7-year recurrence in TB patients in program setting in China
Tuberculosis recurrence over 7-year follow-up period in successfully
treated patients in a routine programme setting in China: a
prospective longitudinal study
Yan Lin , Haoxiang Lin , Lixin Xiao , Yongming Chen , Xu Meng ,
Xianglin Zeng , Chun Chang , Grania Brigden
Reference: IJID 5593
To appear in: International Journal of Infectious Diseases
Received date: 29 June 2021
Revised date: 23 July 2021
Accepted date: 24 July 2021
Please cite this article as: Yan Lin , Haoxiang Lin , Lixin Xiao , Yongming Chen , Xu Meng ,
Xianglin Zeng , Chun Chang , Grania Brigden , Tuberculosis recurrence over 7-year follow-
up period in successfully treated patients in a routine programme setting in China: a
prospective longitudinal study, International Journal of Infectious Diseases (2021), doi:
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A prospective longitudinal study to evaluate tuberculosis recurrence (TBR)
Incidence of TBR was high in treated patients than incidence in general population
Most recurrences happened within 2-year after completion of anti-TB treatments
Risk of recurrence was high in age 34-73 years and those using tobacco products
Tuberculosis recurrence over 7-year follow-up period in successfully treated patients in a routine programme setting
in China: a prospective longitudinal study
Investigators and Institutions:
1 International Union Against Tuberculosis and Lung Disease, Paris, France
2 Department of Social Medicine and Health Education, School of Public Health, Peking University Health Science Center, Beijing, China
3 Xingguo County Tuberculosis Dispensary, Xingguo, China
4 Ganzhou City Center for Disease Control and Prevention, Ganzhou, China
5 Ningdu County Tuberculosis Dispensary, Ningdu, China
Address for correspondence:
E-mail: firstname.lastname@example.org or email@example.com
Details of Paper
Word Count of Abstract: 200
Word Count of the Full Paper: 3,786
Short title: 7-year recurrence in TB patients in program setting in China
Key words: Tuberculosis; 7-year recurrence; longitudinal study; China
Objectives To determine tuberculosis (TB) recurrence in previously successfully treated patients in routine program setting and baseline
characteristics associated with TB recurrence.
Methods A prospective longitudinal study in Jiangxi Province, China. Patients, ≥14 years old, were consecutively registered and were
followed-up for 7-year to assess TB recurrence against patients’ individual baseline data that was entered into a database at TB registration.
Results There were 800 TB patients registered at baseline and 634 (79.2%) of them completed anti-TB treatments. Fifty nine (9.3%) died and
21 (3.3%) were lost to follow-up over the follow-up period. There were 96 patients with recurrent episodes (total incidence 15.2% or annual
incidence 2,200/100,000). Of the recurrent cases, 53 (55.2%) happened within 2-year after completion of anti-TB treatments. After controlling
confounding factors, risk of TB recurrence was significantly higher in age range 34-73 years (P<0.01) and current smokers (P<0.01).
Conclusions Overall recurrence rate among previously treated TB patients was much higher compared to initial incidence in the same
population (61-98/100,000) and settings with similar TB incidence. TB programs should consider closer monitoring for these patients for early
detection of recurrence. Particular attention should be given to those between 34-73 years and those who use tobacco products.
