1 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
2 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
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ABSTRACT |
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drug resistance; tuberculosis
Abbreviations: HIV, human immunodeficiency virus
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INTRODUCTION |
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Concurrent with the shift in tuberculosis case management from sanatorium to outpatient setting was a shift in immigration patterns. In Canada, for example, the number of immigrants arriving from Europe (a region of low prevalence of tuberculosis) declined steadily, and the number arriving from Asia (a region of high prevalence of tuberculosis) increased steadily (figure 1). This trend, together with a declining incidence of tuberculosis in the Canadian-born population, resulted in an increasing proportion of all tuberculosis cases in Canada among the foreign born (2).
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We found that the two westernmost provinces of Canada, Alberta and British Columbia, were uniquely well suited to exploring the extent to which these two events have influenced the pattern of antituberculous drug resistance in the Canadian-born population. Their tuberculosis control programs and disease demographics are almost identical; immigration to both provinces has been continuous and substantial, with 60 percent of the current tuberculosis case load being foreign born; and documentation of the temporal trend in drug resistance in the two provinces was available from a series of published surveys spanning 30 years. Interpretation of the trend in drug resistance observed in the surveys also could be facilitated by new molecular diagnostic and contact tracing data from one of the three large urban centers in the provinces.
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MATERIALS AND METHODS |
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Drug resistance surveys. Published surveys of antituberculous drug resistance in the tuberculosis patient population of Alberta and British Columbia from six time periods, 19631964 (9), 19701974 (3
), 1975 (7
), 19821985 (4
), 19821994 (8
), and 19931994 (6
), formed the basis for the drug resistance trends described herein. The drug susceptibility testing reported in these surveys was performed in either the respective Provincial Laboratories of Public Health or the national Laboratory Centre for Disease Control in Ottawa, Canada. Resistance to isoniazid and streptomycin was reported in all surveys, para-aminosalicylic acid in the first and third, rifampin and ethambutol hydrochloride in the last three, and pyrazinamide in a proportion of the isolates from the last two. The first four surveys used the resistance-ratio method of drug susceptibility testing (10
), the last survey used the radiometric method (11
, 12
), and the second-to-last survey used both methods. The first survey (19631964) may be considered to reflect the preoutpatient, pre-Asian immigration rate of drug resistance in the Canadian-born population and the more recent surveys to reflect the impact of outpatient care and shift in immigration pattern on the antituberculous drug resistance rates of the Canadian-born population. Standard definitions of drug resistanceprimary, acquired, and initialand disease relapse were used throughout, as follows:
Molecular diagnostics, contact investigation, and interpretation of the temporal trend
Study population. The data we analyzed were taken from one of the three major urban centers of the region, metropolitan Edmonton. Calgary and Edmonton are the two major urban centers in the province of Alberta, and Vancouver is the major urban center in the province of British Columbia. In 1996, the populations of Calgary and Edmonton were 851,600 and 891,500, respectively, versus a total of 2,780,600 in the province (Statistics Canada, 1996 census). Together, Calgary and Edmonton accept approximately 90 percent of all new immigrants to the province; in each city, 7080 percent of all new cases of tuberculosis occur in the foreign born.
To enable us to distinguish between the impact of outpatient care and immigration on drug resistance and to further explore the dynamics of tuberculosis transmission among the Canadian born and between the foreign born and Canadian born, in the absence of any impact of either event on resistance, all tuberculosis cases reported during the 5 years 19941998 in metropolitan Edmonton were identified. Demographic, clinical, and laboratory information on each case was extracted from the Alberta Tuberculosis Registry and the Provincial Laboratory of Public Health. The latter performs all mycobacterial cultures in the province as well as first-line drug susceptibility testing on all new isolates (BACTEC 460; Becton-Dickinson Microbiology Systems, Sparks, Maryland). Patients were categorized according to birthplace (Canadian born, foreign born). In each category of cases, age and gender were recorded, and those cases who were culture positive, drug resistant, respiratory, and drug-resistant respiratory were identified.
