Is the delay in diagnosis of pulmonary tuberculosis related to exposure to fluoroquinolones or any antibiotic?

BACKGROUND: Delays in diagnosis of tuberculosis (TB) have been associated with previous use of antibiotics, and in particular fluoroquinolones (FQ), for suspected pulmonary infections. METHODS: We conducted a population-based cohort study with 2232 patients who had active TB between 1997 and 2006 (records obtained from the British Columbia Linked Health Databases). Patients with a record of an initial health care contact preceding the diagnosis of TB were identified for inclusion. Health care delay was defined as the time between initial health care contact and the initiation of anti-tuberculosis medication, and was compared between patients prescribed antibiotics and those not exposed to any antibiotics. RESULTS: A total of 1544 patients were included. After adjusting for covariates, average health care delay for patients exposed to antibiotics was found to be significantly greater, by a factor of 2.10 (95%CI 1.80-2.44), with a median delay of 41 days in the antibiotic group compared to 14 days in the non-antibiotic group. Sex, age, foreign-born status and socio-economic status were non-significant factors. Health care delay increased with the number of antibiotic courses received, but not with the type of antibiotic. CONCLUSIONS: Previous treatment with any antibiotic, and not only a FQ, is associated with a delay in TB diagnosis.

Demographic risk factors of pulmonary colonization by non-tuberculous mycobacteria.

SETTING: British Columbia (BC), Canada. OBJECTIVE: To determine the risk factors for pulmonary colonization by non-tuberculous mycobacteria (NTM). DESIGN: Retrospective study of subjects colonized by NTM from 1990 to 2006. Subjects without mycobacterial disease and with at least three negative cultures served as controls. RESULTS: Mycobacterium avium complex (MAC) species were the most common NTM. Risk factors of colonization included age > or = 60 years (aOR 2.3), female sex (aOR 1.2), residency in Canada for at least 10 years (aOR 3.8), Canadian-born aboriginal (aOR 1.8), and Canadian-born non-aboriginal (aOR 1.4). Predictors of MAC colonization included White race (aOR 1.6) and residency in Canada for at least 10 years, which was the strongest predictor (aOR 6.7). Aboriginal origin was associated with non-MAC colonization (aOR 1.8), and Canadian-born people from the East/South-East Asian ethnic groups were protected from MAC colonization (aOR 0.2), all aOR P < 0.05. CONCLUSION: Older age, female sex, having been born in Canada, long residency in BC and White race predict pulmonary NTM colonization, while Aboriginal origin predicts non-MAC colonization. Further research is needed to identify environmental NTM sources in BC and to determine their relation to colonization and disease.

The incidence of pulmonary non-tuberculous mycobacteria in British Columbia, Canada.

SETTING: British Columbia Centre for Disease Control (BCCDC), Vancouver, Canada. OBJECTIVE: To determine the incidence of non-tuberculous mycobacteria (NTM) and to assess the impact of new laboratory techniques. DESIGN: Population-based study of all subjects with positive cultures for NTM from 1990 to 2006. RESULTS: Mycobacterium avium complex (MAC) was the most common NTM isolate (77%). The median incidence rates per 100 000 population in the total sample were respectively 6.7, 4.5 and <0.7 for all NTMs, MAC and all non-MAC species; for NTM-treated subjects the rates were respectively 1.6, 1.4 and <0.08; and for the NTM-colonised they were respectively 4.7, 2.7 and <0.5. In the period after the introduction of new laboratory techniques, all NTM isolates, the overall MAC rate and the MAC-colonised rate increased by respectively 24%, 35.4% and 76% (P < 0.05). All NTM isolates and rates for all NTMs, NTM-treated and M. tuberculosis subjects (used as comparison group) decreased over time (P < 0.05). CONCLUSION: The most common NTM species was MAC. Episodic increases in the number of isolates and incidence rates of subjects colonised with MAC are likely to be associated with the implementation of new laboratory techniques, which may represent an artefact. The decrease in rates of NTM-treated subjects is reassuring.

