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Trends in Multidrug-Resistant Mycobacterium tuberculosis in Relation to Sputum Smear Positivity in Hong Kong, 1989–1999

  1. Kai Man Kam,
  2. Chi Wai Yip,
  3. Lai Wa Tse,
  4. Oi Chi Leung,
  5. Lai Ping Sin,
  6. Mei Yuk Chan, and
  7. Wai Sum Wong
  1. Tuberculosis Reference Laboratory, Department of Health, Yung Fung Shee Memorial Centre, Cha Kwo Ling Road, Kwun Tong, Hong Kong
  1. Reprints or correspondence: Dr. K. M. Kam, Rm. 802, 8/F, Sai Ying Pun Polyclinic, 134 Queen's Road West, Hong Kong (kmkam{at}dh.gov.hk).

  • Presented in part: 32nd International Union Against Tuberculosis and Lung Diseases World Conference on Lung Health, Paris, 1–4 November 2001.

 
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Abstract

We studied retrospectively the territory-wide occurrence and trends of multidrug-resistant tuberculosis (MDR-TB) in Hong Kong over an 11-year period during which a short-course directly observed therapy (“DOTS-Plus”) strategy has been in operation. The overall MDR rate was 2.1% (primary, 1.4% and acquired, 9.5%) and declined at 0.08% per year: smear-positive primary MDR cases declined at yearly rate of -0.065% (R2 = .23), and smear-negative primary MDR cases increased at 0.035% yearly. With declining rates of smear positivity, sputum culture has become the mainstay of detection of MDR-TB. Although the overall notification rates showed the elderly (age >65 years) age group to be most affected, the occurrence of MDR-TB has been consistently highest in the 35–65 year age group (60.4% of MDR caseload). We demonstrated declining rates of sputum smear positivity of MDR-TB in a DOTS-plus environment and that a centralized laboratory database is essential in gathering epidemiological information for identifying particular risk groups and monitoring trends of MDR-TB in a community.

Drug-resistant tuberculosis (DR-TB) had been recognized soon after introduction of effective chemotherapy [1–3], although more recent concern about multidrug-resistant Mycobacterium tuberculosis (MDR-TB) has arisen partly because of major outbreaks of these organisms in developed countries [4, 5]. The reduced response to standard short-course chemotherapy (SCC) with first-line drugs often leads to higher mortality and treatment failure rates, as well as increased periods of transmissibility [6, 7]. Major efforts have already been made to elucidate the extent of DR-TB in the global situation [8], whereby certain high-incidence (“hot spots”) areas were identified. However, problems in sampling, variations in laboratory methods, and lack of longitudinal data often limit obtaining a clear assessment and the conclusions that can be drawn [9–11].

In Hong Kong, our TB control program was established in 1979, and rifampicin was introduced in 1970. Systematic drug susceptibility testing has been performed since 1986. SCC was introduced in 1987 and is currently estimated to be used in 96% of TB cases, with an overall treatment success rate of 89%. TB notification rates declined from 159 cases per 100,000 population in 1980, to 101 per 100,000 in 1995 but rose again, to 114.7 per 100,000 in 1998 [12]. Age-specific analysis showed a notification rate of >200 cases per 100,000 population for those aged >65 years, with a smaller peak in the 20–24 year age group. However, because the drug costs alone for treating 1 case of MDR-TB can be at least 30 times that of a non-MDR case when SCC is used, we feel the urgent need to properly assess the role of MDR-TB in our territory. There were, in particular, 2 concerns that were associated with the resurgence of TB in Hong Kong. First, what role does MDR-TB play in our situation? Second, what are the main target groups, so that prevention and control efforts can be suitably directed? We therefore sought to answer these questions by reviewing our TB Reference Laboratory data and addressing key areas of concern. Because Hong Kong is one of the first high-incidence areas to fully implement short-course directly observed therapy (DOT), we also performed systematic drug susceptibility testing for all our bacterial isolates, the results of which would lead to a change of regimens that followed the drug susceptibility pattern—a system of practice close to a “DOTS plus” strategy [13]. Our past experience and records, therefore, offered a unique opportunity for us to review the longitudinal changes in MDR-TB, especially with respect to smear and culture positivity, in 1 geographic area. It is hoped that this knowledge will provide experience in monitoring changes among places with similar settings and thus design a more rational approach in which prevention and control of MDR-TB activities can be based.

