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Recurrent tuberculosis in Finland 1995-2013: A clinical and epidemiological cohort study

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  • Finnish Lung Health Association and University of Turku

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Background We investigated the epidemiology and prevalence of potential risk factors of tuberculosis (TB) recurrence in a population-based registry cohort of 8084 TB cases between 1995 and 2013. Methods An episode of recurrent TB was defined as a case re-registered in the National Infectious Disease Register at least 360 days from the date of the initial registration. A regression model was used to estimate risk factors for recurrence in the national cohort. To describe the presence of known risk factors for recurrence, patient records of the recurrent cases were reviewed for TB diagnosis confirmation, potential factors affecting the risk of recurrence, the treatment regimens given and the outcomes of the TB episodes preceding the recurrence. ResultsTB registry data included 84 patients, for whom more than 1 TB episode had been registered. After a careful clinical review, 50 recurrent TB cases (0.6%) were identified. The overall incidence of recurrence was 113 cases per 100,000 person-years over a median follow up of 6.1 years. For the first 2 years, the incidence of recurrence was over 200/100000. In multivariate analysis of the national cohort, younger age remained an independent risk factor at all time points, and male gender and pulmonary TB at 18 years of follow-up. Among the 50 recurrent cases, 35 patients (70%) had received adequate treatment for the first episode; in 12 cases (24%) the treating physician and in two cases (4%) the patient had discontinued treatment prematurely. In one case (2%) the treatment outcome could not be assessed. Conclusions In Finland, the rate of recurrent TB was low despite no systematic directly observed therapy. The first 2 years after a TB episode had the highest risk for recurrence. Among the recurrent cases, the observed premature discontinuation of treatment in the first episode in nearly one fourth of the recurrent cases calls for improved training of the physicians.
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R E S E A R C H A R T I C L E Open Access
Recurrent tuberculosis in Finland 19952013:
a clinical and epidemiological cohort study
Virve Korhonen
1,2,3*
, Hanna Soini
1
, Tuula Vasankari
4,5
, Jukka Ollgren
1
, Pieter W. Smit
1,6
and Petri Ruutu
1
Abstract
Background: We investigated the epidemiology and prevalence of potential risk factors of tuberculosis (TB)
recurrence in a population-based registry cohort of 8084 TB cases between 1995 and 2013.
Methods: An episode of recurrent TB was defined as a case re-registered in the National Infectious Disease Register
at least 360 days from the date of the initial registration. A regression model was used to estimate risk factors for
recurrence in the national cohort. To describe the presence of known risk factors for recurrence, patient records of
the recurrent cases were reviewed for TB diagnosis confirmation, potential factors affecting the risk of recurrence,
the treatment regimens given and the outcomes of the TB episodes preceding the recurrence.
Results: TB registry data included 84 patients, for whom more than 1 TB episode had been registered. After a careful
clinical review, 50 recurrent TB cases (0.6%) were identified. The overall incidence of recurrence was 113 cases per
100,000 person-years over a median follow up of 6.1 years. For the first 2 years, the incidence of recurrence was over
200/100000. In multivariate analysis of the national cohort, younger age remained an independent risk factor at all time
points, and male gender and pulmonary TB at 18 years of follow-up. Among the 50 recurrent cases, 35 patients (70%)
had received adequate treatment for the first episode; in 12 cases (24%) the treating physician and in two cases (4%)
the patient had discontinued treatment prematurely. In one case (2%) the treatment outcome could not be assessed.
Conclusions: In Finland, the rate of recurrent TB was low despite no systematic directly observed therapy. The first 2
years after a TB episode had the highest risk for recurrence. Among the recurrent cases, the observed premature
discontinuation of treatment in the first episode in nearly one fourth of the recurrent cases calls for improved training
of the physicians.
Keywords: Tuberculosis recurrence, Tuberculosis epidemiology, Tuberculosis treatment, Tuberculosis
Background
Tuberculosis (TB) remains a major global health
problem with estimated 10.4 million new TB cases
worldwide in 2015. In 2013, 0.3 million TB cases
were reported as recurrent [1]. After successful treat-
ment, recurrent TB is estimated to occur in 014% of
all TB patients within 13 years [2]. Recurrence of
TB following treatment of an initial disease episode
can occur due to endogenous re-activation with the
same strain of Mycobacterium tuberculosis (relapse) or
exogenous infection with a new strain (re-infection).
In low-incidence countries, recurrence rates have
varied between 0.4% and in a prospective clinical trial
up to 6% [35]. The proportion due to re-infection
has been reported to vary between 4 and 27% [3, 4].
In high-incidence countries the majority of recurrent
cases, up to 77%, are caused by re-infection [6].
Finland is a low-TB-incidence (<10/100000) country
since 2001, and in 2015 TB incidence was 5/100000 [7].
In 2015, 1% of TB cases had HIV infection. However,
emerging challenges for the TB control program include
gradually increasing resistance of M. tuberculosis, with
3% of all isolates multi drug resistant (MDR) in 2015 [7],
concomitantly with a rapid increase in the proportion of
TB cases occurring in immigrants [8]. Finland did not
implement a comprehensive DOT (directly observed
therapy) strategy in patient management until 2013 [9].
