ABSTRACT
Background: A context-specific, spatial-temporal understanding of a chain of tuberculosis (TB) transmission can inform TB elimination strategy.
Methods: Clinical, public health and molecular epidemiologic data were used to: 1) identify and describe a complex cluster of TB cases in Alberta, 2) elucidate transmission sequences, and 3) assess case-patient mobility. Socio-economic indicators in loci of transmission and the province at large were described. Factors seen to be fostering or hampering TB elimination were identified.
Results: Over a 15-year period, 18 TB cases in Alberta and multiple cases in the Northwest Territories were determined to be due to the same strain. One patient was diagnosed at death; all others completed directly-observed therapy (DOT). Case-level analysis revealed that patients were highly mobile with transmission of the strain over 26,569 km^sup 2^, an average of 2.8 different places of residence per patient during treatment, and contacts of sputum smear-positive cases spanning 9 of 17 regional health authorities. The majority of the contacts (57%) were attached to a single infectious case living in a homeless shelter. The three loci of transmission in Alberta were separated geographically but similar in terms of median incomes, rates of unemployment, levels of post-secondary education, and rates of population mobility (p<0.0001).
Conclusion: Upon review of the experience, central oversight, intra- and inter-jurisdictional coordination and DOT were seen as fostering, and the absence of 'real-time' DNA fingerprinting, social network analysis, engineering controls in shelters and better determinants of health in loci of transmission were seen as hampering TB elimination.
Key words: Tuberculosis; transmission; molecular epidemiology; socioeconomic indicators
La traduction du r�sum� se trouve � la fin de l'article.
Can J Public Health 2010;101(3):205-9.
R�SUM�
Contexte : La connaissance spatio-temporelle et contextuelle d'une cha�ne de transmission de la tuberculose pourrait �tayer la strat�gie d'�limination de cette maladie.
M�thode : � l'aide de donn�es cliniques, de sant� publique et d'�pid�miologie mol�culaire, nous avons : 1) mis en �vidence et d�crit une concentration complexe de cas de tuberculose en Alberta, 2) �lucid� les s�quences de transmission et 3) �valu� la mobilit� des cas patients. Nous d�crivons les indicateurs socio�conomiques sur les lieux de transmission et dans le reste de la province. Les facteurs qui semblent favoriser ou entraver l'�limination de la tuberculose sont indiqu�s.
R�sultats : Sur une p�riode de 15 ans, il a �t� d�termin� que 18 cas de tuberculose relev�s en Alberta et plusieurs cas dans les Territoires du Nord-Ouest avaient la m�me souche. L'un des patients a �t� diagnostiqu� apr�s sa mort; tous les autres ont re�u un traitement directement observ� (TDO). L'analyse par cas montre que les patients �taient tr�s mobiles : la souche s'est propag�e sur 26 569 km2, chaque patient a eu en moyenne 2,8 lieux de r�sidence durant son traitement, et les contacts des cas dont les frottis de crachat �taient positifs couvraient 9 des 17 r�gies r�gionales de la sant�. La majorit� des contacts (57 %) �taient rattach�s � un m�me cas infectieux h�berg� dans une maison pour sans-abri. Les trois lieux de transmission en Alberta �taient �loign�s g�ographiquement, mais semblables pour ce qui est des revenus m�dians, des taux de ch�mage, des niveaux d'�tudes postsecondaires et des taux de mobilit� de la population (p<0,0001).
Conclusion : Selon notre analyse, les facteurs favorisant l'�limination de la tuberculose sont la surveillance centrale, la coordination intra- et interprovinciale et le TDO. Les facteurs entravant l'�limination de la tuberculose sont l'absence d'identification � en temps r�el � par le code g�n�tique, l'absence d'analyse des r�seaux sociaux, l'absence de mesures techniques dans les maisons de refuge et l'absence de meilleurs d�terminants de la sant� dans les lieux de transmission.