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Materials and Methods

Although early studies on SCC were carried out in Hong Kong [14–17], standardized laboratory procedures for investigation, including smear microscopy, culture, and drug-susceptibility tests were gradually set up locally. The Tuberculosis Reference Laboratory was set up in 1984 and received specimens from all government chest clinics as well as positive culture isolates from most other clinical laboratories in the territory. This covers ∼80% of all positive mycobacteria isolates from clinical sources in Hong Kong.

Sputa specimens were processed and bacterial isolates were identified by use of standard cultivation and biochemical procedures [18]. In vitro drug susceptibility tests, which used absolute concentration method on slopes of Löwenstein Jensen medium, were done on all M. tuberculosis isolates against streptomycin, isoniazid (“H”), and rifampicin (“R”). Critical concentrations for each drug were determined at regular intervals by running titrations of probably sensitive controls (isolates from newly diagnosed patients) and probably resistant controls (isolates from patients during unsuccessful treatment), according to procedures described elsewhere [19]. Laboratory quality assurance included both internal controls and participation in external quality assurance schemes of acid-fast bacilli smear microscopic examination and drug susceptibility testing (proficiency testing program in the World Health Organization/International Union Against Tuberculosis and Lung Diseases Western Pacific Region Supranational Reference Laboratory Network). We did not use an early isoniazid resistance detection system.

The present retrospective survey was based on the laboratory results on smear microscopy, culture, and drug-susceptibility tests that were reported from 1 January 1989 to 31 December 1999. All patients were classified according to sex, age groups (⩽15, 16–34, 35–65, and >65 years), and any history of anti-TB treatment. Men were affected more than women in almost all situations, and this sex difference was not included in subsequent analyses. Duplicate specimens of the same infection episode from the same patient examined during the course of chemotherapy were not counted. “Primary drug resistance” was defined as in vitro resistance in a patient who had never received anti-TB chemotherapy, and “acquired resistance” was defined as in vitro resistance in a patient previously treated with any anti-TB medication. “MDR” was defined as resistance to at least H and R.

Data were computerized and statistical analyses were performed with use of EPI-INFO version 6.02 (Centers for Disease Control and Prevention, Atlanta, and World Health Organization, Geneva). Tests were done to examine for significant differences in drug resistance rates among different age groups and between specimen categories (primary- and acquired-resistance) with different smear examination results. Mantel-Haenzel tests and linear regression for trend were used to analyze for changes in MDR rates over time. The correlation coefficient (R) was used to indicate the degree of correlation between 2 variables. Fisher's exact test results were used when an expected value was <5. P values tabulated were 2-tailed, and a value <.05 was taken as indicative of statistical significance.

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Results

Out of a total of 29,057 consecutive nonduplicate isolates of MTB obtained during the 11-year study period, 371 (1.4%) of 26,625 and 232 (9.5%) of 2432 were MDR-TB strains isolated from primary- and acquired-resistance cases, respectively, making an overall total of 603 isolates (2.1%) being identified as MDR-TB. The 35–65 year age group accounted for 364 (60.4%) of 603 total MDR cases, although it only made up 13,842 (47.6%) of 29,057 TB (i.e., MDR and non-MDR) cases. On the other hand, the reverse was true for the 16–34 and >65 year age groups, which made up 132 (21.9%) of 603 MDR cases and 7750 (26.7%) of 29,057 TB cases (17.1% and 24.8% of caseloads, respectively). The overall prevalence of MDR was also highest in the 35–65 year group (364 [2.6%] of 13,842 cases), compared with the 16–34 (132 [1.7%] of 7750 cases) and >65 (103 [1.4%] of 7219 cases) year age groups. This difference in overall MDR prevalence between the 35–65 year and the other 2 age groups was significant (P < .0001).