* Correspondence: virve.korhonen@uta.fi
1
Department of Health Security, National Institute for Health and Welfare,
Helsinki, Finland
2
Department of Pulmonary Diseases, Tampere University Hospital, Tampere,
Finland
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Korhonen et al. BMC Infectious Diseases (2017) 17:721
DOI 10.1186/s12879-017-2818-6
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Our previous study shows, that in Finland more than
80% of recurrent cases during 19952013 were relapses
[10]. The aim of the present study was to investigate in a
national, population-based TB cohort the occurrence of
recurrent TB and a few potential factors affecting the risk
of recurrence in Finland during the years 19952013. In
recurrent cases, we describe treatment regimens adminis-
tered and treatment outcome in the first episode, and
other potential factors affecting the risk of recurrence, in
order to strengthen the TB treatment program in the
changing epidemiologic environment.
Methods
Surveillance system and study population
The study population consisted of all TB cases in Finland
reported from January 1, 1995, to December 31, 2013, to
the National Infectious Disease Register (NIDR), main-
tained at the National Institute for Health and Welfare
(THL). Clinical microbiology laboratories mandatorily
notify new M. tuberculosis isolations to NIDR and submit
isolates to the Mycobacterial Reference Laboratory (NRL)
at THL for drug susceptibility testing (ethambutol,
isoniazid, pyrazinamide, rifampicin and streptomycin).
Physicians mandatorily notify to NIDR laboratory-
confirmed cases of TB: the laboratory report of a positive
test result to the clinician automatically includes a
reminder to notify the case. Since 2007, also clinically
diagnosed TB cases, when a decision to give a full course
of TB treatment is made, are notified. Information on HIV
positivity is obtained by linking data within NIDR. Data
on the country of origin and the date of death were
retrieved from the national population registry. Data from
the different sources are automatically linked as a case by
a unique person identifying number.
Case definitions and data collection for the subgroup of
recurrent cases
An episode of recurrent TB was defined as a case re-
registered in NIDR at least 360 days from the date of the
initial registration of a TB infection episode. For the cases
who had a recurrent episode in the register, data on
anatomical site of disease (pulmonary/extrapulmonary),
radiological, histological and microbiological results, HIV
test results, substance abuse, the drug regimen in the first
episode and adverse effects were extracted from patient
charts. In pulmonary TB cases, also sputum smear and
culture results at months 0 and 2, and at the end of the
treatment were obtained. Based on careful review of these
data, a number of cases were excluded from further
analysis as recurrent cases, as they did not meet the
criteria for recurrent TB (Fig. 1). In culture negative
episodes, the diagnoses were based on clinical criteria
[11], including radiological findings in combination with
either histological confirmation or positive nucleic acid
amplification test results, except for one case in which the
diagnosis was only clinical and radiological.
Management of the TB episode preceding recurrence
The treatment regimen, free of charge for the patient,
administered in the first TB episode was grouped into
six categories, based on the national recommendations:
until 2006 as described earlier [12, 13], and from 2006 in
the National TB Control Program [9]. The treatment
regimens and the outcomes of the first TB episodes of
the recurrent cases, including culture negative and extra-
pulmonary cases, were assessed by two clinical TB
experts, and classified [11] as cured, completed treat-
ment, lost to follow-up and not evaluated (no fatal cases
nor failures). Lost to follow-upwas further divided into
subgroups: physicians decision to stop prematurely
(including cases that received ineffective treatment), and
defaulted (interruption due to the patient). Group not
evaluatedwas further divided into subgroups: still on
treatment at 12 months, and treatment outcome not
assessed. In two cases the details of treatment in the first
episode were not available, but in one of these cases the
treatment outcome could be assessed.
Statistical analysis
To calculate the incidence of recurrent TB among all
reported cases of the national cohort, follow-up time in
days was calculated for all cases in the national TB
cohort from 360 days after they were notified until an
event (re-notification), death or censored (December 31,
2013). The date of death was acquired by linkage to
population register using person identifier. The regres-
sion model employed, uses pseudo-observations to
model censored data [14] with Stata version 14.02
(StataCorp LLC, 4905 Lakeway Drive, Collage Station,
TX 77845 USA) to estimate effects (their relative risks)
of risk factors. The censoring was assumed to be inde-
pendent, conditional on the covariates [15]. Gender and
anatomical site of disease were allowed to have time
dependent effects, and predictive margins were calcu-
lated to estimate cumulative risk differences between
genders and anatomical sites of disease, respectively,
adjusting for other factors in the model. Results were
qualitatively checked using the extended time dependent
Cox model. All the explanatory variables with univariate
p-values <0.2 were included in the multivariate model,
and included gender, anatomical site of disease and age.
Cause specific cumulative risks for time points 1 year,
2 years and 18 years were calculated, as the chosen early
time points had most recurrent events for explanatory
variables, and it has been previously reported that the
first 12 years have the highest hazard for recurrence
[3, 16]. The maximum surveillance time point set at
18 years gives the final overall difference estimate for
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 2 of 7
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the cumulative risk of recurrence. The distribution of
continuous variables between groups was compared
using Wilcoxon rank-sum test.
Ethics
The ethics approval for the study was given by the
Ethics Committee of Tampere University Hospital,
Tampere, Finland.
Results
A total of 8084 TB cases were registered in Finland during
the study period (Table 1): 43% were female, and 13.6% of
foreign origin (increased from 4.8% in 1995 to 32.2% in
2013). The median age was 70 years (interquartile range
[IQR], 5679 years) for Finnish-born and 30 years (IQR
2340 years, p< 0,001) for foreign-born cases.