Mots cl�s : tuberculose; transmission; �pid�miologie mol�culaire; indicateurs socio�conomiques
The World Health Organization Global Plan to Stop TB: 2006- 2015 aims to halve by 2015 the prevalence of TB reported in 1990.1 Consistent with this goal, the Canadian Tuberculosis Committee of the Public Health Agency of Canada set a target Canadian TB incidence rate of 3.6 per 100,000 persons (one-half the incidence rate in Canada in 1990) for 2015.2 So far, the achievement of this goal has been hampered by sustained high rates of TB in Aboriginal peoples and the foreign-born. Strategies aimed at eliminating TB focus on interrupting transmission and preventing TB in persons already infected.2
This study is focused on the Canadian-born and describes in detail and places into context a complex cluster (chain of transmission) of TB cases in Alberta. Further, it uses the exercise to inform TB elimination strategy. A cluster of TB cases is one whose causative isolates of Mycobacterium tuberculosis share a common DNA fingerprint, suggesting a transmission link between them.3 In instances where housing is unstable and patients may not know the names and locations of contacts, studies that incorporate DNA fingerprinting of isolates have provided insight into spatial and temporal patterns of transmission as well as factors that might contribute to rapid progression of disease.4-8 In addition to DNA fingerprint data, contact tracing, mobility and socio-economic data were used to further describe the chain of transmission and interpret its implications for TB elimination.
METHODS
This study was performed in Alberta, a province of Western Canada having a population of 2.94 million in 2001 (Statistics Canada) and where the majority of First Nations (66%) are living on-reserve (Indian and Northern Affairs Canada, 2001). In Alberta, initial isolates of M. tuberculosis are DNA fingerprinted in the Provincial Laboratory for Public Health using restriction fragment-length polymorphism (RFLP) supplemented by spoligotyping as necessary. 9,10 Over the 17-year period 1991-2007, all large clusters - defined as those having 15 or more case-patients - were identified and described according to the age, sex, population group (Aboriginal [First Nations, M�tis, Inuit], Canadian-born non-Aboriginal and foreign-born) and place of residence (on-reserve or off-reserve) of their constituent members. One large cluster was selected for study. To assess the inter-jurisdictional spread of this cluster strain, it was compared to all isolates from the Northwest Territories (NWT) in 1993-2001 (n=122) and all isolates from British Columbia (BC), Saskatchewan and Manitoba in 1995-1997 (n=944).11
Case and contact analysis
Public health and hospital records of cluster cases were reviewed retrospectively. Cases were described according to age, sex, population group, date of diagnosis (the start date of treatment), place of residence at diagnosis (city borough, reserve community), disease site (pulmonary or extra-pulmonary), sputum smear status (positive or negative), chest radiograph status (cavitary or non-cavitary), risk factors for reactivation and outcome.2 Epidemiologic links, defined as likely exposure to another case of TB within the cluster within 2 years of diagnosis, were categorized as 'Type 1': clear epidemiologic links confirmed at the time of diagnosis by traditional contact tracing or review of case records or 'Type 2': unclear epidemiologic links, connection based on place of residence at diagnosis, molecular genotyping and diagnosis date within 2 years of another case in the cluster. Results are presented in diagrammatic format to maintain the anonymity of cases and communities.
Contact summary reports for each case were reviewed to identify potential linkages within the cluster (contact tracing had been performed by public health nurses in accordance with the recommendations of the Canadian Tuberculosis Standards).2 Data extracted from contact tracing included total number of contacts, the nature of their association to the source case (close, casual, or other) and geographical location. Contacts were assigned to one of 17 geographical locations based on residence and Regional Health Authority (RHA) divisions used in the province up until 2003. Locations of contacts were tabulated by patient, and average distances of contact locations from source locations were calculated, based on residence at diagnosis.
Mobility analysis
Three indicators were used to assess the mobility of cases: 1) documented out-of-province travel or change of address during treatment for active TB, 2) history of homelessness evidenced by record of residence in a publicly operated shelter in the 12 months preceding diagnosis or during treatment for active TB and 3) geographical location of contacts.
