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Recurrent tuberculosis disease in Singapore
Suay Hong Gan
TB Control Unit
Tan Tock Seng Hospital
Singapore
Kyi Win KhinMar
National Centre for Infectious Diseases
Singapore
Li Wei Ang
National Centre for Infectious Diseases
Singapore
Leo K Y Lim
National Centre for Infectious Diseases
Singapore
Li Hwei Sng
Dept of Pathology
Singapore General Hospital
Yee Tang Wang
TB Control Unit
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Tan Tock Seng Hospital
Singapore
Cynthia B E Chee (corresponding author)
TB Control Unit
144 Moulmein Road
Singapore 308089
Email: Cynthia_Chee@ncid.sg
Summary : Relapse and re-infection contributed to 57% and 43% respectively of recurrent
TB in Singapore, a densely populated intermediate TB incidence country. Positive sputum
smear and concomitant pulmonary and extrapulmonary TB disease were significantly
associated with risk of relapse.
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Abstract
Background: Previously treated ie. recurrent tuberculosis (TB) cases account for ~7-8% of
incident TB globally and in Singapore. Molecular fingerprinting has enabled the
differentiation of these patients into relapsed or re-infection cases.
Methods: Patient demographics, disease characteristics and treatment information were
obtained from the national TB notification registry and TB Control Unit. We performed a
retrospective, case-control study to evaluate factors associated with recurrent TB disease in
Singapore citizens and Permanent Residents with culture-positive TB from 2006 to 2013 and
who developed a second episode of culture-positive TB up to 2016 using multivariable
logistic regression analyses.
Results: 91 cases with culture-positive first and recurrent TB disease episodes were
identified. Recurrent TB was associated with age ≥60 years (adjusted odds ratio [aOR] 1.98,
95% confidence interval [CI] 1.09-3.61), male gender (aOR 2.29, 95% CI 1.22–4.51), having
concomitant pulmonary and extrapulmonary TB (aOR 3.10, 95% CI 1.59–6.10) and
extrapulmonary TB alone (aOR 3.82, 95% CI 1.12-13.31); and was less likely in non-Malays
(aOR 0.52, 95% CI 0.27–0.99). DNA fingerprinting results for both episodes in 49 cases
differentiated these into 28 relapsed and 21 re-infection cases. Relapse was associated with
having concomitant pulmonary and extrapulmonary TB (aOR 9.24, 95% CI 2.50–42.42), and
positive sputum acid fast bacilli smear (aOR 3.95, 95% CI 1.36–13.10).
Conclusion: Relapse and re-infection contributed to 57% and 43% respectively of recurrent
TB in Singapore. Our study highlights the under-appreciated association of concomitant
pulmonary and extrapulmonary TB as a significant risk factor for disease relapse.
Key words: tuberculosis, relapse, exogeneous re-infection, extrapulmonary
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Introduction
Persons with previously treated tuberculosis (TB) account for ~7% of incident TB cases
globally (1). Recurrence of TB disease after clinical cure / treatment completion of a previous
episode may be due to endogenous re-activation of residual tuberculous bacilli from the
original episode (referred to as relapse), or exogeneous re-infection. Over the past two
decades, molecular genotyping techniques has enabled the study of the diversity of
Mycobacterium tuberculosis strains and has demonstrated that exogeneous re-infection
plays a more important role in causing recurrent disease than previously thought (2). It is
likely that re-infection drives the TB epidemic in areas with high TB and HIV prevalence.
Nonetheless, there does not appear to be a consistent correlation in the literature between
the predominant cause of recurrent TB (ie. relapse vs re-infection) and geographical TB
prevalence (3-8).
Singapore is a densely populated island city-state with an intermediate TB incidence of 35-
40 cases per 100,000 population and a very low HIV /AIDS notification rate of 7.9 per
100,000 population in 2018 (9). There are ~3,000 notified TB cases in the country annually,
of whom ~50% are Singapore citizens or Permanent Residents (PRs). Among these,
persons with a history of previously treated TB account for ~8% of notified TB episodes (9).
We undertook a retrospective case-control study to investigate the characteristics of
Singapore citizens and PRs with recurrent culture-positive TB (“recurrent TB”). The
availability of DNA fingerprinting results provided the opportunity to examine factors
associated with recurrent disease due to relapse or exogeneous re-infection.