Characteristics and incidence of recurrent TB
After a careful review of the 84 cases with more than one
episode registered, 50 TB cases (0.6% of all cases in the
cohort) were classified as recurrent (Fig. 1). The mean
overall incidence of recurrence was 112.9 (95% confidence
interval [CI], 85.6148.9); for the first year of follow-up
the overall incidence was 236.4 (95%CI 140.0399.2) and
for the second year of follow-up 206.7 (95%CI 114.5
373.2) per 100,000 person-years. Out of the 50 recurrent
cases, two had three disease episodes and 48 two disease
episodes. Forty cases were culture positive in all episodes.
The median age was 51.5 years (range 695 years) at the
registration of the first episode; eleven cases (22%) were
female. In the first episode 44 cases (88%) and in the sec-
ond episode 39 cases (78%) were classified as pulmonary
TB. Two cases were HIV positive; for 64% of cases HIV
had not been tested. Nine recurrent cases (18%) were of
foreign origin. A history of substance abuse, mostly alco-
hol, was registered in the patient records in at least 1 TB
episode of 59% of males and none of females; 49% of
males had substance abuse recorded in both episodes.
Management of the TB episodes preceding recurrence
Among the 48 recurrent cases (96%) with complete patient
records, 36 cases (75%) received standard treatment in the
first episode (Table 2). Among these, the duration of
Fig. 1 Steps in identifying recurrent cases of tuberculosis, Finland, 19952013.
a
Non-tuberculous mycobacterium registered as M. tuberculosis
(N= 2), registration for false identity (N= 1) or incorrect registration date by the notifier (N= 10).
b
Only one long continuous TB episode (N= 5),
or treating physician decided to give TB treatment without specific evidence of TB and in subsequent expert assessment by the study team there
was another more likely cause for the disease (N=9)
Table 1 Distribution of demographic and potential risk factors
for recurrent tuberculosis in a national TB cohort of 8084 cases,
Finland 19952013
Variable TB recurrence
(n= 50)
No TB recurrence
(n= 8034)
All (n= 8084)
Median age, years 51, 5 66 66
Gender female n(%) 11 (22%) 3457 (43%) 3468 (42.9%)
Foreign origin n(%) 9 (18%) 1066 (13.6%)
a
1074 (13.6%)
b
Pulmonary site of disease
n(%)
44 (88%)
c
5599 (69.2%) 5605 (69.3%)
Culture positive n(%) 48 (96%)
c
6631 (82.5%) 6680 (82.6%)
Prior to year 2007 n(%) 45 (90%)
c
5762 (71.7%) 5807 (71.8%)
a
Origin known for 7862 cases
b
Origin known for 7912 cases
c
Data of the first episode
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 3 of 7
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treatment was short (<5.5 months) in six cases, and the in-
tensive phase (<54 days) in three cases. Twelve cases (25%)
received non-standard treatment due to drug resistance,
adverse effects, or the treating physicians decision. Of
these, six cases received TB treatment regimens that were
assessed as probably effective, one of them for a too short
time period. Treatment regimens of six cases were assessed
as probably ineffective. Six cases (12.5%) received directly
observed therapy (DOT). Among the 49 cases with treat-
ment outcome, it was successful in 27 cases (55.1%). In 12
cases (24.5%) the treating physician had stopped the treat-
ment prematurely, and in two cases (4.1%) interruption was
due to the patient. Eight cases (16.3%) were still on treat-
ment at 12 months (all finally completed treatment).
There were no recurrent cases with an MDR isolate in
either episode. Five cases were initially infected with
isoniazid-resistant isolates, but in three of these cases,
the treatment regimen was not modified accordingly. In
two cases, additional resistance to streptomycin and in
one case resistance to pyrazinamide developed during
treatment. In one case, initially fully susceptible isolate
developed resistance to pyrazinamide.
Risk factors for recurrence in the national cohort
The median follow-up time of cases in the cohort of
8084 TB cases was 6.1 years (IQR 2.711.1 years). The
recurrence occurred within less than 2 years in 25 (50%),
two to less than 4 years in 8 (16%), and later in 17 cases
(34%) (Fig. 2a). No recurrences occurred in females and
for extrapulmonary cases after the first 2 years (Fig. 2b
and c). In univariate analysis of variables available for
the national cohort, the cumulative risks of recurrence
between males and females, and between pulmonary and
extrapulmonary TB did not differ statistically
significantly at 1 and 2 years of follow-up (Table 3).
However, at 18 years of follow-up, the cumulative risk
for males was nearly fourfold compared to females
(Fig. 2b), and more than fivefold for pulmonary TB com-
pared to extrapulmonary TB (Fig. 2c). The risk of recur-
rence decreased with every additional 10 years of age
(Table 3). When only cases that were culture positive in
all episodes were included, the recurrence rate was simi-
lar to that seen in the whole recurrent cases cohort
(Fig. 2d). Whether the first episode occurred prior to
versus after 2007 did not have a significant association
with the risk of recurrence (Table 3).
In the multivariate analysis (Table 3) younger age
remained an independent risk factor for cumulative risk
of recurrence at all time points, and male gender and
pulmonary TB at 18 years of follow-up.
Discussion
We investigated the epidemiology and the prevalence of
risk factors associated with recurrence of TB in Finland
in a comprehensive national, register-based cohort of
8084 TB cases from 1995 to 2013, and found in a
follow-up of up to 18 years that 0.6% of cases during the
study period were recurrent. The overall incidence of
recurrence is 1020 times higher, and for the first 2
years of follow-up 2040 times higher than the inci-
dence of TB in the general population in Finland during
the study period [7]. Patient chart review of the recur-
rent cases revealed that in nearly one fourth of the
recurrent cases, the physician had discontinued the
treatment of the first episode prematurely.