Molecular diagnostics. Transmission dynamics were explored by using molecular diagnostics. The initial isolate of M. tuberculosis from each of the culture-positive metropolitan Edmonton cases was DNA fingerprinted by IS6110-based restriction fragment-length polymorphism analysis and was compared by using GELCOMPAR software (Applied Maths, Ghent, Belgium) (13, 14
). A phylogenetic analysis was performed with the UPGMA method by using the Dice coefficient, based on the restriction pattern of all isolates (15
). Spoligotyping was used to differentiate among M. tuberculosis isolates with five or fewer copies of IS6110 (14
). Clustering (a cluster was defined as two or more isolates that share an identical IS6110 restriction fragment-length polymorphism pattern or spoligotype) was examined within and between foreign-born and Canadian-born cases and within and between drug-resistant strains from these cases. Conventional epidemiologic linkage between clustered cases was based on date of diagnosis, disease type (respiratory or nonrespiratory), and bacillary status.
Contact investigation. Transmission dynamics were explored by investigating contacts. The number and identity of contacts of Canadian- and foreign-born source cases (airway secretion smear-positive respiratory cases) were abstracted from the Tuberculosis Registry. This registry routinely records information on the contact's demographics, the relationship of the contact to the source case, the dates and results of initial and repeat tuberculin tests, and vaccination status. From the list of source case contacts, the number and ethnicity of those contacts reported to be tuberculin converters were abstracted. A tuberculin conversion was defined as a reaction of 10 mm or more when an earlier test within the previous 2 years resulted in a reaction of less than 5 mm. If the earlier result was 59 mm, then an increase of 6 mm or more was considered a conversion.
Statistical analysis
A series of 2 statistics were used to examine the relation between categorical variables. A t test for independent samples was used to examine the differences between two groups, Canadian-born and foreign-born persons, in the contact follow-up investigation.
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RESULTS |
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There was also no change in primary drug resistance in the Canadian-born population over the 31 years spanned by the surveys. Rates varied from 2 to 5 percent, with no systematic change in either direction. In contrast, primary resistance, better described as "initial" resistance because drug-use histories could not for the most part be corroborated by records (16), doubled in the Asian-born tuberculosis cases in the two provinces over the time spanned by the surveys.
Molecular diagnostics, contact investigation, and interpretation of the temporal trend
Study population. During the 5-year period 19941998, there were 768 tuberculosis case notifications in Alberta (315 (41 percent) were Canadian born and 453 (59 percent) foreign born), and the incidence was 5.5 per 100,000 persons. Among these 768 cases, 250 (33 percent) were residents of metropolitan Edmonton (table 3); the incidence was 5.6 per 100,000 persons. Most of these cases (195, 78 percent) were identified through passive case finding (symptoms), the remainder through screening programs (34, 14 percent) and contact tracing (21, 8 percent). Of the 250 Edmonton cases, 73 (29 percent) were Canadian born and 177 (71 percent) were foreign born. Of the 173 foreign-born cases whose year of arrival in Canada was known, 65 (38 percent) had arrived within the past 5 years. The majority of foreign-born cases (121/177, 68 percent) emigrated from five countries: Vietnam, China, the Philippines, India, and Hong Kong; a total of 138/177 (78 percent) emigrated from an Asian country. Compared with Canadian-born tuberculosis cases, foreign-born tuberculosis cases were significantly more likely to have nonrespiratory disease alone (10/73 (14 percent) vs. 53/177 (30 percent), p < 0.01 (2)). Whereas similar proportions of Canadian-born and foreign-born cases were culture positive (55/73 (75 percent) vs. 148/177 (84 percent), p = 0.13, (
2)), compared with Canadian-born, culture-positive cases, foreign-born, culture-positive cases were significantly more likely to be drug resistant (2/55 (4 percent) vs. 22/147 (15 percent), p < 0.05 (Fisher's exact test)).