Cost-effectiveness of a new interferon-based blood assay, QuantiFERON-TB Gold, in screening tuberculosis contacts.

BACKGROUND: Recent approval of interferon-gamma release assays that are more specific for Mycobacterium tuberculosis has given new options for the diagnosis of latent tuberculosis infection (LTBI). OBJECTIVE: To assess the cost-effectiveness of Quanti-FERON-TB Gold (QFT-G) vs. the tuberculin skin test (TST) in diagnosing LTBI in contacts of active TB cases using a decision analytic Markov model. METHODS: Three screening strategies--TST alone, QFT-G alone and sequential screening of TST then QFT-G--were evaluated. The model was further stratified according to ethnicity and bacille Calmette-Guérin (BCG) vaccination status. Data sources included published studies and empirical data. Results were reported in terms of the incremental net monetary benefit (INMB) of each strategy compared with the baseline strategy of TST-based screening in all contacts. RESULTS: The most economically attractive strategy was to administer QFT-G in BCG-vaccinated contacts, and to reserve TST for all others (INMB CA$3.70/contact). The least cost-effective strategy was QFT-G for all contacts, which resulted in an INMB of CA$-11.50 per contact. Assuming a higher prevalence of recent infection, faster conversion of QFT-G, a higher rate of TB reactivation, reduction in utility or greater adherence to preventive treatment resulted in QFT-G becoming cost-effective in more subgroups. CONCLUSIONS: Selected use of QFT-G appears to be cost-effective if used in a targeted fashion.

Risk of tuberculosis in screened subjects without known risk factors for active disease.

SETTING: Tuberculosis (TB) referral clinic in Vancouver, British Columbia, Canada. BACKGROUND: Screening for and treatment of latent TB infection (LTBI) in at-risk populations are the cornerstone of TB control in low-incidence countries. Persons at low risk often undergo the tuberculin skin test (TST) for reasons other than contact. Little information exists on the actual risk of TB in this population. OBJECTIVE: To determine the risk of TB in screened subjects without known risk factors. DESIGN: Retrospective descriptive analysis of demographics, TST reaction size and TB disease occurrence in 98333 low-risk subjects screened from 1990 to 2002. RESULTS: The average annual disease rate was 0.4 per 100000 population (cumulative rate 7.4/100000) from 1990 to 2006, and TB was diagnosed only in the foreign-born. Risk of TB in the foreign-born increased with larger TST reaction size (P < 0.03). Completion of treatment for LTBI was not documented for any of the subsequent active TB cases. CONCLUSION: In a low-risk screened population, active TB disease was found only in the foreign-born. Treatment of LTBI is not recommended in persons with a positive TST and no additional risk factors. Local screening programs should focus on populations with confirmed risk factors for disease.

Adverse drug reactions associated with first-line anti-tuberculosis drug regimens.

BACKGROUND: Standard treatment of active tuberculosis (TB) consists of isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). Although this regimen is effective in treating active TB, it is associated with many adverse drug reactions (ADRs) and poses a significant challenge to completion of treatment. OBJECTIVES: To examine the incidence of major ADRs and risk factors associated with first-line anti-tuberculosis medications. METHODS: This study evaluated patients receiving treatment for active TB from a population-based database (2000-2005). The nature of the ADRs, likelihood of association with the study medications and severity were evaluated. RESULTS: A total of 1061 patients received treatment, of whom 318 (30%) had at least one major ADR. The overall incidence of all major ADRs was 7.3 events per 100 person-months (95%CI 7.2-7.5): 23.3 (95%CI 23.0-23.7) when on all four first-line drugs, 13.6 (95%CI 13.3-14.0) when on RMP, INH and PZA, and 2.4 (95%CI 2.3-2.6) when on INH and RMP. Adjusted hazard ratio (HR) revealed that combination regimens containing PZA, females, subjects aged 35-59 and >or=60 years, baseline aspartate aminotransferase >or=80 U/l and drug resistance were associated with any major event. CONCLUSIONS: First-line anti-tuberculosis drugs are associated with significant ADRs. There are several risk factors associated with the development of ADRs, including exposure to regimens containing PZA.