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Methods
TB disease is notifiable by law in Singapore. The national TB notification registry is also
electronically linked to the two mycobacterial culture laboratories in Singapore, enabling
complete capture of all positive Mycobacterium tuberculosis complex (MTC) culture results.
Singapore citizens and PRs aged 16 and above with first episode culture-positive TB notified
between 1 January 2006 and 31 December 2013 and who developed a second episode of
culture-positive TB in the period up to 31 December 2016 were identified from the national
TB notification registry. For this study, “recurrent TB” was defined as a second episode of
culture-positive TB disease occurring in persons who had completed treatment of a first
episode of culture-positive TB.
Data analyzed in this study pertained to the first disease episode and included age, sex,
ethnic group, and presence of diabetes mellitus (DM) and human immunodeficiency virus
(HIV) co-infection, sputum acid fast bacilli (AFB) smear status, site(s) of disease (pulmonary
TB [PTB] with or without concomitant extra-pulmonary disease), presence of cavitation on
baseline chest x-ray (CXR), treatment regimen, mode of treatment delivery (whether directly
observed therapy [DOT] or self-administered therapy [SAT]], AFB culture results at two
months of treatment, and whether the duration of short-course TB therapy was extended
beyond the conventional six months. This information was obtained from clinical case
records for patients who were treated at the TB Control Unit (70% of patients in this study)
during the first episode of TB; otherwise, the information was extracted from the TB registry
for patients treated in other institutions.
For the case-control study, cases were defined as patients with recurrent TB. Controls were
culture-positive patients who were not notified with recurrent TB within the period of the
study. Two controls were randomly selected for each study case, matched by date of
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notification (+/- five days). For subgroup analyses, cases with available 24-loci mycobacterial
interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) and spacer
oligonucleotide (spoligotyping) results for both TB episodes were classified into those with
identical / near-identical DNA fingerprinting results („relapse cases”) or different results (“re-
infection cases”) for both episodes.
Statistical analysis
The Chi-square test or Fisher‟s exact test, where appropriate, was used to compare baseline
characteristics between individuals with and without recurrent TB. No imputation was carried
out for missing data. We inserted an “unknown” category for variables with missing data. The
main outcome was whether an individual had recurrent TB. Crude and adjusted odds ratio
were calculated using Firth‟s logistic regression analyses. Variables for the multivariable
logistic regression model were selected through stepwise use of Akaike‟s information
criterion. All p values reported were 2-sided and statistical significance was taken as p <
0.05. Statistical analyses were performed using SPSS version 24 (IB, USA) and R version
3.6.2 (R Foundation for Statistical Computing, Vienna, Austria).
Ethics approval
Ethics approval was obtained from the National Healthcare Group Domain Specific
Review Board (Study reference number 2015/01122). Personal identifiers were
removed prior to data analysis.
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Results
There were 7,478 culture-positive TB cases episodes notified between 1 January 2006 and
31 December 2013. Of these, 91 (1.2%) cases had two or more culture-positive TB episodes
as at 31 December 2016 (figure 1).
The median time to disease recurrence was 24 months (1.5-110 months).
Among the 91 cases with recurrent TB, the median age was 53.02 years, 74 (81.3%) were
male, 23 (25.3%) were of Malay ethnicity, 32 (35.2%) had diabetes mellitus, seven (7.7%)
had HIV co-infection at the time of their first disease episode. Eighty-five (93.4%) had PTB in
their first TB episode; among these, 24(26.4`%) had concomitant extra-pulmonary site
disease. Six (6.6%) had extra-pulmonary disease only (2 pleura, 3 lymphatic, 1
gastrointestinal). Forty-one (45.1%) patients had cavitary disease, and 60 (65.9%) were
sputum AFB smear positive. Fifty-five (60.4%) were treated under DOT. At two months (end
of intensive phase) of treatment, 52 (57%) cases were sputum culture negative, four (4.4%)
were sputum culture positive while 35 (38.5%) had unknown sputum culture status. Eleven
(12.1%) had extension of their continuation phase of treatment.
Recurrent TB was significantly associated with age ≥60 years (adjusted odds ratio [aOR]
1.98, 95% confidence interval [CI] 1.09-3.61), male gender (aOR 2.29, 95% CI 1.22–4.51),
having concomitant pulmonary and extrapulmonary TB (aOR 3.10, 95% CI 1.59–6.10) and
extrapulmonary TB alone (aOR 3.82, 95% CI 1.12-13.31); and was less likely to occur in
persons of non-Malay ethnicity (aOR 0.52, 95% CI 0.27–0.99) (table 1).