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Molecular diagnostics. The results of molecular diagnostics are outlined in tables 3 and 4. Of the 203 culture-positive tuberculosis notifications, DNA was extracted successfully from the initial isolates of all but 1, a foreign-born female whose isolate could not be separated from a nontuberculous mycobacterial contaminant. Of the 202 isolates, 26 (13 percent) belonged to one or another of a total of nine clusters. There were six clusters of 2, two clusters of 3, and one cluster of 8 isolates. A significantly larger proportion of isolates from Canadian-born than foreign-born cases were in a cluster (18/55 (33 percent) vs. 8/147 (5 percent), p < 0.001 (2)). Among the Canadian born, clustering was more common in Aboriginals (8/20 (40 percent)) than non-Aboriginals (10/35 (29 percent); data not tabled). Two clusters of 2, one cluster of 3, and one cluster of 8 isolates involved Canadian born only, and two clusters of 2 involved foreign born only. Three clusters involved both Canadian born and foreign born, one cluster of 3 involved 2 foreign born and 1 Canadian born (cluster A), and two clusters of 2 involved 1 Canadian born and 1 foreign born (clusters B and C). According to conventional epidemiologic methods, only 1 foreign-born person (in cluster A) could have given rise to disease in only 1 Canadian-born person.
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Contact investigation. Among the 71 respiratory cases whose airway secretions were acid-fast bacilli smear positive, there were 7,137 close or casual contacts, 4,913 contacts of 24 Canadian-born source cases, and 2,224 contacts of 47 foreign-born source cases (table 5). A few cases, particularly among the Canadian born, had an extraordinarily large number of contacts, with the result that the number of contacts per Canadian-born source case was larger than the number of contacts per foreign-born source case (204.7 vs. 47.3); however, when equality of variance was taken into account, the difference was not statistically significant. Likewise, the number of converters reported per Canadian-born source case was greater than the number of converters reported per foreign-born source case (110/24 = 4.6 vs. 37/47 = 0.8), but the difference only approached significance (p = 0.054 (t test)). Converters among foreign-born contacts of any source case might be difficult to confirm because of the high likelihood of a preexisting positive tuberculin test. The number of Canadian-born converters of foreign-born source cases was significantly lower than the number of Canadian-born converters of Canadian-born source cases (15/47 = 0.3 vs. 67/24 = 2.8, p < 0.05 (t test)). Of Canadian-born converters of foreign-born source cases, three were converters of a drug-resistant source case. Of the eight converters of foreign-born source cases, whose birthplaces were unknown, one was a converter of a drug-resistant source case.
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DISCUSSION |
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The Canadian provinces of Alberta and British Columbia are very fortunate in having been given the resources to build tuberculosis programs that aspire to be in essence "sanatoria without walls." Key elements include central mandatory notification, central level III laboratory services (17), a central uninterrupted drug supply, dedicated physician prescribing rights, no-cost drugs and monitoring, initial four-drug regimens tailored to the drug susceptibility test results for each case, isolation of infectious cases to smear negativity, and outpatient management of individual cases by a dedicated public health nurse with dedicated physician oversight. In addition, the region has so far had the good fortune to have a relatively low seroprevalence of HIV. Conditions were thus favorable to examine the extent to which such a program could withstand the theoretical challenge that outpatient care and immigration pose to the pattern of drug resistance in Canada's native-born population.
Drug resistance surveys
First, with respect to the shift to outpatient care, we found no evidence that it has influenced drug resistance rates. There was no increase in the proportion of all Canadian-born cases who had relapsed, nor was there an increase in the proportion of all Canadian-born relapsed cases who were drug resistant (1213 percent). More importantly, the prevalence of primary drug resistance in Canadian-born patients did not increase over the 31 years spanned by the six drug resistance surveys in the region (3
, 4
, 6
9
). Rates consistently averaged between 2 and 5 percent (table 2). Given that occurrence of primary resistance is a direct consequence of the level of acquired resistance in the community, the stability of these two rates suggests that the Canadian-born population is communicating the disease to its own.