Although the estimated tuberculosis (TB) mortality rate fell by 42% globally between 2000 and 2019, it is still a major public health problem
worldwide.1 In 2019, there were an estimated 10 million new TB cases and 1.5 million people died from the disease.1 Despite the reported
treatment success rate for new cases reaching over 85% in more than half of the high TB burden countries, for some countries, a significant
proportion of people who completed anti-TB treatment have a recurrence of TB.2, 3, 4 Among the studies conducted in different parts of the world,
various recurrence rates have been reported from 4.9% to 47%, which may reflect heterogeneity of study design, definition of recurrence, nature
of TB disease at baseline, local TB incidence and study populations.5, 6, 7 For example, a study conducted in UK and reported a 1.8% recurrence
rate over 5 years; but a 1.5 years recurrence rate in south India was 12.3%.6, 8 Among different types of study design, reported overall recurrence
rates tended to be generally higher in observational studies than those found under trial conditions.9 Some of the major biological and behaviour
factors independently associated with recurrence included residual cavitation, greater area of involved lung tissue, higher sputum smear grade or
positive sputum culture at 2 months of treatment, HIV infection and smoking.5, 8-10
A study on mechanism of recurrence in Cape Town reported that relapse occurs predominantly in the first year after completion of anti-TB
treatment, whereas reinfection of a new strain predominates over the subsequent years after successful treatment.11 Some studies have suggested
that recurrence rate tend to be generally low in regions with low or moderate TB incidence in the general population and are mainly caused by
relapse of a previously cured episode though some researches emphasized that reinfection may also play a role.5, 7 As such, recurrent TB
constitutes a significant threats to anti-TB treatment, especially the emergence of drug resistance caused by increased number of episodes and re-
treatments which can pose challenges to TB programs and to achieving the END TB goals.12 Therefore, recurrence rates are an important
indicator of the effectiveness of TB programs.
China is a high TB burden country with world largest number of drug resistant TB cases.1 The number of notified TB cases in China in 2019 was
accounting for about 8% of TB burden in the world, but accounting for 14% of world multi-drug resistance TB cases, indicating for a need to
strengthen TB programs to improve quality of anti-TB treatment and reduce risk of recurrence. To help address this issue, it is helpful to
understand if previously successfully treated patients remain long-term free of TB disease, and profile of recurrent cases that need to undergo a
new course of anti-TB treatment. During the past decades, treatment outcomes for new patients and associated factors were well known, but the
underlying causes and consequences of recurrent TB were poorly understood. There were two reports of studies on TB recurrence in China - A
retrospective study in Shanghai using surveillance data reported a recurrence rate of 5.3% over 3 years and another retrospective study in Henan
Province using drug resistance surveillance data found a 29.5% recurrence rate over 9 years.3, 13 However, findings of these studies were limited
and were unable to distinguish previously successfully treated patients from patients with unfavourable treatment outcomes in their initial
treatments in the study population. There is no prospective longitudinal cohort study using individual patient data from the beginning of TB
registration and following up for a long period of time after completion of their anti-TB treatments to assess TB recurrence in China. Such
information is important to assess quality of programs under certain treatment regimens. We therefore conducted a prospective longitudinal
study to determine 1) treatment outcomes for presumed drug sensitive TB (DSTB) in routine program settings; 2) cumulative TB recurrences
and time to event detection over 7 years follow-up period after completion of DSTB treatment; and 3) whether certain baseline characteristics
that were recorded were associated with TB recurrence.
Study design, setting and study population:
This was a prospective longitudinal study with a 7 years follow-up period. Major reason for our study to set 7 years as cut off point was a
combination of learning past research experience, specific design of this research and taking account of local TB incidence in general population.
The study was carried out at 2 public health TB clinics at Xingguo and Ningdu County in Jiangxi Province, which are located in the south-east
part of China with a total population of 1.67 million. Participants of this study were TB patients consecutively registered at the public health TB
clinics from 1st March to 31August 2010 and who successfully completed their DSTB treatments by March 2011. Sample size calculation was
based on cox regression. Our hypothesis was that the recurrence rate is about 8%, a value of 0.80 (Beta = 0.20) was used for power and 0.05 for
alpha. Therefore, the minimum sample size was 266. Taking into account of 10% death and 9% lost to follow up or any other administrative
reasons, we need at least 357 patients.
Eligible patients included were 1) aged≥14 years; 2) regular citizen of these two counties with permanent address and unlikely to transfer out
during their anti-TB treatments; 3) newly registered presumed DSTB patients; 4) agreed to be followed-up. Patient exclusion criteria: 1)
Migrant population; 2) severe mental health disorders that limited collaboration with their healthcare providers.
TB diagnosis and treatment:
The diagnosis of TB was made in line with recommendations from WHO and the China National TB Program (NTP) guidelines.14, 15 At the time
of patient recruitment, drug sensitivity testing and molecular diagnosis was not available in the recruitment clinics. Treatment regimens and anti-
TB drug formulations were administered in accordance with those recommended by WHO and in line with the NTP guidelines for DSTB.
