R E S E A R C H A R T I C L E Open Access
Recurrent tuberculosis in Finland 1995–2013:
a clinical and epidemiological cohort study
, Hanna Soini
, Tuula Vasankari
, Jukka Ollgren
, Pieter W. Smit
and Petri Ruutu
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
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 . After successful treat-
ment, recurrent TB is estimated to occur in 0–14% of
all TB patients within 1–3 years . 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% [3–5]. 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 .
Finland is a low-TB-incidence (<10/100000) country
since 2001, and in 2015 TB incidence was 5/100000 .
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 ,
concomitantly with a rapid increase in the proportion of
TB cases occurring in immigrants . Finland did not
implement a comprehensive DOT (directly observed
therapy) strategy in patient management until 2013 .
* Correspondence: email@example.com
Department of Health Security, National Institute for Health and Welfare,
Department of Pulmonary Diseases, Tampere University Hospital, Tampere,
Full list of author information is available at the end of the article
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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
Our previous study shows, that in Finland more than
80% of recurrent cases during 1995–2013 were relapses
. 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 1995–2013. 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.
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
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
, 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 . 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  as cured, completed treat-
ment, lost to follow-up and not evaluated (no fatal cases
nor failures). ‘Lost to follow-up’was further divided into
subgroups: physician’s decision to stop prematurely
(including cases that received ineffective treatment), and
defaulted (interruption due to the patient). Group ‘not
evaluated’was 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.
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  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 . 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 1–2 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
the cumulative risk of recurrence. The distribution of
continuous variables between groups was compared
using Wilcoxon rank-sum test.
The ethics approval for the study was given by the
Ethics Committee of Tampere University Hospital,
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], 56–79 years) for Finnish-born and 30 years (IQR
23–40 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], 85.6–148.9); for the first year of follow-up
the overall incidence was 236.4 (95%CI 140.0–399.2) 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 6–95 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, 1995–2013.
Non-tuberculous mycobacterium registered as M. tuberculosis
(N= 2), registration for false identity (N= 1) or incorrect registration date by the notifier (N= 10).
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,
Variable TB recurrence
No TB recurrence
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%)
Pulmonary site of disease
5599 (69.2%) 5605 (69.3%)
Culture positive n(%) 48 (96%)
6631 (82.5%) 6680 (82.6%)
Prior to year 2007 n(%) 45 (90%)
5762 (71.7%) 5807 (71.8%)
Origin known for 7862 cases
Origin known for 7912 cases
Data of the first episode
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 3 of 7
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 physician’s 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 2.7–11.1 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.
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 10–20 times higher, and for the first 2
years of follow-up 20–40 times higher than the inci-
dence of TB in the general population in Finland during
the study period . 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
Duration of treatment
Duration of treatment
Standard treatment A
15 NA 15 1 14
Standard treatment B
4NA4 2 2
Standard treatment with short intensive
33 NA2 1
Standard treatment D
14 0 14 1 13
Other probably effective combination of
Other probably ineffective combination of
Not evaluated 2 ––– –
NA not applicable, Hisoniazid, RRifampicin, Zpyrazinamide, Eethambutol
HRZ in intensive phase, HR in continuation phase, adequate duration of treatment ≥5.5 months
HRE in intensive phase, HR in continuation phase, adequate duration of treatment ≥8 months
Short intensive phase <54 days in standard treatment A or B
≥4 anti-TB drugs, including HRZ (adequate duration of treatment ≥5.5 months) or HRE (adequate duration of treatment ≥8 months)
Non-standard combinations guided by drug resistance or due to adverse effects, the adequacy of treatment duration assessed by the study group
Drug resistance ignored or inappropriate dosing
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 4 of 7
quality, as demonstrated in our study using a register with
proven high sensitivity and specificity for TB , 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
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, 1995–2013
Variables Univariate RR 95% CI pMultivariate RR 95% CI p
Males at 1 year
1,43 0,48–4,26 0,52 1,93 0,40–9,31 0,41
Males at 2 years
1,18 0,53–2,62 0,69 1,39 0,44–4,38 0,58
Males at 18 years
3,92 1,95–7,91 < 0,001 5,88 2,21–15,66 < 0,001
Pulmonary TB at 1 year
1,72 0,48–6,19 0,40 4,13 0,58–29,67 0,16
Pulmonary TB at 2 years
1,87 0,70–4,99 0,21 2,00 0,43–9,33 0,38
Pulmonary TB at 18 years
5,54 2,17–14,14 < 0,001 15,15 4,98–46,08 < 0,001
Age + 10 years 0,87 0,77–0,98 0,03 0,83 0,70–0,99 0,04
Finnish origin 0,64 0,31–1,33 0,23 –––
1.episode before 2007 1,33 0,81–2,21 0,26 –––
Reference females. Overall p-value for male gender in univariate analysis < 0,0001 and in multivariate analysis 0,0015
Reference extrapulmonary TB. Overall p-value for pulmonary TB < 0,0001
Korhonen et al. BMC Infectious Diseases (2017) 17:721 Page 5 of 7
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 , 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 .
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 . 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 physician’s decision to stop without the reason
being documented in the patient record.
cohort, with a median follow-up period of 6 years,
and up to 18 years, was 113/100000, 10–20 times
higher than for the general population in Finland, in
line with long-term follow-up in low-incidence coun-
tries (71–410/100000) [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  and Denmark , but
clearly lower than in a number of earlier studies from
industrialised countries .
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 [23–25], 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
. 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 .
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  or age
between 25 and 64 years  have been reported as risk
factors for recurrence. In earlier studies, either being an
immigrant [16, 20, 25] or being borne in the country 
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 . There-
fore, we chose this timepoint as a cut-off for recurrence,
in line with eg a large UK cohort . 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 . 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 , 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 2013–2015,
treatment outcome in Finland was successful (cure or
completed treatment) in 75–78% of pulmonary TB cases
, as in the European Region on average .
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.
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
NIDR: National infectious disease register; NRL: Mycobacterial reference
laboratory; TB: Tuberculosis; THL: National Institute for Health and Welfare
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.
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
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
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Department of Health Security, National Institute for Health and Welfare,
Department of Pulmonary Diseases, Tampere University
Hospital, Tampere, Finland.
School of Medicine, University of Tampere,
33014 Tampere, Finland.
Finnish Lung Health Association (Filha), Helsinki,
Faculty of Medicine, University of Turku, Turku, Finland.
Department of infectious diseases, Public health laboratory, GGD
Amsterdam, Amsterdam, The Netherlands.
Received: 13 April 2017 Accepted: 5 November 2017
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