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Subgroup analysis according to relapse or re-infection
MIRU-VNTR and spoligotyping results were available for both TB disease episodes in 49
(53.8 %) of the 91 cases with recurrent TB. There was no significant difference in age,
gender, ethnicity, presence of DM or HIV, sputum AFB smear, presence of cavity, disease
site (PTB with or without concomitant extra-pulmonary disease), sputum AFB culture status
at two months of treatment, treatment delivery mode and duration of treatment between the
cases with and without available DNA fingerprinting results for both TB episodes
(supplementary Table 1). Of the 49 cases with available genotyping, 24 had identical results
and four had results which differed by one or two loci for the first and recurrent disease
episodes - these 28 cases were classified as “relapse cases”. Twenty-one cases with
different MIRU-VNTR results for the first and recurrent episodes were classified as “re-
infection” cases (figure 1).
There was no significant difference in age, gender, ethnicity, and proportion infected with the
Beijing strain between the relapse and re-infection groups. The median time to disease
recurrence was significantly shorter in those who relapsed (22 months, range 2-68)
compared with those who were re-infected (49 months, range 4-110) p=0.003) (table 2).
Relapse cases
Relapse cases were more likely to have PTB and concomitant extra-pulmonary disease
(aOR 9.24, 95% CI 2.50–42.42), and to be sputum AFB smear positive (aOR 3.59, 95% CI
1.36–13.10) (table 3). Relapse was not associated with age, gender, ethnicity, DM, HIV co-
infection, having extrapulmonary TB alone, cavitation on baseline CXR, sputum AFB culture
status at two months of treatment, mode of treatment delivery and duration of TB treatment.
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Re-infection cases
There was no statistically significant difference between re-infection cases and controls in
terms of age, gender, ethnicity, presence of DM or HIV, concomitant PTB and
extrapulmonary disease, extrapulmonary disease alone, bacteriological burden (smear and
cavitary status), sputum AFB culture status at two months of treatment, mode of treatment
delivery and duration of TB treatment (table 4).
Cases with PTB and concomitant extrapulmonary TB disease in the first episode
There were 24 cases of recurrent TB disease who had PTB and concomitant
extrapulmonary TB disease in their first disease episode. A variety of extrapulmonary sites
were involved, the most common being the pleura (n=14), followed by lymph node (n=4),
skeletal (n=3), gastrointestinal (n=2), larynx (n=2), genitourinary (n=2) and central nervous
system (CNS) (n=1). Four patients had two sites of extrapulmonary disease (table 5). All but
one of the 24 cases was sputum culture-positive in their first disease episode. Of these, all
but one had pan-sensitive MTC grown in their sputum. Those with CNS or skeletal TB
received treatment of appropriate duration. The majority (67%) had recurrent disease
confined to the lungs. Fifteen cases had available DNA fingerprinting results for both
episodes; of these, 10 were relapse cases (three were HIV co-infected, one of whom
relapsed with rifampicin resistant disease); five were re-infection cases (one was HIV co-
infected, who had isoniazid resistance in the first disease episode and was re-infected with a
pan-sensitive strain).
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Acquisition of drug resistance
None of the 91 recurrent TB patients had multidrug-resistant TB (i.e. strains resistant to at
least rifampicin and isoniazid) in their first or recurrent disease episodes. Six cases had new
drug-resistant recurrent episodes, of whom four had available MIRU and spoligotyping
results for both disease episodes (figure 1). All six cases had pan-sensitive TB in their first
episode: two HIV co-infected patients relapsed with rifampicin mono-resistant TB, one
patient relapsed with isoniazid-resistant TB, one patient was re-infected with an isoniazid-
resistant strain, while the remaining two patients with isoniazid mono-resistant recurrent TB
disease (one of whom was HIV co-infected) did not have available DNA fingerprinting results
for both episodes. Three cases had streptomycin mono-resistant TB for both first and
recurrent episodes – two were relapse cases, while the third case had no available DNA
fingerprinting result.
All three patients who relapsed with acquired drug resistance did not receive DOT and were
not treated under the national TB programme for their first TB episode.