BCG vaccination and the prevalence of latent tuberculosis infection in an aboriginal population.

SETTING: Estimations of prevalence of latent tuberculous infection (LTBI) are confounded by factors known to influence the results of the tuberculin skin test (TST) such as age, contact history and bacille Calmette-Guerin (BCG) vaccination. Appropriate interpretation of TST results is necessary to ensure LTBI treatment for those at greatest risk. OBJECTIVE: To document the prevalence of LTBI in Aboriginal people living on a reserve in British Columbia (BC) and to determine the influence of BCG. DESIGN: A population-based, retrospective descriptive analysis of all epidemiological data collected for the on-reserve Aboriginal programme in BC (1951-1996). RESULTS: Of 17615 persons who received a TST during the study period, 42% had received BCG. During the study period, an average of 2517 TSTs were completed per year (SD = 1228) among persons with an average age of 26 years (SD = 16). Among all subjects, the average prevalence of LTBI was 25% (95 %CI 24-25). The presence of BCG (OR = 3.1, 95%CI 2.8-3.4) and multiple BCGs (OR = 10.2, 95%CI 7.7-13.6) were both associated with a positive TST. A positive TST was also associated with a shorter duration in years between the most recent BCG and the TST. CONCLUSION: The average prevalence of LTBI in a sequential sample of Aboriginal people living on a reserve in BC was estimated at 25%. BCG, especially in multiple doses, increased the likelihood of a positive TST.

Investigation of suspected laboratory cross-contamination: interpretation of single smear-negative, positive cultures for Mycobacterium tuberculosis.

Restriction fragment length polymorphism (RFLP) analysis can be used to assess genetic relatedness of Mycobacterium tuberculosis isolates. This study reports a collaborative investigation of false-positive cultures for M. tuberculosis, suspected when the DNA fingerprint from an index case matched an epidemiologically improbable source case. RFLP analysis matched fingerprints in ten of 16 cases of suspected laboratory contamination to four separate smear-positive sources that were processed on the same day in the same laboratory. All single smear-negative, positive cultures processed on the same day as smear-positive specimens should be reviewed on a case-by-case basis to identify possible false-positive cultures.

Impact of country of origin on drug-resistant tuberculosis among foreign-born persons in British Columbia.

SETTING: Provincial tuberculosis (TB) services, British Columbia, Canada. OBJECTIVES: To estimate the risk of drug resistance among foreign-born TB patients and to identify risk factors associated with drug resistance. DESIGN: Using the provincial TB database, we examined all culture-positive foreign-born TB patients for the years 1990-2001. The risk of having a drug-resistant isolate was estimated according to country and region of origin. RESULTS: Of 1940 foreign-born patients identified, 247 (12.7%, 95%CI 11.3-14.3) cases had isolates resistant to at least one of the first-line drugs, with 160 (8.3%) isolates showing monoresistance, 24 (1.2%) multidrug resistance (resistance to at least isoniazid and rifampin) and 63 (3.3%) polyresistance (resistance to two or more drugs, excluding MDR). Country-specific analysis showed that immigrants from Vietnam (adjusted OR 2.12, 95%CI 1.37-3.27) and the Philippines (adjusted OR 1.71, 95%CI 1.10-2.66) had a significantly higher risk of resistance than other immigrants. In addition, the risk was the highest for younger TB patients and patients with reactivated disease (adjusted OR 2.12, 95%CI 1.09-4.09). CONCLUSION: The risk of drug resistance was the highest among foreign-born patients from Vietnam and the Philippines. These findings should assist clinicians in prescribing and tailoring anti-tuberculosis regimens for immigrants more appropriately.

A population-based study of risk factors for drug-resistant TB in British Columbia.

