Long term follow-up of drug resistant and drug susceptible tuberculosis contacts in a Low incidence setting

The study was conducted in British Columbia (BC), a Canadian province with a population of 4.4 million and a TB case rate of 7.1 per 100 000 population per year [23]. The BC Centre for Disease Control (BCCDC) maintains a provincial population based TB registry that is informed of all TB cases through legal notification, as well as case notification through a centralized provincial mycobacteriology laboratory and pharmacy. The same agency dispenses all medications used to treat contacts. Contact tracing was performed according to Canadian guidelines and was recorded in the registry using standardized protocols [24].

M. tuberculosis was isolated from clinical specimens using the BacT/Alert mycobacterial culture detection system (BioMerieux, Durham, NC). Phenotypic susceptibility testing was performed using the BACTEC 460 radiometric method and interpreted as per Clinical and Laboratory Standards Institute (CLSI) recommendations [25, 26].

For the purposes of this study, a source case was defined as the first household member to present with culture-positive pulmonary TB and drug susceptibility profile results. The source case date of diagnosis was defined as the date that the first culture positive sample was received by the laboratory. A close contact was defined as any individual identified as a “household contact” or “Type 1 contact” of a source case in the provincial TB registry. In this registry, both “household contact” and “Type 1 contact” represent a close contact and refer to household contacts or those sharing airspace with the source case for >4 hours per week. TSTs were performed according to Canadian guidelines [24]. A positive TST in a given contact was defined as any TST ≥5 mm measured <3 months before to <1 year after source diagnosis. Prior positive referred to a positive TST ≥3 months before source diagnosis. A close contact identified by the source case without a TST measurement or TB disease diagnosis was recorded as no result. Contacts with a positive TST or with signs and symptoms of TB disease were screened with a chest x-ray and in some cases, sputum examination. Contacts with TB disease was defined as a contact with M. tuberculosis complex demonstrated on culture or an individual with radiological, pathological or therapeutic responses consistent with TB disease as per established guidelines. Contacts with TB disease were not classified by their TST result.

We accessed the BCCDC registry for all cases of MDR-TB, HMR-TB and DS-TB diagnosed between 1990 and 2008. Close contacts of all MDR-TB cases were identified from the registry and their demographic profile, clinical features and TST results were recorded. For comparison, close contacts of DS-TB and HMR-TB were also identified with data recorded in a similar fashion. Only close contacts were recorded to limit bias introduced by enhanced contact tracing of drug-resistant sources. To further limit bias introduced by misclassification of close contacts, any sources with >15 close contacts were excluded from analysis.

The number of contacts with TB disease was recorded, and when available, contact resistance profiles were compared with their purported source case. TST positive or TST negative contacts with two sources listed within the same household in the same year were excluded from further TST analysis. BCG status was extracted for each contact, along with demographic variables. When BCG status was unavailable (in 36% of cases), BCG status was estimated from http://​www.​bcgatlas.​org using data on country of origin, age and year of entry to BC [25, 26].

Descriptive statistics were computed using Stata version 11.1 (StataCorp, College Station, Texas). The Wilcoxon Rank Sum test, chi-square test and Ficher’s exact test were used in univariate analysis to assess statistical difference between variables (alpha 0.05). A multivariable logistic regression model was constructed to test the association between source resistance profile and TST positivity. Factors known to predict TST positivity, including adult age (≥18 years), source smear status (positive), male gender, foreign birth, and BCG status were included in the model. After analysis of contact data, the number of contacts per source was added to the model, as the number of contacts varied significantly between HMR contacts and DS-TB contacts. A second model was constructed which excluded BCG status given the limited data for this variable. Odds ratios with 95% confidence intervals were reported. Models were assessed with chi-square goodness-of-fit and ROC curve construction.

We identified 35 MDR-TB cases from the BCCDC registry between 1990 and 2008 (Table 1). Contact tracing was not performed for 7 cases: 5 had extra-pulmonary TB, 1 case entered BC on MDR-TB therapy, and 1 case left BC before contact tracing was initiated. From the remaining 28 MDR-TB sources, 89 close contacts were identified, with a median of 3 total contacts per source (range 1-7) and median follow-up of 123 months (range 19-239). Of the 89 close contacts, 42 (47%) were TST positive, 33 (37%) were TST negative and 9 (10%) were prior positive or no result (Table 2). Latent TB therapy was completed in 12 MDR-TB contacts, including 11 contacts that initiated preventative therapy tailored to the source case susceptibility profile. Five close contacts developed TB disease during follow-up; fully susceptible M. tuberculosis was isolated from 4 cases and the fifth case was diagnosed based on clinical criteria. All 5 contacts with TB disease were diagnosed within 3 months of source diagnosis and had not received preventative therapy.

Between 1990 and 2008, contact tracing of 96 infectious HMR-TB source cases yielded 249 close contacts, of whom 121 (49%) were TST positive (Table 2) and 8 (3%) developed TB disease during follow-up. Of the six contacts with culture-confirmed TB, 3 developed HMR-TB, while 3 developed DS-TB (Table 3). DS-TB contact tracing over the same period yielded 7309 close contacts from 2895 sources (Table 2). There were 2321 contacts (32%) with a positive TST and 168 (2%) contacts with TB disease. Despite a common median of 3 close contacts per source case, the distribution of contacts varied significantly between DS-TB and HMR-TB (p < 0.001).

All seven pre-specified variables predicted TST positivity in the logistic regression model, including adult age (OR 1.76; 95% CI 1.51-2.06), male gender (OR 1.18; 95% CI 1.05-1.32), BCG vaccination (OR 1.42; 95% CI 1.23-1.64), foreign birth (OR 5.37; 95% CI 4.55-6.33), source smear positivity (OR 1.23; 95% 1.09-1.39), source HMR-TB (OR 2.13; 95% CI 1.57-2.90), and source MDR-TB (OR 1.75; 95% CI 1.07-2.86) (Table 4). The number of close contacts attributed to the index case was included in the model because the distribution varied significantly between the HMR-TB and DS-TB groups, and because a lower threshold for classifying contacts as Type 1 may impact the rate of TST positivity. Each single increase in the number of close contacts was associated with a decrease in TST positivity (OR 0.96; 95% CI 0.94-0.98). Estimates did not change significantly after BCG status was excluded from the model. Chi-square goodness of fit was non-significant for models that included and excluded BCG status, indicating that the goodness-of-fit for this model appeared adequate (p = 0.32, p = 0.09 respectively).