In register-based studies on recurrent TB, validation of
the data requires considerable effort to ensure data
Table 2 Distribution of treatment regimens in the first episodes of 50 TB cases with a recurrence
Treatment group Total in group Intensive phase
short
Intensive phase
adequate
Duration of treatment
short
Duration of treatment
adequate
Standard treatment A
a
15 NA 15 1 14
Standard treatment B
b
4NA4 2 2
Standard treatment with short intensive
phase C
c
33 NA2 1
Standard treatment D
d
14 0 14 1 13
Other probably effective combination of
anti-TB drugs
e
6NANA1 5
Other probably ineffective combination of
anti-TB drugs
f
6NANANA NA
Not evaluated 2 –––
NA not applicable, Hisoniazid, RRifampicin, Zpyrazinamide, Eethambutol
a
HRZ in intensive phase, HR in continuation phase, adequate duration of treatment 5.5 months
b
HRE in intensive phase, HR in continuation phase, adequate duration of treatment 8 months
c
Short intensive phase <54 days in standard treatment A or B
d
4 anti-TB drugs, including HRZ (adequate duration of treatment 5.5 months) or HRE (adequate duration of treatment 8 months)
e
Non-standard combinations guided by drug resistance or due to adverse effects, the adequacy of treatment duration assessed by the study group
f
Drug resistance ignored or inappropriate dosing
References [9,12,13]
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 4 of 7
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quality, as demonstrated in our study using a register with
proven high sensitivity and specificity for TB [17], after
which automated notification from the laboratories and
mandatory reminders from the laboratory to the clinician
on the need to notify were introduced. We observed that
out of the 84 cases initially identified in the register data
as recurrent, only 50 cases were truly recurrent. Major
reasons for inaccuracies in our register data included
incorrect notification dates, and notifying clinical TB cases
without microbiological confirmation, which the chart
review revealed to be incorrect. Without validation of the
data for recurrent TB cases, the proportion of recurrent
a b
c d
Fig. 2 Cumulative risk of recurrence of TB by follow-up time (and its pointwise 95% confidence limits). aOverall cohort; (b) By gender; (c)By
anatomical site of disease; (d) Only culture positive TB
Table 3 Univariate and multivariate analysis for risk factors of TB recurrence in a national cohort of TB cases in Finland, 19952013
Variables Univariate RR 95% CI pMultivariate RR 95% CI p
Males at 1 year
a
1,43 0,484,26 0,52 1,93 0,409,31 0,41
Males at 2 years
a
1,18 0,532,62 0,69 1,39 0,444,38 0,58
Males at 18 years
a
3,92 1,957,91 < 0,001 5,88 2,2115,66 < 0,001
Pulmonary TB at 1 year
b
1,72 0,486,19 0,40 4,13 0,5829,67 0,16
Pulmonary TB at 2 years
b
1,87 0,704,99 0,21 2,00 0,439,33 0,38
Pulmonary TB at 18 years
b
5,54 2,1714,14 < 0,001 15,15 4,9846,08 < 0,001
Age + 10 years 0,87 0,770,98 0,03 0,83 0,700,99 0,04
Finnish origin 0,64 0,311,33 0,23 ––
1.episode before 2007 1,33 0,812,21 0,26 ––
a
Reference females. Overall p-value for male gender in univariate analysis < 0,0001 and in multivariate analysis 0,0015
b
Reference extrapulmonary TB. Overall p-value for pulmonary TB < 0,0001
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 5 of 7
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cases out of the total cohort in our study would have been
almost double, stressing the need for rigid patient chart
review when assessing TB recurrence.
Over 80% of recurrent cases in Finland are relapses of
the previous infection [8], as elsewhere in low-incidence
countries [3, 18, 19]. In register-based investigations of
recurrent TB in low incidence-countries, careful review
of the actual treatment in the first TB period of recur-
rent cases has rarely been reported [20, 21]. We
observed that approximately two thirds, including those
who received treatment lasting over 12 months, had
received an adequate treatment. Just over one half
among the recurrent cases had in the first episode a
successful outcome according to WHO criteria [11].
Important for training policy was the finding that clearly
more frequently than interruption due to the patient,
the treating physician had discontinued treatment pre-
maturely, as described in our previous report [12]. Inad-
equate treatments were caused by the presence of drug
resistance without appropriate treatment regimen modi-
fication, absence of appropriate extension of duration of
treatment when treatment was modified, adverse effects,
or the physicians decision to stop without the reason
being documented in the patient record.
Theoverallincidenceofrecurrenceinthenational
cohort, with a median follow-up period of 6 years,
and up to 18 years, was 113/100000, 1020 times
higher than for the general population in Finland, in
line with long-term follow-up in low-incidence coun-
tries (71410/100000) [3, 16]. For the first year of
follow-up, starting at 12 months from the registration
of the first episode, the incidence of recurrence was
236/100000, of the same magnitude as in recent
studies from Australia [3] and Denmark [18], but
clearly lower than in a number of earlier studies from
industrialised countries [22].
Our observation in the national cohort of male gender
as a risk factor for recurrence is in line with some previous
reports from low-incidence countries [2325], but this
finding has been inconsistent [20, 21]. Substance abuse
data is not collected in the NIDR for the national cohort,
but we found in nearly 60% of the recurrent male cases a
history of substance abuse in patient charts, but none in
females, which could contribute to the excess risk seen in
males. An association between treatment adherence and
alcoholism has been reported in recurrent TB in the USA
[20]. We found in the national cohort the risk of recur-
rence higher for pulmonary than for extrapulmonary TB,
in line with earlier studies [16, 23, 26]. More than 40% of
our recurrent cases (data not shown) had both pulmonary
and extrapulmonary infection in the first episode, which
has been reported to be a risk factor for recurrences [25].