SETTING: Provincial tuberculosis (TB) services, British Columbia, Canada. OBJECTIVE: To investigate risk factors associated with resistance to anti-tuberculosis drugs in British Columbia and to determine if there are differences in risk factor characteristics among different resistance categories. DESIGN: Using population-based data from provincial TB services, all patients with positive culture for Mycobacterium tuberculosis from 1990 to 2001 were identified and included in the study. Logistic regression analyses were performed to assess risk factors for drug resistance. RESULTS: Among 3041 eligible TB cases, 295 (10%) were found to be drug-resistant. Significant risk factors for resistance were younger age, foreign birth, ethnicity, reactivated TB and place of initial diagnosis. Foreign-born subjects (OR 3.18, 95%CI 2.26-4.49) were three times more likely to present with resistance than Canadian-born subjects. Among ethnic groups, Chinese (OR 2.32, 95%CI 1.51-3.57), South-East Asian (OR 2.92, 95%CI 1.88-4.52) and Other Asian subjects (OR 4.40, 95%CI 2.77-7.01) were 2-4 times more likely to present with resistance than Caucasians. Reactivated cases (OR 2.69, 95%CI 1.91-3.77) were three times as likely to have resistance as new cases. CONCLUSION: These results document and quantify the risk of drug-resistant disease in a large population-based cohort, and highlight patient groups who should be identified as at risk for drug-resistant disease in the industrialised world.

Risk of tuberculosis in children from smear-negative source cases.

SETTING: British Columbia, Canada. OBJECTIVE: To determine the frequency of smear-negative tuberculosis (TB) transmission events from adults to children in epidemiologically linked pairs and to determine the predictors for identifying the source case. DESIGN: We extracted demographic, clinical and mycobacteriology information of 190 children with TB and their 83 source cases reported from 1990 to 2001 in the province of British Columbia. Smear-negative transmission events from adults to children were determined by identifying the smear results of epidemiologically linked source cases. We compared the sex, age, ethnicity, contact history, site of disease and tuberculin skin test (TST) results of children who had a source case identified with those who had not. RESULTS: Smear-negative source cases transmitted the disease to 10% of children (95%CI 5-17). Aboriginals (OR 4.9, 95%CI 1.5-13.4), those with primary TB (OR 7.3, 95%CI 3.3-16.0) and those with a positive TST (OR 2.9, 95%CI 1.2-7.0) were independent predictors for source case identification. CONCLUSION: This study suggests lower rates of transmission of disease to children from smear-negative sources compared to other studies involving all ages. Ethnicity of children, site of disease and a positive TST predict source case identification.

Successful treatment of multidrug-resistant tuberculosis following drug-induced hepatic necrosis requiring liver transplant.

A 28-year-old female developed multidrug-resistant (MDR) tuberculous lymphadenitis following a trip to India. She was initially treated with a four-drug regimen of first-line anti-tuberculosis medications, but when sensitivities indicated resistance to isoniazid and rifampin, her regimen was altered to ciprofloxacin (CFX), pyrazinamide (PZA) and ethambutol. She subsequently developed a rash, flu-like symptoms and fever, which progressed to acute hepatic necrosis despite discontinuation of medication. The clinical presentation and subsequent investigations suggested a hypersensitivity reaction, possibly related to the quinolone. The patient subsequently had an orthoptic liver transplant; second-line anti-tuberculosis medications were restarted to which she responded clinically and radiologically. Our findings raise the possibility that the CFX and PZA combination was responsible for the hepatic necrosis. The patient also illustrates that active, even MDR tuberculosis is not a contraindication to hepatic transplant.

Transmission of tuberculosis from smear negative patients: a molecular epidemiology study.