Directly observed therapy (DOT) was implemented throughout the anti-TB treatment by village doctors/other medical staff, family members or
others according to local practice. Patients were advised to visit the same TB clinics on monthly basis to receive necessary examination and to
collect TB drugs for the next month treatment.
Operational definitions used in this study:
TB recurrence: defined as the presence of a new episode of TB disease in a TB patient who was declared cured or treatment completed and
remained TB disease-free for a minimum of 6 months after end of the most recent anti-TB treatment. This includes bacteriologically confirmed
cases and clinically diagnosed cases.
Non-smoker: a person who had never smoked as many as 20 packs of cigarettes in his/her lifetime or one cigarette per day for at least one year.16
Ex-smoker: a person who was previously a smoker, but had completely quit smoking for at least 7 days before the study.
Current smoker: a person who had ever smoked as many as 20 packs of cigarettes over in his/her lifetime or one cigarette per day for at least one
year, and was smoking daily at the time of his/her TB registration.
Following up the registered TB patients:
An Excel data file including the patient’s demographic data, smear status and location of TB (pulmonary TB vs extrapulmonary TB), tobacco
use, home addresses and telephone numbers was established. Records of the registered TB patients were updated along with anti-TB treatment
progress and any further episodes of TB. Only new patients declared as cured or treatment completed were considered eligible to be recruited to
this study. Recurrent TB disease in the registered patients were regularly traced through annual TB notification register for recurrence every year
and visited by township disease control staffs or village doctors at their own communities. In practice, tracing recurrent cases was performed
using the following steps or channels. 1) As public health TB clinics, there is a specific folder established immediately after TB registration for
every patient. For any patient visiting the clinic after initial visit, health worker will use the same folder for reference. A colour sticker was
placed on the folder for patients recruited to this study for the purpose of identifying any recurrent cases. 2) Recruited patients were grouped
into patient lists by their townships and copies of the list were delivered to every health worker at the TB clinics. 3) There is a monthly disease
control meeting attended by all disease control staff across the county and reviewing TB recurrence was on the agenda of the meetings. 4) The
recruited patients were visited by village doctors or township doctors once a year. Those with symptoms suggestive of TB were referred to TB
clinics for further investigation.
Our data analysis was conducted in three steps. First, we employed descriptive statistics to present the overall characteristics of our sample.
Second, we analysed the association between baseline characteristics with TB recurrence using Cox proportional hazards models. Then, we
estimated the cumulative incidence of TB recurrence by Kaplan-Meier curves. A p-value of <0.05 was considered significant. All statistical
analyses were conducted in SPSS 19.0. No imputation was performed for missing data.
Step 1. Descriptive statistics: Continuous variables were reported as means and standard deviations. Categorical variables were presented as
counts and percentages. Comparisons between different groups were performed used chi-squared test.
Step 2. Cox proportional hazards model were used to investigate risk factors associated with recurrent TB. Crude and adjusted hazard ratios (HR)
for the risk of recurrence and their 95% CI were calculated by univariate and multivariate analysis. In adjusted model, we included the variables
of sex, age groups, type of TB, pre-treatment lung cavitation and smoking status.
Step 3. Cumulative incidence of TB recurrence was estimated by Kaplan-Meier curves stratified by their sex, age groups, types of TB, pre-
treatment lung cavitation and smoking status. We calculated the cumulative incidence of TB recurrences at 1-7 years of follow-up. Groups were
compared using the log rank test.
Treatment outcomes at baseline:
There were 800 new TB patients consecutively registered from 1st March to 31August 2010. Of them, 634 (79.2%) were successfully completed
their DSTB treatments including those meeting the criteria of cure and those who completed 6-month anti-TB treatments but did not have a
bacteriological result at the end of treatment period (treatment completion). Of the remaining patients, 21 (2.6%) died, 2 (0.3%) were recorded as
treatment failure, 127 (15.9%) lost to follow up, 16 (2.0%) were not evaluated for any reason.