An unexpected finding in the national cohort was that the
risk of recurrence was associated with younger age,
whereas in two earlier studies, age > 65 years [20] or age
between 25 and 64 years [23] have been reported as risk
factors for recurrence. In earlier studies, either being an
immigrant [16, 20, 25] or being borne in the country [21]
were reported as risk factors, while origin was not a risk
factor for recurrence in our national cohort study.
Limitations of our cohort study include the fact that we
may fail to identify some recurrences, as recurrences
before 360 days from the date of the initial episode (early
recurrences) were not analysed from the register data. The
standard cut-off time recommended by WHO, at which
treatment outcome is recorded, is 12 months [11]. There-
fore, we chose this timepoint as a cut-off for recurrence,
in line with eg a large UK cohort [16]. The proportion of
early recurrences in retrospective studies is small [3, 18].
In addition, in retrospective studies, it may be difficult to
distinguish between treatment failures and early recur-
rences as sputum samples are not systematically collected
during treatment, and in our study we also included
culture negative and extrapulmonary cases. Almost one
third of our recurrent cases do not meet the WHO treat-
ment regimen description and outcome criteria for a
recurrent case [11]. However, the careful validation
process of our register data demonstrates that the same
challenges are likely to be present in other register-based
studies, unless careful validation has been performed. As a
country with very low incidence for HIV [7], the absence
of systematic testing of all TB cases for HIV is unlikely to
introduce a bias in the risk analysis.
The observations on the shortcomings of treatment
among the first episodes of the recurrent cases are
important for guiding training and system development
for the integrated TB control program. In 20132015,
treatment outcome in Finland was successful (cure or
completed treatment) in 7578% of pulmonary TB cases
[7], as in the European Region on average [27].
Conclusions
In the absence of a comprehensive DOT strategy, the rate
of TB recurrence was found to be low in Finland. An
important finding was that in one fourth of the recurrent
cases, the physician had discontinued the treatment pre-
maturely, which implies that training of physicians needs
to be improved and, as TB becomes rare, treatment
should possibly be provided in fewer centers. The first 2
years after a TB episode is a very high-risk period for
recurrence: this could be incorporated as an automated
high-risk signal in the developing integrated electronic
patient management systems for reducing the delays in
implementing TB diagnostics and treatment.
Abbreviations
CI: Confidence interval; DOT: Directly observed therapy; HIV: Human
immunodeficiency virus; IQR: Interquartile range; MDR: Multi drug resistant;
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 6 of 7
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NIDR: National infectious disease register; NRL: Mycobacterial reference
laboratory; TB: Tuberculosis; THL: National Institute for Health and Welfare
Acknowledgements
We thank Pirjo Turtiainen, Jan-Erik Löflund and Teemu Möttönen at the
National Institute for Health and Welfare for technical assistance and
Professor Lauri Lehtimäki at the School of Medicine, University of Tampere
for critically reviewing this article.
Funding
The study was supported by the Tampere Tuberculosis Foundation, Väinö
and Laina Kivi Foundation and The Research Foundation of the Pulmonary
Diseases. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
All data generated or analysed during this study are included in this
published article.
Authorscontributions
VK participated in designing the study, collected the clinical data, and was
involved in analysing the data and writing the manuscript. HS participated in
designing the study, supervised the laboratory work and was involved in
analysing the data and writing the manuscript. TV participated in designing
the study, and was involved in analysing especially the clinical data and
writing the manuscript. JO participated in designing the study and
performed the statistical analysis. PS participated in designing the study and
writing the manuscript. PR participated in designing the study, and was
involved in analysing the data and had a major role in writing the
manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The ethics approval for the study was given by the Ethics Committee of
Tampere University Hospital, Tampere, Finland. Consent to participate: Not
applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Health Security, National Institute for Health and Welfare,
Helsinki, Finland.
2
Department of Pulmonary Diseases, Tampere University
Hospital, Tampere, Finland.
3
School of Medicine, University of Tampere,
33014 Tampere, Finland.
4
Finnish Lung Health Association (Filha), Helsinki,
Finland.
5
Faculty of Medicine, University of Turku, Turku, Finland.
6
Department of infectious diseases, Public health laboratory, GGD
Amsterdam, Amsterdam, The Netherlands.
Received: 13 April 2017 Accepted: 5 November 2017
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... Likewise, higher reinfection rates of 1.5-2.8% have been found in countries with a high incidence of TB compared with 0.1-0.3% in countries with a low incidence of TB [4,[8][9][10][11][12][13][14][15][16][17][18][19][20]. ...
... Even though risk factors for reactivation of TB in countries with a low TB incidence have been described, previous studies have had limited power to explore the findings over an extended time period. Additionally, only a few studies explored the effect of interrupted treatment on the risk of reactivation [6,13]. ...
... [6][7][8][9] and reinfection rates of 0.1-0.3% [4,[8][9][10][11][12][13][14][15][16][17][18][19][20]. ...
