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 treatment, recurrent TB is estimated to occur in 0–14% of all TB patients within 1–3 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% [
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 [
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].
Our previous study shows, that in Finland more than 80% of recurrent cases during 1995–2013 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 1995–2013. In recurrent cases, we describe treatment regimens administered 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.
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 10–20 times higher, and for the first 2 years of follow-up 20–40 times higher than the incidence of TB in the general population in Finland during the study period [
7]. Patient chart review of the recurrent 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 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 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 recurrent 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 prematurely, as described in our previous report [
12]. Inadequate treatments were caused by the presence of drug resistance without appropriate treatment regimen modification, 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.
The overall incidence of recurrence in the national 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 countries (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 [
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 [
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 [
20]. We found in the national cohort the risk of recurrence 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]. Therefore, 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 recurrences 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 treatment 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 2013–2015, treatment outcome in Finland was successful (cure or completed treatment) in 75–78% of pulmonary TB cases [
7], as in the European Region on average [
27].