Characteristics of the included TB patients for tuberculosis recurrence study:
634 (79.2%) who successfully completed their anti-TB treatments and remained TB disease free for at least 6 months following the completion
of their anti-TB treatments were included to the cohort and followed-up for 7 years. Amongst the 634 study participants, 188 were cured and 446
were successfully completed their anti-TB treatments. 443 (69.9%) were male and the mean age was 44.5±16.9 years. Among them, 240 (37.9%)
were smear positive pulmonary TB patients and 90 (14.2%) had pre-treatment cavitation. Per our definition on smoking status, 357 (56.3%) were
non-smokers, 94 (14.8%) were Ex-smokers and 183 (28.9%) were current smokers.
Tuberculosis recurrences over 7-year:
Over a 7 years follow-up period, 59 (9.3%) patients died and 21 (3.3%) were lost to follow up. There were 96 (15.2%) patients with at least one
episode of TB recurrence (Figure 1), translating to an annual incidence of 2.2%. Of the 96 patients with TB recurrence, details of the recurrences
are showed in table 1. There was no significant difference of TB recurrence rate between those with cured results and those with treatment
completion at baseline (P=0.146). More than half of the recurrent cases were diagnosed within 2-year after completion of their anti-TB
treatments and 15.6% were within 1-year. However, there was no significant difference between incidence density of TB recurrences and
patient’s age groups, sex, types of TB, pre-treatment lung cavitation and smoking status at baseline. Of the 21 patients who had 2 or 3 episodes
of recurrence, their baseline characters were: 14 (66.7%) were in the age group of 45-64 years, 18 (85.7%) were male, 13 (61.9%) were smear
positive pulmonary TB, 4 (19.0%) had lung cavity and 12 (57.1%) were current smoker.
Figure 2 shows risk of recurrence episodes over the entire timeframe of the follow up period stratified by genders, age groups, types of TB, pre-
treatment lung cavitation, and baseline smoking status. Baseline characteristics of TB patients with recurrence in relation to their age, nature of
disease, and smoking status are displayed in Table 2 and figure 3. Univariate analysis showed male sex, 34-73 years, Ex-smoker and current
smoker significantly increased the risk of TB recurrence. Controlling confounding with cox proportional hazards multivariate analysis revealed
that factors independently associated with TB recurrence were age 34-73 years (P<0.01) and current smoker (P<0.01).
In this large prospective longitudinal study with a 7 years follow-up period, 96 (15.2%) TB patients were identified as TB recurrence with the
age range of 34-73 years and being a current smoker independently confirmed risk factors for TB recurrence. To our knowledge, this is the first
longitudinal study to assess long-term TB recurrence among previously successfully treated TB patients in a routine program setting in China.
Our study recruited patients consecutively registered in a routine program setting and the patients received standard anti-TB treatment regimen
for 6 months recommended by WHO and NTP. The observed treatment success rate of 79.2%, is lower than international treatment target set by
WHO1 and TB program needs to examine potential reasons for this lower treatment success rate.