Article
Background Not all treated tuberculosis (TB) patients achieve long-term recovery and reactivation rates reflect effectiveness of TB treatment. Aim We aimed to estimate rates and risk factors of TB reactivation and reinfection in patients treated in the Netherlands, after completed or interrupted treatment. Methods Retrospective cohort study of TB patients with available DNA fingerprint data, registered in the Netherlands Tuberculosis register (NTR) between 1993 and 2016. Reactivation was defined as an identical, and reinfection as a non-identical Mycobacterium tuberculosis strain in sequential episodes. Results Reactivation rate was 55/100,000 person-years (py) for patients who completed, and 318/100,000 py for patients who interrupted treatment. The risk of reactivation was highest in the first 5 years after treatment in both groups. The incidence rate of reactivation was 228/100,000 py in the first 2 years and 57/100,000 py 2–5 years after completed treatment. The overall rate of reinfection was 16/100,000 py. Among those who completed treatment, patients with male sex, mono or poly rifampicin-resistant TB and a previous TB episode had significantly higher risk of reactivation. Extrapulmonary TB was associated with a lower risk. Among patients who interrupted treatment, directly observed treatment (DOT) and being an undocumented migrant or people experiencing homelessness were associated with a higher risk of reactivation. Conclusions Both patients who completed or interrupted TB treatment should be considered as risk groups for reactivation for at least 2–5 years after treatment. They patients should be monitored and guidelines should be in place to enhance early detection of recurrent TB.
... 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][19][20][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. ...
... 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. ...
Article
Full-text available
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.
... A WHO report estimated that 6.8% of TB cases recurred worldwide in 2019 [11], and recurrence occurs not only in high TB incidence countries, but also in low countries [12][13][14]. A retrospective study of surveillance data and clinical records in Finland showed 0.6% of TB cases were recurrent from 1995 to 2013 [15], and 1.3% of TB cases were recurrent in Barcelona from 2003 to 2006 [12], and the proportion of recurrent cases between 4.2 and 5.7% in the United States during 1993-2010 [16]. In addition, 5.3% of successfully treated bacteriologically confirmed cases had a recurrence in Shanghai [5], China, and 6.8% in Beijing [6]. ...
Article
Full-text available
Background Recurrence continues to place significant burden on patients and tuberculosis programmes worldwide, and previous studies have rarely provided analysis in negative recurrence cases. We characterized the epidemiological features of recurrent pulmonary tuberculosis (PTB) patients, estimated its probability associated with different bacteriology results and risk factors. Methods Using 2005–2018 provincial surveillance data from Henan, China, where the permanent population approximately were 100 million, we described the epidemiological and bacteriological features of recurrent PTB. The Kaplan–Meier method and Cox proportional hazard models, respectively, were used to estimate probability of recurrent PTB and risk factors. Results A total of 7143 (1.5%) PTB patients had recurrence, and of 21.1% were bacteriological positive on both laboratory tests (positive–positive), and of 34.9% were negative–negative. Compared with bacteriological negative recurrent PTB at first episodes, the bacteriological positive cases were more male (81.70% vs 72.79%; P < 0.001), higher mortality risk (1.78% vs 0.92%; P = 0.003), lower proportion of cured or completed treatment (82.81% vs 84.97%; P = 0.022), and longer time from onset to end-of-treatment. The probability of recurrence was higher in bacteriological positive cases than those in bacteriological negative cases (0.5% vs 0.4% at 20 months; P < 0.05). Conclusions Based on patient’s epidemiological characteristics and bacteriological type, it was necessary to actively enact measures to control their recurrent.
... 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 A c c e p t e d M a n u s c r i p t 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). ...
Article
Full-text available
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.
... 19 In this study, recurrent pulmonary TB is significantly higher in male patients, confirming that males become one of the risk factors contributing to recurrent cases. 20,21 Other risk factors associated with recurrent TB cases include smoking, poor treatment adherence, uncontrolled HIV-comorbid infection, and specific clinical pictures such as residual cavitation, more significant area of involved lung tissue, and positive sputum culture at two months of first treatment. 3 Previous studies have shown associations between TB recurrence and drug resistance. ...
Article
Full-text available
Purpose: N-acetyltransferase-2 enzyme in the liver, encoded by NAT2 gene, plays a central role in metabolizing tuberculosis (TB) drug isoniazid (INH). Low compliance of patients toward six-month TB therapy and internal host factors, ie comorbid diseases, immune status, and genetic profiles, are factors leading to treatment failure and recurrence of pulmonary TB infection. This study aimed to explore the NAT2 acetylator status among newly diagnosed and recurrent pulmonary TB patients in eastern part of Indonesia. Patients and methods: Archived DNA of TB patients (n=124) and healthy controls (n=124) were sequenced, and NAT2 acetylator status was determined, then categorized as fast, intermediate, or slow acetylators. Pulmonary TB patients who had no previous TB treatment history were designated as newly diagnosed pulmonary TB, whereas patients with a history of TB treatment were designated as recurrent pulmonary TB. The demographic, clinical, and microbiological data between pulmonary TB groups were compared, and acetylator status was described among groups. Results: Male was more significantly prevalent in the recurrent pulmonary TB group (p=0.025), and anemia was more prevalent in new pulmonary TB (p=0.003). The acetylator status in pulmonary TB patients compared to healthy controls were rapid (33.9% vs 48.1%), intermediate (57.8% vs 33.0%), and slow acetylators (8.3% vs 18.9%), respectively. Interestingly, the rapid and intermediate acetylator were significantly more prevalent in pulmonary TB patients than in healthy controls (p=0.023, OR=2.58 (1.12-5.97). Furthermore, no differences were found in acetylator status between new and recurrent pulmonary (p=0.776). Conclusion: Rapid and intermediate acetylators status predominated the pulmonary TB patients in Kupang, eastern part of Indonesia, postulating different genetic makeup in this area. As the pulmonary TB patients in Kupang exhibit more rapid acetylator phenotype, the acetylator status might be relevant to be checked before TB therapy for adjusting treatment dose to prevent drug resistances.
