We describe here the identification of the most prevalent M. tuberculosis strain in the West Midlands, which we have termed the Mercian strain. Concordant MIRU-VNTR and RFLP data from six different geographical locations across the West Midlands indicated that this strain is present in 3 major cities. Regional, national, and global genotyping databases provided evidence that this strain was restricted to the West Midlands region in England. Regional data showed that this strain primarily infected UK-born, Black Caribbean patients less than 65 years old.

The regional and Wolverhampton epidemiological investigations presented in this report identified significant associations for the Mercian strain. However, they do not provide a full explanation of why the Mercian strain is more prevalent compared to other strains in the West Midlands. Drug and alcohol use were identified as significant social factors in Wolverhampton. Alcohol and drug use have been identified as significant associations in previously reported tuberculosis outbreaks particularly in low-incidence countries [19]–[22]. The cumulative number of cases and continuing presence of the Mercian strain does not follow a typical point-source outbreak pattern. The significant association with younger age suggests that cases caused by the Mercian strain have arisen as a result of recent transmission and not re-activation in older patients. A possible transmission scenario is that after the initial emergence of the Mercian strain there have been several independent clusters of transmission each with their own common social link. This has resulted in a large, complex social network where transmission persists and the complete transmission scenario is yet to be fully elucidated.

Both epidemiological investigations presented in this report were retrospective and did not involve direct patient interviews. The Mercian strain continues to be identified in the West Midlands which means that enhanced epidemiological knowledge could be obtained by prospectively investigating social links as each new patient is diagnosed. Investigation of potential factors which may cause a delay in diagnosis should be investigated as well. The data presented by us identified the infected patient population and also important common social factors. The exact interaction of patient population and social factors should be investigated further to identify and fully understand any confounding factors.

It must be noted that the Wolverhampton epidemiological investigation applied a detailed questionnaire that was only used in this location. Of the three major cities in the West Midlands, Wolverhampton had the highest proportion of the Mercian strain (21%). Patients with the Mercian strain in Birmingham and Coventry might differ in their use of drugs and alcohol. The results from the Wolverhampton and region-wide analysis do not concord exactly as different ethnic population groups were identified as at highest risk: the White population in Wolverhampton but the Black Caribbean group across the West Midlands.

Detection of this strain was only possible with the commencement of universal prospective typing of all M. tuberculosis isolates in the West and East Midlands. Only with universal prospective DNA fingerprinting was the full extent of the Mercian strain in the West Midlands fully characterized. Since the Mercian strain is not a drug-resistant strain without associated phenotypic properties that could differentiate it from other M. tuberculosis complex strains, it would only have been possible to detect this strain by universal prospective typing. The patient population in which the Mercian strain has been identified is different to the UK-wide situation for TB as the majority of patients diagnosed each year in the UK are not born in the UK and originate from the Indian Sub-Continent [9].

The 156 individual patients detected between 2004 and 2008, make the Mercian strain one of the largest known community-based clusters in the world. Previous major prevalent strains have been identified in New York [23], [24], Rotterdam [25], North London [3], and Rio de Janeiro [26].

The most prevalent strain detected in the UK was an isoniazid resistant strain in North London that was previously reported in 70 patients [3], with a current total of over 300 cases caused by this strain (Ibrahim Abubakar, Consultant Epidemiologist & TB Section Head, Respiratory Diseases Department - Tuberculosis Section, Health Protection Agency, personal communication). Isoniazid resistance acted as a very useful marker for detection of the strain. It was noted that without the drug resistance marker only prospective typing of all isolates would have detected this large, complex outbreak. This strain was predominantly found in young White or Black Caribbean UK-born adults with drug misuse as a common epidemiological factor [3]. It is possible that patients in this population group take longer to present clinically as TB may not be suspected when initial symptoms develop or they might not seek medical help soon after onset. Both factors aid strain transmission and disease progression.

A strain was identified in 93/314 (30%) patients in Rio de Janeiro that uniquely lacked a major region of genomic DNA (>26.3 kb) which contained 10 genes including two potentially immunogenic PPE genes [26], [27]. The RD^Rio strain was associated with a higher frequency of cavitary pulmonary disease [28]. The major deletion identified in the RD^Rio strain has been hypothesized as having a major impact on the virulence properties of the RD^Rio strain. As the genomic content of the Mercian strain has not been characterized, further work should determine whether such a deletion or other similar major genomic variation has altered the virulence of this strain leading to multiple transmission events in and between three cities in the West Midlands.

Retrospective epidemiological studies have identified the earliest isolate of the Mercian strain from 1995 in an archive strain collection. This isolate was part of a cluster of 11 isoniazid resistant strains identified between 1995 and 2000 which was reported previously before the full regional extent of the Mercian strain was known [2]. We have typed very few archived M. tuberculosis strains from 1995 so the full extent of drug sensitive and drug resistant Mercian strains 15 years ago has not yet been assessed. The cluster of isoniazid resistant Mercian strains was present in one specific location. From 1995–2000, there was no other investigated instance of increased isoniazid resistance in the rest of the West Midlands caused by the Mercian strain.

As the Mercian strain has been present since prospective DNA fingerprinting was commenced in 2004 with a median of 30 isolates per year (range 27–37) and has represented a consistent proportion of strains (Figure 1), it is likely that the Mercian strain first emerged in the West Midlands well before 2004.

Universal prospective DNA fingerprinting is an essential part of many countries TB control programs as it has been used to estimate transmission in specific populations groups. The Netherlands have undertaken universal prospective DNA fingerprinting of all M. tuberculosis isolates since 1993 [29]. This enabled the identification of transmission after migration in patients recently arrived in the Netherlands as infections in 30% to 40% of Turkish, Moroccan, and Somali patients could be attributed to recent transmission [29].

Secondly, it has also been shown in the Netherlands that combining data obtained from nationwide tuberculosis contact investigation and DNA fingerprinting surveillance greatly increased the number of defined epidemiological links. In 2,206 clustered cases, DNA fingerprinting increased the number of epidemiologic links from 462 before DNA fingerprinting data was known to 1,002 epidemiologic established links after cluster investigation involving a combination of molecular and epidemiological data. DNA fingerprinting did not increase the number of patients identified as contacts but cluster monitoring did enable the identification of transmission events not detected by contact investigations, the development and evaluation of focused interventions and evaluation of regional tuberculosis eradication programs [30]. A study in Maryland showed that cluster investigation including DNA fingerprinting analysis identified 43/113 (38%) of all detected patient links. [31] .

A more recent study showed that DNA fingerprinting data could be used to prospectively identify rapidly expanding clusters before expansion actually occurred based on the properties of the first two patients in a cluster. If the first two patients in a cluster were identified within 3 months of each other, one or both were <35 years old, and both patients resided in an urban area and originated from Sub-Saharan Africa, there was a more than 5 times increased probability that this strain in an initial cluster of two paired patients would be identified in 5 or more patients within 2 years [32].

We describe here the identification of the most prevalent M. tuberculosis strain in the West Midlands region of the UK, with 156 isolates in a 5 year period between 2004 and 2008. The Mercian strain has been significantly associated with UK-born patients, appears to be geographically restricted to the West Midlands region in the UK with evidence of ongoing transmission.