During the patient recruitment and follow-up period, the WHO estimated TB incidence in China fell from 98/100,000 in 2010 to 61/100,000 in
2019.1, 17 Results from this study showed that total incidence among previously successfully treated TB patients was 23-36 times higher than
total incidence for general population at the same period based on this indirect estimation. This result indicates that a considerable number of
apparently successfully treated patients did not achieve long-term cure or had a higher likelihood of reinfection. We therefore suggest that
patients who have completed treatment or are cured are still at increased risk for recurrent disease and National TB programs should consider
this group in active case-finding strategies. Although similar trends were also reported from other studies, the risk of recurrence among
successfully treated patients compared with rates of initial episode in general population in our study was much greater than that observed in
other studies.18-21 Previous studies reported that 58.2-69.0% of recurrent TB in China were resulted from relapse of the original M. tuberculosis
strain rather than from reinfection with a new strain.22-23 However, we are not able to comment on this as we did not test those who represented
with TB to establish if it was relapse or reinfection. As relapse usually occurs because of inadequate treatment,5 and may reflect the quality of
program for certain treatment regimens and TB programs need to pay attention to recurrence rates in those people cured or successfully
completing treatment. Some studies have demonstrated that prolonged treatment for certain groups can reduce the rate of relapse. 24-25
Incidence of TB recurrence observed in our study was much higher than that documented from some settings with similar or slightly higher TB
incidence in general population. A study conducted in Yemen reported a 5 years recurrence rate of 9.5% and a similar study in South Africa
reported a 7.1% recurrence for HIV negative patients over 3 years18, 26 compared to the 15.2% seen in this study. Heterogeneity of study design,
including studying risk factors, and the definition of recurrence could be the reasons for the differences seen. Our study subjects included both
smear positive and smear negative cases, and the definition of recurrence included any types of TB among previously successfully treated
patients; whereas in Yemen, the study subjects and recurrence included smear/culture positive cases only. Similarly, the study in South Africa
applied drug susceptibility test and excluded patients who were resistance to any drug. In contrary, our study performed in routine program
setting and was not possible to apply drug susceptibility tests as they were not available in routine program setting during the recruitment and
study period, which may have led to a fairly high rate of recurrence due to potentially drug resistance TB. Additionally, certain treatment
regimens may cause different recurrence rates. A report from Indonesia concluded that the use of fixed-dose combination anti-TB therapy
increases the risk for TB recurrence compared with using separate drug formulation.27
Of the recurrence episodes, over 74% of them occurred within 3 years of completion of anti-TB treatments. Similar trends were also observed in
other studies. 18, 19, 21 These findings suggest that TB patients should be monitored even after completion of their treatments, particularly during
the first 3 years. Although the study sites were not high TB incidence settings, with these rates of recurrence, special attention should be given in
the first year following completion of initial treatment as relapse generally happens earlier than reinfection.11
Our study highlighted certain factors associated with TB recurrence in persons with previously treated DSTB according to their baseline
demographic and clinical characteristics. Among the age groups, being between 34-73 years was a strong risk factor for TB recurrence.
The reasons for the highest risk of recurrence in the 34–73 years age group rather than in the 14–33 years age group could be due to a
combination of many social and physical factors: as 34–73 years olds are of mainly working age, they may have higher pressure from their work,
more challenges to strictly adhere to treatment or have higher likelihood of exposure to new infection.28 On the other hand, advancing age is
associated with diminution of immunity, a higher likelihood of multimorbidity and a higher risk of previous TB, all of which may contribute to
an inadequate treatment and reactivation of the strain later on.26, 29 A study in South Africa indicated that risk of recurrence is greater in
retreatment cases than that in new patients.30 Although being 74 years and over was not statistically confirmed as a risk factor in the multivariate
analysis, the HR value was still higher compared to 14-33 years group. Previous studies shown that TB recurrence might depend on background
demographic characteristics and TB incidence.9 In our cohort, about half were 45 years and over, 14.8% were over 65 years. A recent study in
China concluded that the elderly have a much higher TB incidence than that in the general population.31 However, these were not consistent
observations with reports in Yemen, Brazil, India and South Africa which found no significant association between advancing age and TB
recurrence; possibly due to a lower proportion of older age groups in their recruited patients.14, 32-34
We found current smoking was an independently confirmed risk factor for TB recurrence. This reflects findings from other studies.5-6, 18-19, 35-38
Nicotine inhibits production of tumour necrosis factor alpha by macrophages; and is therefore thought to increase baseline disease severity,
reduce the treatment response and increase the risk of recurrence. A study in Hong Kong concluded that smoking was associated with more
extensive lung disease, lung cavitation, bacteriological result at baseline.36 However, a recent study in Spain showed that smoking was not a
predictive factor for recurrence.39 Exact reasons of these homogeneous results need to be further studied, and could be to the different definitions
of smoking status used. In contrary to our study, the definition used in the Spain study was persons who smoke any number of cigarettes every
day during the past month. By this definition, the reference used in the multivariate analysis was non-smoker plus Ex-smoker.