Community-level analysis
Loci of transmission were assigned according to address and postal code at diagnosis. The major locus of transmission in Edmonton consisted of three adjoining census areas; in Calgary one census area. Data were obtained from the 2001 census on total population, income, employment, and population mobility for crude comparison of area-based socio-economic measures between loci of transmission and the province at large.
Statistical analysis
The statistical significance of differences between area-level indicators was assessed using chi-squared tests for proportions and t-tests for quantitative variables with STATA, version 9.2. The study was approved by the Health Research Ethics Board of the University of Alberta.
RESULTS
Between 1991 and 2007, there were 1,926 cases of culture-positive TB in Alberta; 404 (21.0%) in Aboriginal peoples, 262 (13.6%) in Canadian-born non-Aboriginal peoples and 1,260 (65.4%) in foreignborn peoples. Initial isolates from 1,880 (97.6%) cases were DNA fingerprinted and 7 large clusters identified (Table 1). Subsets of clusters 'C' and 'G' had been reported previously.12 Cluster 'D' was chosen as being the most likely to inform TB elimination strategy. It involved four different population groups and a drug-susceptible strain; its extent was unrecognized at the time (routine and catchup [historical isolates] RFLP typing did not begin until later). All cluster cases occurred within 2 years of each other. Between 1993 and 2001, there were multiple (>10) NWT cases with the same strain. Between 1995 and 1997, there were no BC, Saskatchewan and Manitoba cases with the same strain. The incidence of TB in Alberta was 6.7 and 3.2 per 100,000 persons in 1991 and 2007, respectively.13
Case and contact analysis
Most of the 18 Cluster "D" cases were young (median age 39 years), male (72.2%), and Aboriginal (72.2%) (Table 2). All had pulmonary or pleuro-pulmonary TB. Three cases had 1 and five cases had 2 independent determinants of infectiousness (sputum smear positivity and cavitation on chest radiograph).14 Fourteen patients were HIV tested and negative; non-tested patients had no record of a positive HIV test result in the provincial HIV database up to the end of 2007. Substance abuse was very common (88.2% of the adult cases). Intra- and inter-jurisdictional management was well coordinated and all but one case (#4 who was diagnosed at death) completed directly observed treatment (DOT).15 Three loci of transmission were identified: a reserve community, an Edmonton borough, and a Calgary borough, spanning 26,569 km2 (Figure 1). Ten cases had 'Type 1' and 7 cases had 'Type 2' transmission links.
Most contacts (57.0% of 1,080) were attached to a single highly infectious homeless shelter resident (#8). Many (24.4%) of this case's contacts were already known to be tuberculin skin test (TST) positive. Most of the 254 non-assessed case contacts (186 or 73.2%) were contacts of this case. Of the 71 new TST positive/TST converted contacts of this patient, 58 (81.7%) were recommended, 30 (42.3%) accepted, and 16 (22.5%) completed treatment of latent tuberculosis infection (LTBI). Close contacts were more likely than those who were casual or 'other' to have a new positive TST or TST conversion, 51.3% versus 31.3% versus 20.4%, respectively (Table 3).
Case mobility
On average, the five most infectious cases and all cases changed addresses 4 times and 2.8 times, respectively, during treatment. Five patients had a history of shelter living before and 3 during treatment; shelters were without engineering controls. Three cases (case #s 1, 7, and 14) originated from an NWT band and had a documented history of travel to the NWT either prior to diagnosis or during treatment. Contacts of sputum smear-positive cases were widely distributed, involving 9 of 17 RHAs.
Area-based socio-economic indicators
Median household income and rates of higher education were lower and unemployment rates and population mobility higher in the transmission loci than in the province at large, p<0.0001 (Table 4).