The low proportion of Canadian-born relapsed cases who were drug resistant and the low rate of primary resistance may reflect, among other things, the policy of isolating smear-positive patientsusually in hospital, hence directly observed therapyto smear negativity. Should a patient, who was at the outset infected with a fully susceptible isolate, fail or relapse after an initial 68 weeks of in-hospital, multidrug, directly observed therapy, the failure/relapse isolate may be expected to have retained its original drug susceptibility pattern (18, 19
). On the other hand, most outpatient treatment was self-administered; use of directly observed therapy outside of the hospital was only gradually introduced over the past 1015 years and is targeted at infectious pulmonary cases, the HIV co-infected, and those persons demonstrated to be recalcitrant. Yet, wider application of directly observed therapy may prove beneficial given the unchanged relapse rate in the Canadian-born population (20
). Relapses in the foreign born were almost always related to treatment events that preceded immigration. Stability of the primary drug resistance rate in Canadian-born cases despite a doubling of the primary (initial) resistance rate in Asian-born cases over the time spanned by the surveys suggests that, to date, the shift in immigration pattern has also had no measurable impact on the pattern of drug resistance in the Canadian-born population.
Molecular diagnostics and contact investigation
DNA fingerprinting of all culture-positive tuberculosis cases over a 5-year period in one of the three major urban centers of the region provided no objective evidence that drug-resistant strains were being circulated among the Canadian born or that drug-resistant strains were being transmitted from the foreign born to the Canadian born. There were no clustered drug-resistant strains among the Canadian born, and, while three small clusters (one 3-person cluster and two 2-person clusters) crossed ethnic groups, none involved a drug-resistant isolate (tables 3 and 4). Moreover, according to conventional epidemiologic methods, only 1 foreign-born person, in the cross-group clusters, could have given rise to disease in only 1 Canadian-born person. Although case finding in the region was largely passive, the time window was relatively short (5 years), and the majority of cases were foreign born of diverse origin, interpretation of our molecular epidemiologic data was optimized because information was provided on case ascertainment, case defi-nition, geographic area, time period, definition of clustering, cluster size distribution, and demographics (21).
In New York City, foreign-born tuberculosis patients were found to be at increased risk for infection with a cluster strain if they were homeless or had multidrug-resistant tuberculosis, and most clustered strains in the foreign born appeared to have been acquired from US-born tuberculosis cases (22). In Alberta and British Columbia, multidrug resistance on the initial isolate of M. tuberculosis is very rare (<1 percent) and is virtually always imported, unclustered, and unrelated to HIV (23
, 24
). In Texas, a study involving DNA fingerprinting of 201 drug-resistant isolates collected between 1992 and 1994 found limited evidence for "cross-ethnic-group" transmission of resistant strains; only 20 drug-resistant clusters (41 patients) were identified, and, of these, 12 (25 patients) clusters were in persons of the same ethnicity (25
). Molecular diagnostic data from San Francisco, California, and from Switzerland strongly suggest that, in general, tuberculosis in immigrants does not extend much to the general population (26
, 27
).
Contact follow-up data further supported the low probability of transmission of either drug-resistant or susceptible strains of tuberculosis from foreign-born to Canadian-born persons, countering the potential bias introduced by the use of fingerprint data in transmission studies, a bias that tends to highlight the determinants of rapid progression to active disease (28). In metropolitan Edmonton over the 5-year period 19941998, only 15 converters were found among Canadian-born contacts of infectious, foreign-born cases (table 5); of these, only 3 were converters of a drug-resistant source case. Where it has been looked at elsewhere, immigration has not substantially affected the annual risk of infection in developed countries (29
). In contrast to the foreign born, Canadian-born source cases were more likely to transmit the organism (i.e., more clustering and more converters per source case), but drug resistance was so uncommon (only 2 of 55 culture-positive, Canadian-born cases were drug resistant, and neither was smear positive) that transmission had no measurable impact on the circulation of resistant strains (there were no converters among the contacts of Canadian-born, drug-resistant cases).
Clustering, which may suggest recent transmission, among all tuberculosis cases in metropolitan Edmonton over the 5-year period 19941998 was low (13 percent) in comparison to the frequency of clustering reported in several major US cities (3550 percent) (28, 30
34
). This difference may be explained in part by the very low seroprevalence of HIV in the Edmonton tuberculosis cases (3 percent of those tested)HIV can facilitate the spread of tuberculosis, especially drug-resistant tuberculosisas well as the very high proportion of foreign-born cases relative to the rates found in many major US cities. In both US and Canadian cities, clustering has consistently been shown to be less common in the foreign-born than the native-born population. Clustering in Canadian-born cases was more common in Canadian-born Aboriginals, where it may not reflect recent transmission but rather reactivation of strains circulating many years before.
