Introduction

Finland had a very severe tuberculosis (TB) epidemic in the beginning of the 20^th century, with respiratory TB mortality rates of 250-300 per 100,000 [1]. After the Second World War, TB mortality rates started to decline reaching 51 per 100,000 in 1951. This rapid decrease was related to an improved standard of living, effective TB control program and availability of TB medication [1]. In 2001, Finland became a low incidence country when TB incidence fell below 10 per 100,000, and in 2012 the TB incidence was 5/100,000.

However, the epidemiological situation in Finland is different from neighboring low incidence countries. In Sweden, Norway and Denmark, a transition took place from the native population to foreigners, that currently account up to 80% of the new TB cases [2–4]. In Finland, most cases are still Finnish born but the number of foreign born cases is steadily increasing over time. In our neighboring countries in the East and South, the TB incidence is high and predominantly associated with Mycobacterium tuberculosis isolates belonging to the Beijing genotype family [5]. Multidrug resistant (MDR) TB is a significant problem in Russia and Estonia, while in Finland this remains a rare occurrence [6–8]. Puustinen et al. showed that M. tuberculosis isolates belonging to the Beijing lineage were infrequently encountered in Finland [9]. However, MDR-TB cases will most likely increase in Finland as well, because of the rapid spread of the Beijing lineage across Europe and increasing immigration to Finland.

To better understand the current epidemiology of TB in a country with a history of high TB incidence, the aim of the study was to evaluate the current TB situation in Finland by genotypic characterization of M. tuberculosis complex isolates. Our first objective was to use the typing data to provide a general overview of the genotypes retrieved from TB cases in Finland, and compare the situation in Finland to our neighboring countries.

Materials and Methods

Since 1995, the reporting of approximately 70 infectious diseases, including TB, to the National Infectious Disease Registry has been mandatory for physicians and clinical microbiology laboratories in Finland [8]. In addition, all M. tuberculosis complex isolates are sent to the Mycobacterial Reference Laboratory at the National Institute for Health and Welfare (THL) for species confirmation, genotyping, drug susceptibility testing, and strain collection.

Results

Of the 1048 patients, 733 (69.9%) were born in Finland, 264 (25.2%) were foreign born and for 51 (4.9%) patients the place of birth was unknown. 481 patients were ≥65 years old (45.9%) and the median age of the patients was 61 years (range: 0-103), and 601 (57.3%) patients were male.

M. tuberculosis genotypic lineages

The most common TB lineages found from the Finnish isolates were T (n=346, 33.0%) and Haarlem (n=237, 22.6%) (Table 1 and Figure 1). For 130 isolates (12.4%) the lineage could not be defined (i.e. was unknown). Out of the 130 isolates, 103 (79.2%) were obtained from Finnish born patients. Based on phylogeographical mapping, the distribution of lineages closely resembles the distribution seen in Sweden (Figure 2). The main difference was for the Ural lineage, which according to the SITVIT2 database, was not regularly found in Sweden. Both Ural-1 and Ural-2 (42 and 18 isolates respectively) were predominantly found among Finnish born cases (50/60, 83.3%). Additionally, isolates not belonging to any known lineage (i.e. undefined clade) were found more commonly among Finnish born (n=103, 79.2%) than foreign born patients (n=25, 19.2%) (p: <0.05).

Lineage	Total	Finnish-born	Foreign-born	Unknown origin	Median age	Pulmonary	Extra-pulmonary	Pan-susceptible	Drug resistant	MDR
AFRI	3	0	2	1	33	1	2	3	0	0
Beijing	55	11	40	4	34	41	14	31	14	10
BOV	1	0	1	0	25	0	1	0	1	0
Cameroon	1	0	1	0	42	1	0	1	0	0
CAS	44	6	33	5	27	22	22	33	8	3
EAI	70	5	53	12	31	34	36	53	17	0
Haarlem	237	214	20	3	73	143	94	217	19	0
LAM	77	65	10	2	55	57	20	73	3	1
Manu	1	0	1	0	24	0	1	1	0	0
S	14	6	5	3	50	7	7	12	1	1
T	346	268	63	15	66	201	145	325	19	1
Turkey	3	3	0	0	64	0	3	3	0	0
Unknown	130	103	25	2	64	75	55	115	14	1
Ural	60	50	6	4	71	40	20	56	4	0
X	6	2	4	0	66	3	3	6	0	0
	1048	733	264	51		625	423	929	100	17

Table 1. An overview of the lineages found in Finland, 2008-2011.

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Figure 1. Cluster analysis of all isolates found in this study.