DISCUSSION
At a time when the overall incidence of TB in Alberta was falling, sustained transmission was occurring in a difficult-to-reach population. Cluster cases were from multiple population groups, occurred over an extended period of time, and with few exceptions were not connected one with another at the time. Though cluster cases were HIV negative and the cluster strain drug-susceptible, there was ongoing intra-jurisdictional transmission between three loci in Alberta and inter-jurisdictional transmission between Alberta and the Northwest Territories. Upon review of the experience, central oversight, integrated case management and DOT were seen as fostering TB elimination. The absence of 'real-time' DNA fingerprinting (see definition of 'real-time' in next paragraph), social network analysis, and engineering controls in shelters and the presence of poor determinants of health in loci of transmission were seen as sustaining the outbreak and hampering TB elimination.
In contrast to outbreaks in isolated or semi-isolated reserve communities which rely on conventional epidemiology - sometimes to the point of screening 'community contacts' - complex outbreaks such as the one reported here rely on molecular epidemiology, geographical-spatial analysis, and the application of unconventional contact-tracing paradigms for investigation.12,16-22 They can be much more challenging. Clearly, it would have been helpful to have recognized the extent of the outbreak earlier. In this regard, newer, polymerase-chain-reaction-based methods of genotyping M. tuberculosis (for example, "mycobacterial interspersed repetitive-unit-variable number tandem repeats" [MIRU-VNTR]) offer the promise of 'real-time' (results in 1 to 2 weeks [national], versus 2 to 12 weeks for RFLP [provincial]) intra- and interjurisdictional outbreak detection.23-26 Such genotyping can also unmask the role that social networks play in disease transmission and the extent to which failure to consider unnamed contacts can lead to missed cases. Disease control in the context of social networks requires identification of groups of persons who share similar social settings and mores with infected people. Once these groups are identified, testing and treatment is offered not only to the infected person and the few named contacts, but to the entire network. This approach improves rapport with clientele, helps eliminate stigma, and identifies persons who may have otherwise been missed.27,28
Such strategies might have minimized the effect of case-patient mobility which was substantial. In general, high degrees of mobility are seen in young adults and those with unstable or transient living conditions.29 With respect to the former, migration of First Nations off-reserve is known to have a clear age pattern with young adults being the most mobile. Two of the most infectious First Nations cases were mobile across jurisdictions. With respect to those with unstable or transient living conditions, 57% of the contacts were attached to a single highly infectious shelter resident. Shelter contacts are difficult to assess (30% of this patient's contacts went unassessed), subject to re-infection (8 of the cluster cases had a history of TB or a positive TST) and difficult to treat if infected (only 22.5% of this patient's newly infected/TST-converted contacts completed treatment of LTBI). Engineering controls such as ultraviolet light might have reduced transmission had they been present in the shelter in question.30 Mandated compliance with TB screening, as a condition of admission, and spot sputum screening are strategies that have been used with success in homeless shelters in the United States.31,32
Our crude comparison of socio-economic indicators at the community level suggested a link between TB and social determinants of health. TB cluster size and social disadvantage are known to be associated.33 Substance abuse was a common risk factor among casepatients; excessive alcohol use is known to be disproportionately high in clustered patients.23 Substance abuse is the most commonly reported modifiable behaviour impeding TB elimination efforts in the United States.34 Poor socio-economic conditions and substance abuse have been linked; together they may contribute to delayed diagnosis and more advanced disease (greater transmission) at presentation.
The major limitation of this study is its retrospective design, requiring the use of proxies for mobility analysis and aggregate data for area-based analysis.
In conclusion, as TB rates continue to decline, an increasing proportion of cases are likely to occur in difficult-to-reach populations. New technology and better understanding of complex chains of transmission can expose barriers to TB elimination.
[Reference]
REFERENCES
1. Stop TB Partnership and World Health Organization. Global Plan to Stop TB 2006-2015. WHO/HTM?STB/2006.35. Geneva, Switzerland: World Health Organization, 2006.
2. The Canadian Lung Association and the Public Health Agency of Canada. The Canadian Tuberculosis Standards, 6th Edition, 2007. Available at: http://www.publichealth.gc.ca/tuberculosis (Accessed August 4, 2009).