The low likelihood of clustering among foreign-born tuberculosis cases may be related to their disease type, the infectivity of their contacts, and social/cultural exigencies. Refugees and those applying for landed immigrant status are screened for active respiratory tuberculosis in their country of origin. If determined to have active disease, they must complete a satisfactory course of treatment in their country of origin before they are permitted to emigrate. Those with inactive disease and lung scars are referred for medical surveillance in Canada and are often given preventive treatment. Thus, respiratory disease is actively screened for and treatment provided. Our own and other data have confirmed the significantly lower likelihood of respiratory, and the greater likelihood of nonrespiratory, tuberculosis in the foreign born (2, 35
). The present data as well as national data also suggest that, compared with Canadian-born patients with respiratory disease, foreign-born patients with respiratory disease are less likely to be sputum smear positive (36
), perhaps because active case finding among foreign-born persons referred for medical surveillance leads to earlier diagnosis.
Most Asian communities in Canada are relatively insular, with much freer association within the community than outside of the community. As a result, the immediate contacts of foreign-born cases are more likely to be foreign born and, as a consequence, already infected with tubercle bacilli (28, 37
). Such latent infection may offer some protection against reinfection. Contact with the more vulnerable (having a very low incidence of infection) Canadian-born non-Aboriginal population and the less vulnerable (having a higher incidence of infection) Canadian-born Aboriginal population might be expected to be limited (2
). To the extent that recent compared with remote arrivals are even less well integrated into the native population, transmission of (drug-resistant) disease from foreign-born to native-born persons will be further limited; recently arrived immigrants are at greater risk of developing tuberculosis (2
, 38
), and the M. tuberculosis strains isolated from them are more likely to be resistant (5
, 8
). In the Netherlands, clustering between immigrants and the indigenous population was found to depend on time since arrival, reflecting the degree of social integration (39
). In immigrants to Italy with tuberculosis, the mean period of stay was significantly longer in clustered than in nonclustered patients (40
).
In settings of low HIV seroprevalence, transmission of isoniazid-resistant strains, whether from a foreign-born patient with imported resistance or a Canadian-born patient with acquired resistance, to a new patient, with subsequent development of tuberculosis with preformed resistance, may in general be relatively infrequent, presumably because the metabolic compromises made by the microbes to enable drug resistance have made them modestly less virulent (41). In the normal host, whose immune system has a 90 percent chance of containing a tuberculosis infection for a lifetime, even a small reduction in pathogenic capacity would make transmission of drug-resistant disease quite uncommon (42
). In settings of high HIV seroprevalence, on the other hand, this host advantage is lost, and recent infection with drug-resistant strains progresses rapidly to disease.
In settings of low HIV seroprevalence, it would thus appear that 1) provided that the tuberculosis control program itself is sound and its funding secure, outpatient management of tuberculosis patients does not translate into increased drug resistance; and 2) despite overwhelming evidence that the foreign born are importing tuberculosis into industrialized countries such as Canada and that the strains isolated from these cases are more likely to be drug resistant, there is no evidence, at least in the provinces of Alberta and British Columbia, that their disease is impacting significantly on the native-born population. This situation may change if the prevalence of multidrug-resistant tuberculosis and HIV increases.
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ACKNOWLEDGMENTS |
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The authors are grateful to Sylvia Chomyc, Provincial Laboratory of Public Health; Shirley Chorney, Denise Whittaker, and Shirin Ali, Alberta Health and Wellness, Disease Control and Prevention Branch; Karen Sutherland, Research Associate, Alberta Health; and Diane Doering, Nurse Manager, Capital Region Tuberculosis Clinic, for their technical assistance; Dr. Jure Manfreda for his advice; and Susan Falconer for preparing the manuscript.
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NOTES |
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REFERENCES |
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