Discussion
Our case-control analysis showed age ≥ 60 years, male gender, Malay ethnicity, PTB with
concomitant extrapulmonary TB and extrapulmonary TB alone in the first disease episode to
be significantly associated with recurrent TB disease. This information is useful to raise
awareness as to the local epidemiological risk groups for TB disease recurrence (whether
due to relapse or re-infection). Consistent with the TB literature, recurrent disease due to
relapse occurred significantly earlier than that from exogeneous re-infection. The odds of
disease relapse were significantly higher in persons with PTB and concomitant extra-
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pulmonary disease, and with sputum AFB smear positivity in the first episode. Our study did
not identify any factors associated with exogeneous re-infection.
A key objective of TB treatment is to eradicate populations of persisting bacilli to achieve
durable cure (ie. to prevent relapse). The risk of relapse arises when there is suboptimal
bacteriologic response to treatment of the first episode – this may be due to high
bacteriological burden, or treatment factors such as inappropriate regimens, poor adherence
or drug pharmacokinetic / pharmacodynamic factors affecting therapeutic drug levels in
individual patients. Indicators of disease burden such as cavitation/extensive disease on
chest radiograph, and slower response to treatment as indicated by lack of sputum culture
conversion at two months of treatment, presence of cavity on end-of-treatment chest
radiograph, and lack of weight gain during the intensive phase of treatment have been well
shown to be associated with risk of relapse (10-15). Our finding that baseline sputum AFB
smear positivity was significantly associated with relapse is not unexpected as this is an
indicator of high initial disease burden. The association of concomitant extrapulmonary and
PTB with risk of relapse was reported by a study in Hongkong (Chang et al) in 2004 (16).
Their study however did not have the benefit of genotyping to distinguish between true
relapse and exogeneous re-infection cases. The predominant extrapulmonary site in their
patients was the lymph node (mainly cervical), followed by the pleura. Interestingly, all 12 of
their patients with co-existing lymph node TB relapsed with lymph node disease (two with
concomitant PTB in their relapse episode). Only nine out of their 22 cases with concomitant
extrapulmonary and PTB had positive sputum cultures. Our finding of a significant
association of concomitant extrapulmonary TB and PTB with relapse highlights this
previously underappreciated risk group for relapse. Of note, the extrapulmonary disease
sites in our patients was wide-ranging. As persons with multi-site TB disease presumably
have higher bacterial burden, this association is biologically plausible. Interestingly, unlike
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the experience of Chang et al, the majority (70%) of our patients relapsed with pulmonary TB
only.
Current international guidelines recommend extending the continuation phase of the
standard six-month short-course therapy by three months (ie. a total of nine months of
treatment) in persons with cavitation on their baseline CXR who have positive cultures at two
months of treatment (17). Other factors to consider in the decision to prolong treatment in
patients with either baseline CXR cavitation or positive culture at two months (but not both)
are: being > 10% below ideal body weight, being an active smoker, having diabetes mellitus,
HIV co-infection or any other immunosuppressing condition, or having extensive disease on
chest radiograph (17). Pertaining to extrapulmonary disease, these guidelines recommend
extension of treatment duration only for CNS and skeletal TB. That our study found no
association of relapse risk with cavitation on baseline CXR or sputum AFB culture at two
months of treatment may have been influenced by the practice in TB Control Unit of routinely
extending the treatment continuation phase for persons with these factors. Our finding that
persons with concomitant PTB and extrapulmonary disease involving a variety of
extrapulmonary sites are at risk of relapse may suggest the need for extending treatment in
these patients, regardless of the site of extrapulmonary disease.
DNA fingerprinting has shed light on the relative contribution of relapse (57%) versus re-
infection (43%) to the burden of recurrent TB in Singapore. The risk of exogeneous re-
infection is influenced by the prevalence and transmission of TB in the community and host
immunological factors. That exogeneous re-infection accounted for almost half of the
recurrent TB cases may not be surprising as Singapore is a densely populated, intermediate
TB incidence (albeit low HIV-incidence) country. The rate of relapsed culture-positive TB in
Singapore was reassuringly low during the study period. We believe that this is testimony to
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the effectiveness of the Singapore TB Elimination Programme (STEP) which has, since
1998, utilized in-person DOT (daily during the intensive phase and thrice weekly in the
continuation phase) at the patients” nearest public health care clinic for the majority of the
country‟s TB cases (18,19). The STEP‟s Treatment Surveillance Module which actively
tracks all TB cases in Singapore until their final outcome, has also served to ensure high
treatment completion rates nationally (20).