Although acquired-resistance cases made up only 2432 (8.4%) of 29,057 TB cases, they accounted for 232 (38.5%) of 603 MDR cases. Table 1 shows the distribution of all MDR cases in relation to smear positivity in the different age groups during the study period. Out of a total of 11,931 smear-positive cases detected, 328 (2.7%) were from patients with MDR-TB, with the highest percentage in the 35–65 year age group (3.5%). This age group alone accounted for 208 (63.4%) of 328 smear-positive MDR cases. A comparison among age groups of MDR-TB showed that only differences between smear- positive 16–34 and 35–65 year (P < .001) and 35–65 and >65 year (P = .004) age groups were significant. The main reason being the higher rate of MDR in the 35–65 year age group for both smear-positive as well as smear-negative cases. Further breakdown of smear-positive cases to primary- and acquired-resistances revealed that the former (16–34 vs. 35–65 years) age-group difference was mainly found in primary resistance cases (P = .001), whereas the latter (35–65 vs. >65 years, respectively) age-group difference was due to acquired resistance ones (P = .004). This lends support to the hypothesis that major (smear-positive) source of MDR-TB transmission may largely be due to the 35–65 year age group, despite an apparently higher overall TB notification rate in the >65 year age group.

Table 1
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Table 1

Distribution of multidrug-resistant (MDR) cases in relation to sputum smear positivity in different age groups in Hong Kong, 1989–1999 (nonduplicate).

Examination of smear-negative cases showed a slightly different picture when the same age-group specific analysis was applied. Although the same peak in the 35–65 year age group was seen, there was a low overall MDR rate (0.95%) in the >65 year age group. Comparison of overall smear-negative MDR rates between this latter and the 16–34 (P = .003) or 35–65 (P < .001) year age groups showed these differences to be significant. A further breakdown to primary- and acquired-resistance categories revealed that the former age-group difference was mainly found in the acquired resistance category (P < .001), whereas the latter between—age-group difference was in primary resistance (P < .001).

Figure 1 shows the longitudinal changes in overall percentage of MDR over the 11-year period. It can be seen that although there was a general decline (P = .006) at a rate of ∼0.083% per year, analyses showed that differences between individual and adjacent years (interyear difference) did not reach statistical significance for any paired adjacent years. This may mean that short-term monitoring (2–3 years) of MDR rates in an area with a high TB incidence would be unlikely to reveal the trends that we observed over a longer period. A breakdown into primary- and acquired-resistance MDR cases, figure 2A and 2B, showed that the decline was more significant for acquired MDR cases (0.85% per year, P < .0001) than for primary resistance cases (0.013% per year, P = .66). Examination of interyear difference showed that only the increase in primary MDR from 1993 through 1994 (P = .025) and the decline in acquired MDR cases from 1992 through 1993 (P = .019) appeared to be significant.

Figure 1
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Figure 1

Trend in multidrug resistance (MDR; %) among all tuberculosis cases in Hong Kong, 1998–1999. χ2 for linear trend, 7.71, P = .0055. Linear regression formula: R2 = .48, x-coefficient, -.083; SE, 0.029.

Figure 2
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Figure 2

Percentage of multidrug resistance among (A) primary and (B) acquired tuberculosis cases in Hong Kong, 1998–1999. A, Primary, χ2 for linear trend, 0.20, P = .66. Linear regression formula: R2 = .034, x-coefficient, -.013; SE, 0.022. B, Acquired, χ2 for linear trend, 19.5, P = .0001. Linear regression formula: R2 = .48, x-coefficient, -0.85; SE, 0.29.