3. Barnes P, Cave D. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56.
4. Nolan CM, Elarth AM, Barr H, Saeed AM, Risser DR. An outbreak of tuberculosis in a shelter for homeless men. A description of its evolution and control. Am Rev Respir Dis 1991;143:257-61.
5. Barnes P, El-Hajj H, Preston-Martin S, Cave D, Jones BE, Otaya M, et al. Transmission of tuberculosis among the urban homeless. JAMA 1996;275:305-7.
6. Curtis AB, Ridzon R, Novick LF, Driscoll J, Blair D, Oxtoby M, et al. Analysis of Mycobacterium tuberculosis transmission patterns in a homeless shelter outbreak. Int J Tuberc Lung Dis 2000;4:308-13.
7. Lathan M, Mukasa LN, Hooper N, Golub J, Baruch N, Mulcahy D, et al. Crossjurisdictional transmission of Mycobacterium tuberculosis in Maryland and Washington, DC, 1996-2000, linked to the homeless. Emerg Inf Dis 2002;8:1249-51.
8. Klovdahl AS, Graviss EA, Yaganehdoost A, Ross MW, Wanger A, Adams GJ, et al. Networks and tuberculosis: An undetected community outbreak involving public places. Soc Sci Med 2001;52:681-94.
9. van Embden JDA, Cave MD, Crawford JT, Dale JW, Eisenach KD, Gicquel B, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: Recommendations for standardized methodology. J Clin Microbiol 1993;31:406-9.
10. van Soolingen D. Molecular epidemiology of tuberculosis and other mycobacterial infections: Main methodologies and achievements. J Intern Med 2001;249:1-26.
11. FitzGerald JM, Fanning A, Hoeppner V, Hershfield E, Kunimoto D and the Canadian Molecular Epidemiology of TB Study Group. The molecular epidemiology of tuberculosis in Western Canada. Int J Tuberc Lung Dis 2003;7:132-38.
12. Long R, Whittaker D, Russell K, Kunimoto D, Reid R, Fanning A, et al. Pediatric tuberculosis in Alberta First Nations (1991-2000): Outbreaks and the protective effect of Bacille Calmette-Gu�rin (BCG) vaccine. Can J Public Health 2004;95:249-55.
13. Public Health Agency of Canada. Tuberculosis in Canada 2007 - Pre-release. Available at: http://www.publichealth.gc.ca/tuberculosis (Accessed August 4, 2009).
14. Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis. MMWR 2005;54(RR15):1-37.
15. Long R. Tuberculosis control in Alberta. Can J Public Health 2002;93:264-66.
16. Mah MW, Fanning EA. An epidemic of primary tuberculosis in a Canadian Aboriginal community. Can J Infect Dis 1991;2:133-41.
17. Marks SM, Taylor Z, Qualls NL, Shrestha-kuwahara RJ, Wilce MA, Nguyen CH. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 2000;162:2033-38.
18. Sebek M. DNA finger printing and contact investigation. Int J Tuberc Lung Dis 2000;4(2):S45-S48.
19. Reichler MR, Reves R, Bur S, Thompson V, Mangura BT, Ford J, et al. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 2002;287:991-95.
20. Mohle-Boetani JC, Flood J. Contact investigations and the continued commitment to control of tuberculosis. JAMA 2002;287:1040-42.
21. Weis S. Contact investigations. How do they need to be designed for the 21st century? Am J Respir Crit Care Med 2002;166:1016-17.
22. Daley CL, Kawamura LM. The role of molecular epidemiology in contact investigations: A US perspective. Int J Tuberc Lung Dis 2003;7:S458-S462.
23. Dunlap NE. The use of RFLP as a tool for tuberculosis control: Utility or futility. Int J Tuberc Lung Dis 2000;4(12):S134-S138.
24. Sterling TR, Thompson D, Stanley RL, McElroy PD, Madison A, Moore K, et al. A multi-state outbreak of tuberculosis among members of a highly mobile social network: Implications for tuberculosis elimination. Int J Tuberc Lung Dis 2000;4:1066-73.