It is noteworthy that all three patients who relapsed with acquired drug-resistant disease
were not treated under the national TB programme and did not receive DOT during their first
TB episode. Two were HIV co-infected at the time of their first TB episode. This observation
is consistent with the established fact that HIV co-infected TB patients are at high risk for
acquisition of drug (particularly rifampicin) resistance and underscores the vital role of DOT
in these persons to achieve best treatment outcomes (21). Also noteworthy was that,
contrary to WHO 2017 recommendations, the use of intermittent dosing (ie. thrice weekly
DOT) in the treatment continuation phase by our national TB Programme did not diminish its
effectiveness as evidenced by our low relapse rate (22). This attests to the quality of in-
person DOT administered by our Programme through the years.
A strength of our study was the complete capture of all MTC culture positive cases in
Singapore. A study limitation was the lack of MIRU-VNTR and spoligotyping results for both
disease episodes in 46% of the cohort, resulting in a small sample size for analysis.
However, we believe that these cases were representative of the cohort as there was no
difference in characteristics between those with and without available DNA fingerprinting
results for both disease episodes. The unavailability of whole genome sequencing (WGS) to
more definitively exclude re-infection for our cases with same DNA fingerprints for both
disease episodes was another study limitation. Although MIRU-VNTR and spoligotyping
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have been used successfully in Northern European countries to distinguish re-infection and
relapse (23,24), it has been shown that these methods lack discriminatory power for strains
of non-Euro-American lineage (25,26). The Beijing family strain and the East-African-Indian
(EAI) strain account for 47% and 24% respectively of the strains in the country (27). Another
study limitation was the lack of data on pharmacodynamic factors such as therapeutic
rifampicin levels and N-acetyltransferase type 2 (NAT2) status (which are not performed in
routine clinical practice) of our study population which could potentially influence treatment
outcomes (28,29). Socio-economic and lifestyle factors, which may be important
determinants of risk for exogenous re-infection, were also not captured and analyzed in this
study.
In conclusion, our study provides insights into recurrent TB disease in Singapore and its
associated risk factors. We believe our finding of a significant association of concomitant
PTB and extra-pulmonary TB with relapse has identified a risk group for whom measures to
mitigate this outcome may be considered.
Conflicts of Interest
The authors do not have any association which might pose a conflict of interest.
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Figure legend
Figure 1
There were 7,478 culture-positive TB cases notified from 1 January 2006 to 31 December
2013. Of these, 91 had two or more culture-positive TB episodes as at 31 December 2016.
MIRU-VNTR and spoligotyping results were available for both TB disease episodes in 49
(53.8%) of the 91 cases. Twenty-four cases had identical results and four had results which
differed by one or two loci (relapse cases). Twenty-one cases had different DNA fingerprint
results for the first and recurrent episodes (re-infection cases).
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we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?
Antimicrob Agents Chemother 2005; 49(5):1733-1738
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Table 1
Odds ratios of candidate predictors for recurrent tuberculosis