The total smear-positive primary MDR cases, as a percentage of all smear-positive primary cases, declined at a rate of -0.065% per year (R2 = .23), whereas smear-negative primary MDR cases increased at ∼0.035% per year (R2 = .13). A further breakdown analysis of the smear-positive primary TB cases in the different age groups showed a decline in smear-positive primary MDR cases, with the biggest decline seen for the 35–65 year group (-0.10% per year) and the smallest in the elderly age group (>65 years, -0.012% per year). This is probably due to early detection and successful treatment of smear-positive primary MDR cases in the former group. Examination of interyear differences showed that a peak of cases in the 16–34 year age group in 1991 (P = .05), the fall in cases in the 35–65 year age group between 1994 and 1995 (P = .03), and the peak in >65 year age group in 1995 (P = .02) were significant. For smear-negative primary TB cases, the percentage of MDR showed an increasing trend for all 3 age groups, with the highest rate (0.10% per year) in the 16–34 year age group. This highlights the increasing importance of culture (i.e., detection of smear-negative, culture-positive cases), in contrast to smear microscopy alone, as an indispensable tool in detection of MDR-TB cases in which DOTS-plus had been in operation for a number of years.

Examination of the trend in smear-positive acquired MDR cases, as a percentage of all acquired TB cases, showed an overall decline in the percentage of smear-positive acquired MDR for all 3 age groups, with the >65 year age group showing the steepest decline (-1.3% per year, R2 = .31), followed by the 35–65 year age group (-1.1% per year, R2 = .41). A study of changes in smear-negative acquired MDR cases over the study period showed that the percentage of MDR cases in both the 35–65 and >65 year age groups declined at yearly rate of -0.08% (R2 = .003) and -0.69% (R2 = .43), respectively. A yearly increase of 0.47% (R2 = .04) was also seen for the 16–34 year age group. Between—age-group comparisons showed that the larger numbers of cases that occurred in the 16–34 year age group (with 35–65 years as the reference group) in 1991 (P = .03) and in the 35–65 year age group (with >65 years as reference group) in 1992 (P = .05) and 1999 (P = .02) were significant.

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Discussion

Early studies have shown that resistant tubercle bacilli evolve in the absence of exposure to antimicrobials, but they are diluted by the large pool of drug-susceptible organisms [20, 21]. The presence of antimicrobial pressure favors the selection of resistant strains that multiply to form the predominant population. This occurs especially in extensive cavitation disease, where a large bacterial load is usually found [22]. The emergence of MDR-TB has been associated with a variety of management-, health provider—, and patient-related problems [23, 24], of which the lack of a properly organized system to ensure prompt diagnosis and effective treatment constitutes a crucial component [25]. The “DOTS-Plus” strategy has been proposed to tackle the global MDR-TB problem [26, 27]. There are controversies as to how exactly these prevention and control efforts should be carried out, especially on the level of laboratory support services required for implementation [28].

Whether a case of TB is smear-positive or -negative depends more on the degree of the host patient's underlying hypersensitivity to TB and the functioning of their cell-mediated immunity rather then on whether their TB was recently or remotely acquired (either situation can result in cavitary disease). From a public health standpoint, the smear-positive patients bear greater significance than smear-negative patients in terms of the bacillary load in the hosts, as well as their potential to spread the organism in the community. Prevention and control efforts must therefore be directed toward identification and prompt treatment of this smear-positive group of patients.