25. McElroy PD, Rothenberg RB, Varghese R, Woodruff R, Minns GO, Muth SQ, et al. A network-informed approach to investigating a tuberculosis outbreak: Implications for enhancing contact investigations. Int J Tuberc Lung Dis 2003;7(Suppl 3):S486-S493.
26. van Deutekom H, Hoijng SP, de Haas PEW, Langendam MW, Horsman A, van Soolingen D, et al. Clustered tuberculosis cases - Do they represent recent transmission and can they be detected earlier? Am J Respir Crit Care Med 2004;169:806-10.
27. Fitzpatrick LK, Hardacker JA, Heirendt W, Agerton T, Streicher A, Melnyk H, et al. A preventable outbreak of tuberculosis investigated through an intricate social network. Clin Infect Dis 2001;33:1801-6.
28. Cook VJ, Sun SJ, Tapia J, Muth SQ, Arg�ello F, Lewis BL, et al. Transmission network analysis in tuberculosis contact investigations. JID 2007;196:1517-27.
29. Norris MJ, Cooke N, Clatworthy S. Aboriginal mobility and migration patterns and the policy implications. In: White JP, Maxim PS, Beavon D (Eds.), Aboriginal Conditions: Research as a Foundation for Public Policy. Vancouver, BC: UBC Press, 2003;108-29.
30. Escombe AR, Moore DAJ, Gilman RH, Navincopa M, Ticona E, Mitchell B, et al. Upper room ultraviolet light and negative air ionization to prevent tuberculosis transmission. PLoS Med 2009;6:e1000043. doi:10.1371/journal.pmed.1000043.
31. Rendleman NJ. Mandated tuberculosis screening in a community of homeless people. Am J Prev Med 1999;17:108-13.
32. Kimmerling ME, Shakes CF, Carlisle R, Lok KH, Benjamin WH, Dunlap NE. Spot sputum screening: Evaluation of an intervention in two homeless shelters. Int J Tuberc Lung Dis 1999;3:613-19.
33. Moro ML, Salamina G, Gori A, Penati V, Sacchetti R, Mezzetti F, et al. Two-year population-based molecular epidemiological study of tuberculosis transmission in the metropolitan area of Milan, Italy. Eur J Clin Microbiol 2002;21:114-22.
34. Oeltmann JE, Kammerer JS, Pevzner ES, Moonan PK. Tuberculosis and substance abuse in the United States, 1997-2006. Arch Int Med 2009;169:189-97.
Received: August 4, 2009
Accepted: February 5, 2010
[Author Affiliation]
Anne Aspler, MSc,1 Huey Chong, BSc,1 Dennis Kunimoto, MD,1,2 Linda Chui, PhD,2 Evelina Der, BScN,3 Jody Boffa, MIH,1 Richard Long, MD1
Author Affiliations
1. Tuberculosis Program Evaluation and Research Unit, University of Alberta, Edmonton, AB
2. Provincial Laboratory for Public Health, Edmonton and Calgary, AB
3. Edmonton Tuberculosis Clinic, Edmonton, AB
Correspondence: Dr. Richard Long, Tuberculosis Program Evaluation and Research Unit, Room 8325, Aberhart Hospital, 11402 University Avenue, Edmonton, AB T6G 2J3, Tel: 780-407-1427, Fax: 780-407-1429, E-mail: richard.long@ualberta.ca
Acknowledgements: The authors thank Karen Sutherland and Norah Landry for their assistance in preparing the manuscript and the Canadian Molecular Epidemiology of TB Study Group for the use of their Western Canada DNA fingerprint database (1995-1997).
Supported by grants from the Aboriginal Health Strategy Project Fund, Alberta Health and Wellness, and First Nations and Inuit Health, Health Canada, Alberta Region.
This work was prepared in partial fulfillment of a Master's of Science degree in Public Health by Anne Aspler.
Conflict of Interest: None to declare.
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