Cases
Controls
Univariable model
Multivariable model^
(N=91)
n (%)
(N=182)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
Age group
<60 years
61 (67.0)
145 (79.7)
1.00 (reference)
1.00 (reference)
≥60 years
30 (33.0)
37 (20.3)
1.92 (1.09–3.38)
0.024
1.98 (1.09–3.61)
0.026
Gender
Female
17 (18.7)
61 (33.5)
1.00 (reference)
1.00 (reference)
Male
74 (81.3)
121 (66.5)
2.15 (1.20–4.03)
0.010
2.29 (1.22–4.51)
0.009
Ethnic group
Malay
23 (25.3)
33 (18.1)
1.00 (reference)
1.00 (reference)
Non-Malay
68 (74.7)
149 (81.9)
0.65 (0.36–1.20)
0.167
0.52 (0.27–0.99)
0.047
Diabetes
No
59 (64.8)
131 (72.0)
1.00 (reference)
Yes
32 (35.2)
51 (28.0)
1.39 (0.81–2.38)
0.225
HIV infection
No
84 (92.3)
171 (94.0)
1.00 (reference)
1
Yes
7 (7.7)
11 (6.0)
1.32 (0.49–3.40)
0.569
TB site
PTB
61 (67.0)
154 (84.6)
1.00 (reference)
1.00 (reference)
PTB with
extrapulmonary TB
24 (26.4)
22 (12.1)
2.74 (1.44–5.24)
0.002
3.10 (1.59–6.10)
0.001
Extrapulmonary TB
6 (6.6)
6 (3.3)
2.51 (0.79–7.95)
0.011
3.82 (1.12–13.31)
0.033
Cavitation present in
baseline CXR
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Cases
Controls
Univariable model
Multivariable model^
(N=91)
n (%)
(N=182)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
No
50 (54.9)
120 (65.9)
1.00 (reference)
1.00 (reference)
Yes
41 (45.1)
62 (34.1)
1.58 (0.95–2.65)
0.078
1.63 (0.94–2.84)
0.081
Sputum AFB smear
Negative
31 (34.1)
82 (45.1)
1.00 (reference)
Positive
60 (65.9)
98 (53.8)
1.61 (0.96–2.73)
0.07
Not done
0 (0.0)
2 (1.1)
0.52 (0.004–6.67)
0.66
Sputum culture
conversion at 2 months
of treatment
No
4 (4.4)
7 (3.8)
1.00 (reference)
Yes
52 (57.1)
120 (65.9)
0.73 (0.22–2.66)
0.610
Unknown
35 (38.5)
55 (30.2)
1.07 (0.31–4.01)
0.919
Treatment delivery
mode
SAT
36 (39.6)
64 (35.2)
1.00 (reference)
DOT
55 (60.4)
118 (64.8)
0.83 (0.49–1.39)
0.473
Extension of
continuation phase of
treatment
No
71 (78.0)
140 (76.9)
1.00 (reference)
Yes
11 (12.1)
26 (14.3)
0.85 (0.39–1.77)
0.674
Unknown
9 (9.9)
16 (8.8)
1.13 (0.47–2.60)
0.776
^ Adjusted for age group, gender, ethnic group, TB site and whether cavitation was present in baseline CXR.
AFB, acid fast bacilli; aOR: adjusted odds ratio; CI: confidence interval; CXR, chest x-ray; DOT, directly observed therapy; OR: odds ratio; PTB, pulmonary
tuberculosis; SAT, self-administered therapy; TB, tuberculosis
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Table 2
Comparison between characteristics of relapse and re-infection cases
Variable
Relapse cases
(N=28)
Re-infection cases
(N=21)
p-value^
Age group, n (%)
<60 years
≥60 years
20 (71.4%)
8 (28.6%)
15 (71.4%)
6 (28.6%)
1.000
Gender, n (%)
Female
Male
7 (25%)
21 (75%)
5 (23.8%)
16 (76.2%)
1.000
Ethnic group, n (%)
Malay
Non-Malay
11(39.3%)
17 (60.7%)
5 (23.8%)
16 (76.2%)
0.359
Median time to disease recurrence
(months)
22.0
49.00
0.003
Infecting strain, n (%)
Beijing
Non-Beijing
18 (64.3%)
10 (35.7%)
13 (61.9%)
8 (38.1%)
1.000
^ P values comparing relapse and reinfection cases are from Fisher‟s exact test for categorical variables and Mann-Whitney U test for the continuous variable.
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Table 3
Odds ratios of candidate predictors for relapsed cases
Cases
Controls
Univariable model
Multivariable model^
(N=28)
n (%)
(N=56)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
Age group
<60 years
20 (71.4)
45 (80.4)
1.00 (reference)
≥60 years
8 (28.6)
11 (19.6)
1.64 (0.57–4.59)
0.349
Gender
Female
7 (25.0)
16 (28.6)
1.00 (reference)
Male
21 (75.0)
40 (71.4)
1.17 (0.43–3.34)
0.762
Ethnic group
Malay
11 (39.3)
14 (25.0)
1.00 (reference)
1.00 (reference)
Non-Malay
17 (60.7)
42 (75.0)
0.52 (0.20–1.36)
0.179
0.38 (0.12–1.18)
0.094
Diabetes
No
22 (78.6)