There were limitations that should be considered when interpreting the present findings. First, the detection of recurrent TB relied on passive
case detection and a limited number of patient visits. We therefore do not know if there was any asymptomatic individuals or those with mild
symptoms who neither accessed health services nor reported to our visitors. This could lead to an underestimation of the true rates of recurrent
TB. However, the data capture was also facilitated by a well-developed health infrastructure with a freely accessible TB service and regular
follow-up of TB patients. A second limitation was that we did not perform a systematic physical examination and did not collect information on
comorbidities, which might have impacted TB recurrence rates. Thirdly, although we collected detailed information such as smoking, lung
cavity and pulmonary status of the TB cases, our results may be subject to confounding by unmeasured variables. For example, we did not
collect information on variables such as alcohol abuse or sputum smear grade. Lastly, we did not perform culture at the end of treatment among
the microbiologically confirmed cases. Therefore, we do not know how many of them did not achieve sterilizing cure despite achieving sputum-
smear conversion. A recent study in Pakistan revealed that viable cultivable bacilli was detected in 6% of cured patients.40
In contrast to other studies that rely on aggregate data, the strengths of this longitudinal study were the large number of TB patients
consecutively enrolled from a routine program setting with the individual patient followed up for a long period of time to observe for
recurrences. There were only 21 (3.3%) lost to follow up during 7 years. We believe that the study findings are representative of a true situation.
However, current programmatic setting may be changed as molecular diagnosis is widely available in China. Further research is needed to
identify risk factors in a holistic approach and better understand contribution of each of these risk factors to the recurrence rates stratified by
relapse or reinfection. Particular attention is required to assess whether combinations of certain risk factors can serve as indicator of risk of
relapse or needing a longer period of treatment in routine practice.
Findings from this study revealed that considerable proportion of previously successfully treated patients in routine program setting in China did
not remain long-term free of TB disease. The recurrence rate of TB in the study sites was higher compared to countries with similar TB
incidence. These findings indicate a need to improve the quality of TB care through strengthening patient-centered care including follow up after
completing treatment as part of an established disease control strategy. More specially, out study highlighted patients between age 34-73 years
and current smoking are at increased risk of recurrence. TB programmes may want to increase monitoring of these patients beyond the end of
their anti-TB treatments and counsel them on their increased risk of recurrence and the role of smoking, a modifiable risk factor, in the risk of
recurrence. Patients should be informed of the need to attend healthcare facilities if their symptoms return. Additionally, these results again
suggested integration of smoking cessation intervention into routine TB service should be urgently scaled up nationwide.41
CONFLICTS OF INTEREST
The authors have No conflicts declared.
We thank all staff in the TB clinics in the two counties in Jiangxi Province for managing TB patients. A special appreciation is extended to the
township disease control staff and village doctors who helped with tracing of the TB patients.
CONFLICTS OF INTEREST
No conflicts declared.
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
All authors bore their own cost for this research.
YL made the research design, performed field monitoring and daft the paper. HXL did validation, managed data, performed analysis and input
on the draft. LX, YC, XZ helped managing patients. XM did field coordination. CC and GB gave input on the conceptualization and final draft.
All authors have read and approved the final paper for submission. YL and HXL contributed equally.
The study was formally approved by ethics committee at the provincial CDC and the Ethics Advisory Group, the International Union Against
Tuberculosis and Lung Disease, Paris, France (EAG number: 7/17).
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Table 1: Classification and details of the 96 tuberculosis recurrence cases
No. (%) of TB patients
No. of recurrence
Time of the
At year 5-7
Table 2: Baseline characteristics of the 634 tuberculosis patients who successfully completed their
anti-tuberculosis treatments in relation to their tuberculosis recurrences in a univariate analysis
No. (%) with TB recurrence
Univariate HR (95% CI)
Type of TB
HR = hazard ratio; CI = confidence intervals; smear+ = smear positive; smear- = smear negative; EPTB = extra-pulmonary tuberculosis;
Figure 1: Flow diagram of patient inclusion, exclusion, follow up and outcomes
Figure 2: Accumulative incidence of TB recurrences stratified by
age groups, sex, types of TB, pre-treatment cavitation and smoking status
Figure 3: Baseline characteristics of the 634 tuberculosis patients who successfully completed their
anti-tuberculosis treatments in relation to their tuberculosis recurrences in a multivariate analysis