:

Mycobacterial interspersed repetitive unit-variable number tandem echo

TB:

Tuberculosis

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Acknowledgements

We wish to thank the KwaZulu-Natal Department of Health and its TB Director, Ms. Jacqueline Ngozo for their help with this study. Nosotros also wish to thank the nursing staff and management at the Umgungundlovu District primary healthcare clinics.

Funding

This work was supported by the Fogarty International Center [grant number 1K01TW011194-01A1 to P.Chiliad.T.C] at the National Institutes of Health and a fellowship from the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Postdoctoral Fellowship in Tropical Infectious Diseases to P.G.T.C. The funders had no role in study blueprint, data collection and analysis, determination to publish, or training of the manuscript.

Author information

Affiliations

1. Section of Communicable diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

   Patrick George Tobias Cudahy

2. Section of Internal Medicine, Edendale Hospital, University of KwaZulu-Natal, 5th Flooring, Individual Handbag X 509, Plessislaer, KZN, Pietermaritzburg, 3216, South Africa

   Patrick George Tobias Cudahy & Douglas Wilson

3. Section of Epidemiology (Microbial Diseases), Yale University School of Public Health, New Haven, CT, United states

   Ted Cohen

Contributions

PGTC, TC and DW conceived of and deigned this written report. PGTC conducted the information analysis. All authors contributed to manuscript grooming and approval of the terminal version.

Corresponding authors

Correspondence to Patrick George Tobias Cudahy or Douglas Wilson.

Ethics declarations

Ideals approval and consent to participate

The Biomedical Research Ethics Committee at the University of KwaZulu-Natal and the KwaZulu-Natal Section of Health, also as the Partners Human Research Committee (Boston, Massachusetts), approved the protocol for the original written report. The University of KwaZulu-Natal'due south Biomedical Inquiry Ethics Committee, the KwaZulu-Natal Department of Wellness, and the Yale University Human Investigations Commission approved the additional use of ETR data for this analysis. Written informed consent was obtained from all participants.

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Not applicative.

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The authors declare that they have no competing interests.

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Cudahy, P.Thousand.T., Wilson, D. & Cohen, T. Risk factors for recurrent tuberculosis after successful treatment in a loftier burden setting: a accomplice study. BMC Infect Dis 20, 789 (2020). https://doi.org/10.1186/s12879-020-05515-4

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• Received: thirteen May 2020

• Accepted: 15 October 2020

• Published: 23 October 2020

• DOI : https://doi.org/ten.1186/s12879-020-05515-iv

Keywords

• Mixed-infection
• South Africa
• Relapse
• Reinfection
• Fuzzy match

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