40 (71.4)
1.00 (reference)
1.00 (reference)
Yes
6 (21.4)
16 (28.6)
0.71 (0.24–1.95)
0.513
0.34 (0.09–1.16)
0.086
HIV infection
No
25 (89.3)
52 (92.9)
1.00 (reference)
Yes
3 (10.7)
4 (7.1)
1.60 (0.34–7.09)
0.536
TB site
PTB
16 (57.1)
49 (87.5)
1.00 (reference)
1.00 (reference)
PTB with
extrapulmonary TB
10 (35.7)
5 (8.9)
5.73 (1.83–19.79)
0.003
9.24 (2.50–42.42)
0.001
Extrapulmonary TB
2 (7.1)
2 (3.6)
3.00 (0.43–20.92)
0.250
3.93 (0.50–32.76)
0.183
Cavitation present in
baseline CXR
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Cases
Controls
Univariable model
Multivariable model^
(N=28)
n (%)
(N=56)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
No
15 (53.6)
41 (73.2)
1.00 (reference)
Yes
13 (46.4)
15 (26.8)
2.33 (0.92–6.01)
0.075
Sputum AFB smear
Negative
9 (32.1)
31 (55.4)
1.00 (reference)
1.00 (reference)
Positive
19 (67.9)
24 (42.9)
2.64 (1.05–6.97)
0.038
3.95 (1.36–13.10)
0.011
Not done
0 (0.0)
1 (1.8)
1.11 (0.01–22.57)
0.953
0.90 (0.01–21.61)
0.953
Sputum culture
conversion at 2 months of
treatment
No
2 (7.1)
1 (1.8)
1.00 (reference)
Yes
16 (57.1)
37 (66.1)
0.26 (0.02–2.14)
0.206
Unknown
10 (35.7)
18 (32.1)
0.34 (0.03–2.91)
0.319
Treatment delivery mode
SAT
11 (39.3)
20 (35.7)
1.00 (reference)
DOT
17 (60.7)
36 (64.3)
0.85 (0.34–2.17)
0.738
Extension of continuation
phase of treatment
No
23 (82.1)
42 (75.0)
1.00 (reference)
Yes
2 (7.1)
6 (10.7)
0.70 (0.12–2.99)
0.638
Unknown
3 (10.7)
8 (14.3)
0.74 (0.17–2.69)
0.663
^ Adjusted for ethnic group, diabetes, TB site and smear result.
AFB, acid fast bacilli; aOR: adjusted odds ratio; CI: confidence interval; CXR, chest x-ray; DOT, directly observed therapy; OR: odds ratio; PTB, pulmonary
tuberculosis; SAT, self-administered therapy; TB, tuberculosis
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Table 4
Odds ratios of candidate predictors for re-infection cases
Cases
Controls
Univariable model
Multivariable model^
(N=21)
n (%)
(N=42)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
Age group
<60 years
15 (71.4)
35 (83.3)
1.00 (reference)
≥60 years
6 (28.6)
7 (16.7)
1.98 (0.58–6.72)
0.269
Gender
Female
5 (23.8)
19 (45.2)
1.00 (reference)
1.00 (reference)
Male
16 (76.2)
23 (54.8)
2.49 (0.83–8.34)
0.105
2.48 (0.82–8.39)
0.109
Ethnic group
Malay
5 (23.8)
7 (16.7)
1.00 (reference)
Non-Malay
16 (76.2)
35 (83.3)
0.63 (0.18–2.30)
0.477
Diabetes
No
11 (52.4)
30 (71.4)
1.00 (reference)
1.00 (reference)
Yes
10 (47.6)
12 (28.6)
2.23 (0.77–6.56)
0.140
2.22 (0.76–6.68)
0.146
HIV infection
No
18 (85.7)
37 (88.1)
1.00 (reference)
Yes
3 (14.3)
5 (11.9)
1.29 (0.27–5.42)
0.733
TB site
PTB
15 (71.4)
36 (85.7)
1.00 (reference)
PTB with
extrapulmonary TB
5 (23.8)
4 (9.5)
2.88 (0.72–12.12)
0.133
Extrapulmonary TB
1 (4.8)
2 (4.8)
1.41 (0.12–11.53)
0.751
Cavitation present in
baseline CXR
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Cases
Controls
Univariable model
Multivariable model^
(N=21)
n (%)
(N=42)
n (%)
OR (95% CI)
p-value
aOR (95% CI)
p-value
No
15 (71.4)
26 (61.9)
1.00 (reference)
Yes
6 (28.6)
16 (38.1)
0.67 (0.21–1.98)
0.478
Sputum AFB smear
Negative
9 (42.9)
16 (38.1)
1.00 (reference)
Positive
12 (57.1)
25 (59.5)
0.85 (0.30–2.46)
0.763
Not done
0 (0.0)
1 (2.4)
0.58 (0.00–12.02)
0.736
Sputum culture
conversion at 2 months of
treatment
No
1 (4.8)
1 (2.4)
1.00 (reference)
Yes
12 (57.1)
25 (59.5)
0.49 (0.04–6.50)
0.557
Unknown
8 (38.1)
16 (38.1)
0.52 (0.04–7.08)
0.592
Treatment delivery mode
SAT
7 (33.3)
19 (45.2)
1.00 (reference)
DOT
14 (66.7)
23 (54.8)
1.60 (0.56–4.84)
0.381
Extension of continuation
phase of treatment
No
16 (76.2)
32 (76.2)
1.00 (reference)
Yes
4 (19.0)
6 (14.3)
1.36 (0.34–5.18)
0.652
Unknown
1 (4.8)
4 (9.5)
0.66 (0.06–3.94)
0.663
^ Adjusted for gender and diabetes.