Article
There is a growing awareness of the importance of sex and gender in medicine and research. Women typically have stronger immune responses to self and foreign antigens than men, resulting in sex-based differences in autoimmunity and infectious diseases. In both animals and humans, males are generally more susceptible than females to bacterial infections. At the same time, gender differences in health-seeking behavior, quality of health care, and adherence to treatment recommendations have been reported. This review explores our current understanding of differences between males and females in bacterial diseases. We describe how genetic, immunological, hormonal, and anatomical factors interact to influence sex-based differences in pathophysiology, epidemiology, clinical presentation, disease severity, and prognosis, and how gender roles affect the behavior of patients and providers in the health care system.
Article
Full-text available
Abstract SETTING: Even among persons who have completed a course of treatment for their first tuberculosis (TB) episode, patients with a history of TB are at higher risk for having TB. OBJECTIVE: To describe factors from the initial TB episode associated with recurrent TB among patients who completed treatment and remained free of TB for at least 12 months. DESIGN: During 1993-2006, US TB cases stratified by birth origin were examined. Cox proportional hazards regression was used to assess the association of factors during the initial episode with recurrence at least 12 months after treatment completion. RESULTS: Among 632 US-born patients, TB recurrence was associated with age 25-44 years (adjusted hazard ratio [aHR] 1.77, 99% confidence interval [CI] 1.02-3.09, attributable fraction [AF] 1-34%), substance use (aHR 1.57, 99%CI 1.23-2.02, AF 8-22%), and treatment supervised by health departments (aHR 1.42, 99%CI 1.03-1.97, AF 2-28%). Among 211 foreign-born patients, recurrence was associated with human immunodeficiency virus infection (aHR 2.24, 99%CI 1.27-3.98, AF 2-9%) and smear-positive TB (aHR 1.56, 99%CI 1.06-2.30, AF 3-33%). CONCLUSION: Factors associated with recurrence differed by origin of birth, and might be useful for anticipating greater risk for recurrent TB among certain patients with a history of TB.
Article
Full-text available
Recurrent tuberculosis (TB) can result from reactivation of a previous TB episode or reinfection with a new Mycobacterium tuberculosis strain. A retrospective analysis of all recurrent TB cases reported in the United States during 1993-2010 was conducted. The proportion of recurrent cases remained stable during the study period (annual range 4.2-5.7%). Compared with persons without a previous diagnosis of TB, persons with recurrent TB experienced lower treatment completion within 12 months and higher mortality during the recurrent episode. Persons with recurrent TB have poorer outcomes, suggesting the need for targeted interventions to ensure treatment completion.
Article
Full-text available
Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California. The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode. Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p = 0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p = 0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p = 0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p = 0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p = 0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p = 0.0171). The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions.
Article
Full-text available
Programmatic data from the United States on tuberculosis (TB) recurrence are limited. To determine the TB recurrence rate and to determine if chronic lung disease (CLD) and human immunodeficiency virus (HIV) infection are risk factors for recurrence in this population. Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2006. Time at risk for recurrence was through 31 December 2007. Multiple imputation accounted for missing data. Of 1431 TB cases, 20 cases recurred (1.4%, 95%CI 0.9-2.1). Median time at risk for recurrence was 4.5 years (interquartile range 2.7-6.1). Initial and recurrent Mycobacterium tuberculosis isolates were available for genotyping for 15 patients; 12 were consistent with relapse (0.8%, 95%CI 0.4-1.5) and three with re-infection (0.2%, 95%CI 0.04-0.6). HIV infection (OR 5.01, P = 0.04) and CLD (OR 5.28, P = 0.03) were independently associated with recurrent TB, after adjusting for a disease risk score. HIV infection was a risk factor for TB re-infection (P < 0.001). In this low-incidence US population, the TB recurrence rate was low, but CLD and HIV were independent risk factors for recurrence. HIV infection was also a risk factor for TB re-infection.
Article
Full-text available
Information on recurrent tuberculosis can provide an indication of the effectiveness of tuberculosis services and identify patients who are most vulnerable. The objective of this study was to estimate the incidence of, and investigate risk factors for, recurrent episodes of tuberculosis in England and Wales. Episodes of recurrent tuberculosis were identified among prospectively collected records of tuberculosis cases reported to the Health Protection Agency between 1998 and 2005. An episode of recurrent tuberculosis was defined as a re-notified case in the same patient after at least 12 months from the date of the initial notification. To estimate incidence, follow-up time was calculated for all cases until re-notification or censure. Multivariable Cox proportionate hazard models were used to determine hazard ratios (HR) for recurrence of tuberculosis and investigate the risk associated with clinical, demographic and microbiological factors. Five hundred and eighty-eight recurrent tuberculosis events were identified among 53 214 cases reported between 1998 and 2005, a rate of 4.1 (95% CI 3.8 to 4.5) episodes per 1000 person years of follow-up. Factors independently associated with a greater risk of recurrent tuberculosis were HIV co-infection (HR 1.64, 95% CI 1.13 to 2.38) and belonging to a South Asian ethnic group (HR 1.54, 95% CI 1.23 to 1.93). Tuberculosis recurrence is uncommon in England and Wales despite the absence of a universal directly observed treatment policy. The identification of HIV co-infection as a risk factor for recurrent tuberculosis is consistent with findings elsewhere. The higher risk among South Asians, however, requires further investigation.