Colors of nodes depict the lineage of the strain.

https://doi.org/10.1371/journal.pone.0085027.g001

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Figure 2. Phylogeographical distribution of M. tuberculosis lineages in neighboring countries.

Colors of nodes depict the lineage of the strain. Note that the proportion of Ural lineage (notably Ural-1) is not negligible in the following countries: Russia, Latvia, Estonia, and Finland [11].

https://doi.org/10.1371/journal.pone.0085027.g002

A minimum spanning tree using spoligotyping and MIRU as categorical data shows the phylogenetic similarity of the M. tuberculosis strains. The 68 isolates with a spoligotype only found in Finland (F-type) were mostly unlinked and seemed phylogenetically remote to SIT strains (Figure S1 ; Hierarchical layout shows that F-types appear at terminal position in this Spoligoforest).

Discussion

This study provides an update of the molecular epidemiology of TB in Finland. The 4-year nationwide data showed that the majority of the TB cases were Finnish born and a large proportion was aged 65 or older. This is uncommon for a low TB incidence country, as can be seen, for example in Sweden or Denmark where the vast majority of TB cases are immigrants [2,4]. This is primarily explained by a different immigration situation of these countries, as in Sweden and Denmark 10% of the population is born abroad, while the corresponding figure in Finland is less than 3%. This could also be the reason why there seems to be less transmission in Finland between foreign and Finnish born cases, compared to Sweden and Denmark [3,4].

In Finland, a relatively high clustering rate (33.9%) was noted compared to Sweden (23.6% using MIRU-VNTR and spoligotyping) [12]. Clustering rate was higher among Finnish born than immigrant cases, which was also found in Denmark using a different methodology [4]. The interpretation of clustering in population based studies is complicated, particularly if it covers stable urban and rural populations. While clustering is associated with recent transmission in urban settings, it is more complicated to interpret on population levels due to possible predominance of certain well-preserved strains in the population [13,14]. Additionally, Finland – and other Nordic countries- had endured a very high tuberculosis incidence before the second world war [1]. As reported from Sweden and Norway, certain lineages (Haarlem and T) were predominately found among elderly cases, suggesting that these lineages were most likely associated with the epidemic during the first half of the 20^th century [15,16]. As found in this study, Haarlem and T were also the most common lineages found among Finnish born TB cases. The relatively high rate of clustering could partly be explained by well conserved strains in the Finnish population.

The overall analysis shows that the isolates belonged to many different genotypic lineages, reflecting the wide variety of M. tuberculosis strains circulating in Finland. The most common lineages were T and Haarlem as in the case in the rest of Western Europe [10], although for many isolates the lineage was unknown. Based on phylogeographical analysis, the distribution of TB lineages in Finland seems to be similar to Sweden, but not to the other neighboring countries. The main difference between the lineages in Sweden and Finland was the presence of the Ural lineage in Finland (5.7% of isolates). The relatively recently named Ural lineage [17] was primarily found among Finnish born cases. This lineage is common in Estonia, Russia, and Latvia (Figure 2). Certain lineages such as Beijing, which is dominant in Russia, was barely seen in Finland 12 years ago and is now one of the more common lineages [9]. MDR-TB is still rare and most of the isolates belonged to the Beijing lineage.

Almost all lineages were seen in both foreign born and Finnish born patients, but only one large cluster was shared by the two groups, suggesting that transmission of TB between Finns and foreigners does not occur frequently. In-depth cluster analysis and epidemiological research is warranted to investigate this conclusively.

Although the majority of our isolates could be genotyped and classified successfully, many of the spoligotypes and MIRU profiles found in this study were not recognized in the international databases. We identified 68 isolates with spoligopatterns that were exclusively encountered in Finland (F-type), and of those 51 were orphan spoligotypes. This could be due to information lacking in the databases or could reflect the unique nature of Finnish M. tuberculosis isolates. These strains were genetically distinct from the more common SIT strains, but more research is needed to explore this in-depth.

In conclusion, a large proportion of the M. tuberculosis isolates seen in Finland originated from Finnish born elderly patients. Moreover, many previously unidentified spoligotype profiles and isolates belonging to unknown lineages were encountered. Based on these study results, the TB situation in Finland is different from other low incidence countries. More research and in-depth assessment is needed to obtain a better insight in the unusual TB situation in Finland.

Supporting Information

Acknowledgments

The authors would like to thank Anna Musku, Tiina Nurmio, Elisa Rehnberg, and Arto Talvitie for their contribution in analyzing the isolates. Additionally, we would like to thank Aftab Jasir for critically reading the manuscript.