AFB, acid fast bacilli; aOR: adjusted odds ratio; CI: confidence interval; CXR, chest x-ray; DOT, directly observed therapy; OR: odds ratio; PTB, pulmonary
tuberculosis; SAT, self-administered therapy; TB, tuberculosi
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Table 5
Sites of disease in 24 cases with PTB and concomitant extrapulmonary TB in their
first TB episode
SITES OF
DISEASE
First Episode
Duration of
treatment of first
episode
(months) / Mode
of treatment
delivery
SITES OF
DISEASE
Recurrent
Episode
Remarks
Relapsed cases (ie. matching DNA fingerprints for both disease episodes)
N=10
1
PTB + Pleura
9 / DOT
PTB
2
PTB + Pleura
15 / SAT
Non-rifampicin
containing regimen
PTB
3
PTB + larynx
6 / DOT
PTB
4
PTB + Pleura
6 / DOT
PTB + GI
5
PTB + Larynx
6 / DOT
PTB
6
PTB + GI
8.5 / SAT
PTB
7
PTB+Pleura+LN
6 / DOT
PTB
8
PTB + Skeletal
16 / SAT
PTB + LN
HIV-infected
(Rifampicin-
resistant)
9
PTB+LN+GU
6 / DOT
CNS
HIV-infected
10
PTB + CNS
12 / SAT
PTB+LN+CNS
HIV-infected
Re-infection cases (ie. different DNA fingerprints for both disease episodes)
N=5
1
PTB + Pleura
12 / SAT
PTB
2
PTB+Pleura+LN
6 / DOT
PTB
3
PTB + Pleura
6 / DOT
PTB
4
PTB + Pleura
6 / DOT
PTB
5
PTB+Pleura+LN
(Isoniazid-
resistant)
9 / DOT
PTB
(Pan-sensitive)
HIV-infected
Cases without DNA fingerprint results for both disease episodes N=9
1
PTB + Pleura
6 / DOT
PTB
2
PTB + GU
10 / DOT
PTB
3
PTB + Pleura
18 / DOT
Non-rifampicin
containing regimen
PTB + Eye
4
PTB + Skeletal
9 / DOT in
institutional setting
PTB + GI
5
PTB + Skeletal
10 / SAT
Skeletal
6
PTB + GI
12 / SAT
PTB
7
PTB + Pleura
6 / DOT
PTB
8
PTB + Pleura
7 / DOT
PTB
9
PTB + Pleural
9 / SAT
Pleural
PTB: pulmonary tuberculosis, CNS: central nervous system, GI: gastrointestinal, GU:
genitourinary, LN: lymph node DOT: directly-observed therapy, SAT: self-administered
therapy
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Figure 1
7,478 culture-positive TB
episodes notified between 2006 to
2013
91 cases with two or more
culture-positive episodes notified
up to
December 2016
49 cases
with DNA fingerprinting results
for first and second episodes
21 cases with different DNA fingerprint
results for first and second episodes
“Re-infection cases”
28 cases with identical / near-identical
DNA fingerprint results for first and second
episodes
“Relapse cases”
Two cases with pan-sensitive first
episode TB relapsed with rifampicin
mono-resistance (both were HIV co-
infected)
One case with first-episode pan-
sensitive TB relapsed with isoniazid
mono-resistance
25 cases (including two streptomycin
mono-resistant cases) did not
develop acquired drug resistance in
their relapse disease episodes
One case with pan-sensitive first-
episode TB was re-infected with
INH mono-resistant strain
20 cases were re-infected with
pan-sensitive strains (one was
resistant to streptomycin and
another resistant to isoniazid in the
first episode)
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