Article
Full-text available
Denmark, a country with a low-incidence of tuberculosis (TB). To analyse the proportion of relapse vs. re-infection and to compare selected characteristics between the two subgroups. A population-based cohort study. All 4154 Mycobacterium tuberculosis isolates from patients in Denmark genotyped by insertion sequence 6110 restriction fragment length polymorphism were followed for recurrent TB over 13.5 years. Recurrent cases were classified as relapse or re-infection by genotype patterns in initial and serial disease episodes. Recurrent TB was found in 73 (1.8%) cases. Identical M. tuberculosis genotypes in initial and serial episodes were found in 54 (1.3%), indicating relapse, whereas different genotypes, representing re-infection, were found in 19 (0.5%) cases. Cavitary TB in the initial episode was significantly associated with relapse (OR 4.6, 95%CI 1.1-26.9) compared to re-infection. The rate of recurrent TB is low in Denmark. Comparing selected characteristics between the relapse and re-infection subgroups revealed that only the presence of cavitary disease was associated with relapse. Although recurrent TB was rarely due to re-infection, the risk of re-infection increased with time.
Article
Recurrent tuberculosis (TB) is caused by an endogenous re-activation of the same strain of Mycobacterium tuberculosis (relapse) or exogenous infection with a new strain (re-infection). Recurrence of TB in Finland was analysed in a population-based, 19-year study, and genotyping was used to define relapse and re-infection. The M. tuberculosis isolates from suspected relapse cases were further analysed by whole genome sequencing (WGS) to determine the number and type of mutations occurring in the bacterial genome between the first and second disease episode. In addition, publicly available tools (PhyResSE and Spolpred) were used to predict drug resistance and spoligotype profile from the WGS data. Of the 8299 notified TB cases, 48 (0.6%) patients had episodes classified as recurrent. 42 patients had more than one culture-confirmed TB episode, and isolates from two episodes in 21 patients were available for genotyping. In 18 patients, the M. tuberculosis isolates obtained from first and second TB episodes had identical spoligotypes. WGS analysis of the 36 M. tuberculosis isolates from the 18 suspected relapse patients (average time between isolates 2.8 years) revealed 0 to 38 SNPs (median 1, mean 3.78) between the first and second isolate. There seemed to be no direct relation between the number of years between the two isolates, or treatment outcome, and the number of SNPs. The results suggest that the mutation rate may depend on multiple host, strain and treatment –related factors.
Article
The etiology of recurrent tuberculosis is typically presumed to be reactivation of residual Mycobacterium tuberculosis infection, but reinfection may account for a greater proportion of recurrent tuberculosis than previously recognized. To use M. tuberculosis genotyping to characterize the etiology of recurrent tuberculosis ≥12 months after treatment completion. The study population for this national population-based cohort was drawn from the estimated 3,039 persons reported to the National Tuberculosis Surveillance System with 2 episodes of tuberculosis in the United States during 1993-2011; 194 had genotyping results from both the initial and subsequent episode. We analyzed the proportion of recurrent tuberculosis attributable to and the risk factors associated with reinfection. Among 136 recurrences meeting inclusion criteria, genotypes between episodes were the same for 116 (85%) recurrences during 1996-2011; the 20 (15%) with differing genotypes were categorized as reinfection. Using exact logistic regression, factors associated with reinfection included Mexican birth with both TB episodes diagnosed in the United States within 12 years of immigration (adjusted odds ratio, 10.7; 95% confidence interval, 1.7-86.3) and exclusive use of directly observed therapy for treatment of the first episode (adjusted odds ratio, 4.5; 95% confidence interval, 1.0-29.2). Reinfection was the cause for 15% of late recurrent tuberculosis cases in this US cohort. The proportion caused by reinfection increased to 60% in certain subpopulations, such as recent immigrants from Mexico, suggesting that despite successful treatment for TB during their first episode, they remain in a social environment where they are reexposed to M. tuberculosis. Public health interventions to prevent novel reinfection might require a broader focus on these communities.
Article
Increasing immigration from high tuberculosis (TB) incidence countries is a challenge for surveillance and control in Finland. Here, we describe the epidemiology of TB in immigrants by using national surveillance data. During 1995–2013, 7030 (84·7%) native and 1199 (14·4%) immigrant cases were identified. The proportion of immigrant cases increased from 5·8% in 1995 to 32·1% in 2013, consistent with increasing immigrant population (2·1–5·6%) and decreasing incidence of TB in the native population (from 12·1 to 3·5/100 000). TB cases in immigrants were significantly younger, more often female, and had extrapulmonary TB more often than native cases ( P < 0·01 for all comparisons); multidrug resistance was also more common in immigrants than natives ( P < 0·01). Immigrant cases were born in 82 different countries; most commonly in Somalia and the former Soviet Union/Russia. During 2008–2013, 433 Mycobacterium tuberculosis isolates from immigrants were submitted for spoligotyping; 10 different clades were identified. Clades were similar to those found in the case's country of birth. Screening immigrants from high-incidence countries and raising awareness of common characteristics and symptoms of TB is important to ensure early diagnosis and to prevent transmission.
Article
We draw upon a series of articles in which a method based on pseu- dovalues is proposed for direct regression modeling of the survival function, the restricted mean, and the cumulative incidence function in competing risks with right-censored data. The models, once the pseudovalues have been computed, can be fit using standard generalized estimating equation software. Here we present Stata procedures for computing these pseudo-observations. An example from a bone marrow transplantation study is used to illustrate the method.