BACKGROUND: While smear positive patients with tuberculosis (TB) are considered more infectious than smear negative patients, the latter can also transmit TB. METHODS: In a molecular epidemiology study of 791 patients in the Greater Vancouver regional district, the number of episodes of TB transmission from two groups of smear negative clustered patients by RFLP (assumed to be involved in recent transmission) was estimated after assessing for potential bias. Group 1 (n = 79) included patients with pulmonary TB or pulmonary + extrapulmonary disease (PTB or PTB+EPTB); group 2 (n = 129) included all patients in group 1 + extrapulmonary cases alone. RESULTS: In the total sample the mean (SD) age was 51 (21) years, 54.3% were male, and 17.0% of patients were clustered. Compared with smear negative patients, smear positive patients were more likely to be in a cluster (OR = 2.0, 95% CI 1.1 to 3.6) and to have had a history of ethanol abuse (OR = 2.7, 95% CI 1.0 to 6.7), diabetes mellitus (OR = 2.8, 95% CI 1.1 to 7.0), injection drug use (OR = 3.1, 95% CI 1.1 to 8.3), and to have had a previous hospital admission (OR = 8.5, 95% CI 5.1 to 14.0). The proportion of episodes of transmission from smear negative clustered patients ranged from 17.3% to 22.2% in group 1 and from 25% to 41% in group 2. CONCLUSION: In Greater Vancouver, smear negative cases appear responsible for at least one sixth of culture positive episodes of TB transmission.

A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements.

BACKGROUND: The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin test results requires knowledge of the possible confounding factors such as previous BCG vaccination. Uncertainty about the effect of BCG vaccination on tuberculin skin testing and the strength with which recommendations are made to individual patients regarding treatment of LTBI have identified a need to analyse the available data on the effect of BCG on skin testing. A meta-analysis of the evidence for the effect of BCG vaccination on tuberculin skin testing in subjects without active tuberculosis was therefore performed. METHODS: Medline was searched for English language articles published from 1966 to 1999 using the key words "BCG vaccine", "tuberculin test/PPD", and "skin testing". Bibliographies of relevant articles were reviewed for additional studies that may have been missed in the Medline search. Articles were considered for inclusion in the meta-analysis if they had recorded tuberculin skin test results in subjects who had received BCG vaccination more than 5 years previously and had a concurrent control group. Only prospective studies were considered. The geographical location, number of participants, type of BCG vaccine used, type of tuberculin skin test performed, and the results of the tuberculin skin test were extracted. RESULTS: The abstracts and titles of 980 articles were identified, 370 full text articles were reviewed, and 26 articles were included in the final analysis. Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 2.65 [corrected] (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination. CONCLUSIONS: In subjects without active tuberculosis, immunisation with BCG significantly increases the likelihood of a positive tuberculin skin test. The interpretation of the skin test therefore needs to be made in the individual clinical context and with evaluation of other risk factors for infection. The size of the induration should also be considered when making recommendations for treatment of latent infection.

Tuberculosis among aboriginal and nonaboriginal persons in British Columbia.

OBJECTIVE: To compare cases of tuberculosis (TB) diagnosed among aboriginal persons with a random sample of nonaboriginal persons diagnosed with TB, and evaluate the trends in rates of disease between both groups during the same period. DESIGN: A case-control study. SETTING: A provincial TB control program. PATIENTS AND METHODS: All patients with TB diagnosed among aboriginal persons in British Columbia between 1992 and 1996 were compared with control patients diagnosed during the same period. For each patient a control patient was identified. INTERVENTION: The demographic details, type of disease, bacteriology, risk factors for TB, therapy received as well as mode of administration were documented. The number of contacts identified for each patient as well as the number of patients completing chemoprophylaxis were identified. The rates of disease during the same period were also documented. RESULTS: During the study, 202 patients with TB were diagnosed among aboriginal persons and 201 controls were chosen. Apart from age at diagnosis (35.1+/-20 years versus 45.7+/-19.7), differences in the prevalence of lymphadenopathy (5.9% versus 16.4%, P=0.0008) and pleural disease (21.3% versus 16.4%, P=0.00008), there were no differences in presentation between aboriginal and nonaboriginal people. Aboriginal people were more likely to have a history of contact with a patient with TB (53% versus 17.9%, P<0.05), to have received directly observed therapy (55% versus 33.8%, P=0.00002) and to have contacts who were purified protein derivative (PPD) positive (4+/-9 versus 2+/-3, P=0.002). These contacts were more likely to start isoniazid (2+/-3 versus 1+/-1, P=0.002). Overall, there was a significant decline in rates of TB among aboriginal persons compared with the general population, but there was a small increase in rates among all subjects in the final year of the study. CONCLUSIONS: In the present study, significant variations in rates of TB among different population groups in British Columbia were found. During the study period, there was a greater decline in the rates of TB among aboriginal persons. A greater use of directly observed therapy and greater use of chemoprophylaxis occurred among aboriginal persons, which may have contributed to this decline, or alternatively, it simply reflects the natural evolution of the TB epidemic.