We observed more smear-negative than smear-positive TB, with a 60 : 40 ratio overall, and a 65 : 35 ratio in the >65 year age group. The consistent trend of decline in smear-positive cases in both the primary- and acquired-resistance categories emphasized that our system of laboratory-based detection and timely reporting played a vital role in the sustained control of MDR-TB in our locale. Similar experience has also been documented in an outbreak situation in developed countries with a much lower endemic level of TB [5, 29, 30]. In contrast, our high endemic levels demanded that a population-based approach be adopted before we could formulate a rational strategy to prevent and control the main problem areas within our TB situation [31]. Our differential age group—stratified approach to analysis enabled us to distinguish the exact trends that are occurring within each age group and thus target these age groups in our efforts to control MDR-TB in our community. In particular, the trend of continuing decline in smear-positive MDR-TB cases may mean that transmission to new cases is declining, and, on the basis of this observation, a further future decline in numbers can be predicted. There is, however, no room for complacency, because the elimination of DR-TB will not be possible unless TB is eradicated. Hong Kong is surrounded by neighboring areas where MDR-TB has been found to be highly prevalent [32]. Moreover, our results in the present study have shown the importance of routine culture in detection of MDR-TB cases cannot be overemphasized. Although sputum-smear conversion is the primary indicator in assessing treatment outcome [33], our data suggest that culture techniques become indispensable in detection of MDR-TB in situations where, in particular, sputum-positive rates appear to be declining. In geographic areas where only smear microscopy is affordable, the introduction of simple culture methods is a logical step toward the establishment of an effective drug resistance surveillance system whereby drug susceptibilities can then be regularly tested. Because of resource constraints, we did not routinely use Gen-Probe MTD or other commercial system in earlier diagnosis of smear-negative TB.

We have shown how a centralized TB laboratory in a high endemic area can directly affect an effective drug treatment program [34–37] by providing timely information concerning the events that occur in different sectors (age groups) of the community. On the basis of this information, targeted efforts can then be made for these high-risk groups. Although retrospective analysis enabled us to compare incidences and trends in different age groups, more definitive evidence on the importance of recent transmissions in proportion to reactivations would require molecular typing techniques done on a population scale. In particular, restriction fragment—length polymorphism typing that uses IS6110 would allow transmission studies to be performed to identify clusters and thus assess the relative importance of reinfection versus reactivation in our elderly population. Such studies are presently being carried out.

There are several limitations of our study. First, laboratory methods may have gradually changed such that the decline in smear positivity may be attributed to poorer performance of microscopists, whereas improvements in culture techniques have resulted in higher culture pickup rates. Although this is a possibility that cannot be completely ruled out, our internal and external quality performance showed that laboratory performance remained very stable throughout the study period. Moreover, it is likely that this error would result in systematic bias that affected all specimens rather than the MDR ones alone. Second, the categorization of patients into primary- and acquired-resistance cases based on retrospective medical history-taking alone are well known to be fraught with potential error. In particular, a history of previous anti-TB treatment were often not obtained, thereby inflating the number of drug-resistant cases that were primary in origin. Migration of patient populations across our borders with neighboring countries is a distinct possibility, as is that multidrug-resistant patients moved out of Hong Kong for therapy, although it is equally likely that a sizable proportion of these patients came to Hong Kong for their TB treatment, which is, at present, free of charge. Definitive data concerning immigrants from other high-prevalence Southeast Asian countries are lacking. We also did not test every patient with TB for HIV. There is no exact figure of HIV infection among our patients with TB, although our unlinked anonymous screening program showed that the present HIV prevalence is probably very low, ∼0.4%.

Despite these shortcomings, we have been able to study the trends in changes of smear positivity among MDR-TB cases in our community, where a “DOTS-Plus” environment has been in operation for a number of years. We illustrated the importance of a centralized TB laboratory in supporting an effective drug regimen, which can only be built on a strong DOTS environment. We also document that particular age groups, which may be different from those deduced from examining gross TB notification rates alone, should be targeted in future TB prevention and control programs.

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Acknowledgments

We are indebted to the technical staff in the Tuberculosis Reference Laboratory and the medical, nursing and clerical staff in the Hong Kong TB and Chest Service. We also thank the Director of Health, Dr. Margaret Chan, for permission to review the laboratory data and publish the present article.

  • Received April 26, 2001.
  • Revision received August 15, 2001.
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  1. Clin Infect Dis. (2002) 34 (3): 324-329. doi: 10.1086/324164
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