The significance of the persistent presence of acid-fast bacilli in sputum smears in pulmonary tuberculosis.

STUDY OBJECTIVES: Identification of acid-fast bacilli (AFB) in the sputum smear at the completion of tuberculosis therapy is in some settings considered evidence of treatment failure. However, some patients with pulmonary tuberculosis (TB) will have positive smear results with negative sputum culture results at the end of therapy. The objectives of this study were to estimate the prevalence of persisting positive sputum smear results in patients with TB and to identify characteristics that distinguish patients with persistently positive sputum smear results who also had negative sputum culture results from patients identified as treatment failures. DESIGN: A population-based, historical cohort study with nested case control study. SETTING: British Columbia Division of Tuberculosis Control central case registry. PATIENTS: All 428 patients with culture-proven pulmonary TB in British Columbia over 7 years with sputum that was positive for AFB. METHODS: Review of laboratory data of all 428 patients, as well as clinical data of a subset of 30 patients with persistently positive smear results beyond 20 weeks. RESULTS: Sputum smears were positive for AFB in 205 patients (48%) at 4 weeks, in 30 patients (7%) at 20 weeks, and in 12 patients (3%) at 36 weeks. Of the patients with smear results that were persistently positive at 20 weeks, 23 (77%) had negative sputum culture results and 7 (23%) had positive sputum culture results (ie, they were treatment failures). Patients identified as treatment failures had more localized disease as shown on chest radiographs, had less radiographic improvement at follow-up, had a higher prevalence of drug resistance, and were less compliant with medications than patients with persistently positive smear results and negative culture results. No subject with a negative culture result relapsed over the 6- to 48-month observation period. CONCLUSION: Sputum that is persistently positive for AFB in patients in developed countries is more likely to be associated with negative culture results than with treatment failure.

Use of incentives to increase compliance for TB screening in a population of intravenous drug users. Vancouver Injection Drug Use Study Group.

SETTING: Intravenous drug users (IDUs) represent a high risk group for dual human immunodeficiency virus (HIV) and tuberculosis (TB) infection. Screening with TB skin testing has therefore been suggested in this group. Subjects' compliance for returning to have TB skin test results read is a major problem. In the setting of a needle exchange program we evaluated the role of financial incentives to increase compliance. METHODS: We evaluated the role of giving a small financial incentive of Can $5 to subjects if they returned to have their purified protein derivative (PPD) skin test read. IDUs who had previously been skin-tested were compared with IDUs drawn from a similar population who, prospectively, were offered a financial incentive. RESULTS: During the initial period 558 subjects were evaluated and no incentive was offered. During the second phase of the study 549 IDUs were assessed but were also offered Can $5 if they returned to have their skin test read. Use of incentives increased compliance from 43% to 78% (P = 0.001). During the same period three active cases of TB were also diagnosed. CONCLUSIONS: We suggest that use of financial incentives can increase the return of IDUs to have their skin tests read. Further studies are required to assess the efficacy of follow-up interventions, especially the use of isoniazid chemoprophylaxis.