Martien W. Borgdorff

Molecular Epidemiology of Tuberculosis in the Netherlands: A Nationwide Study from 1993 through 1997

To disclose risk factors for active tuberculosis transmission in the Netherlands, restriction fragment length polymorphism (RFLP) patterns of 78% of the Mycobacterium tuberculosis isolates, from the period 1993-1997, were analyzed. Of the respective 4266 cases, 46% were found in clusters of isolates with identical RFLPs, and 35% were attributed to active transmission. The clustering percentage increased strongly with the number of isolates; taking this into account, fewer cases were clustered than has been reported in other studies. Contact investigations in the five largest clusters of 23-47 patients suggested epidemiological linkage between cases. Of patients identified through contact tracing, 91% were clustered. Demographic risk factors for active transmission of tuberculosis included male sex, urban residence, Dutch and Surinamese nationality, and long-term residence in the Netherlands. Human immunodeficiency virus infection was not an independent risk factor for active transmission. Isoniazid-resistant strains were relatively less frequently clustered, suggesting that these generated fewer secondary cases.

Progression to Active Tuberculosis, but Not Transmission, Varies by Mycobacterium tuberculosis Lineage in The Gambia

BACKGROUND There is considerable variability in the outcome of Mycobacterium tuberculosis infection. We hypothesized that Mycobacterium africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease. METHODS In a cohort study of patients with tuberculosis and their household contacts in The Gambia, we categorized 1808 HIV-negative tuberculosis contacts according to exposure to M. tuberculosis or M. africanum. Positive skin test results indicated transmission, and development of tuberculosis during 2 years of follow-up indicated progression to disease. RESULTS Transmission rates were similar, but rates of progression to disease were significantly lower in contacts exposed to M. africanum than in those exposed to M. tuberculosis (1.0% vs. 2.9%; hazard ratio [HR], 3.1 [95% confidence interval {CI}, 1.1-8.7]). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR relative to M. africanum, 6.7 [95% CI, 2.0-22]). CONCLUSIONS M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.

Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review

Background The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data. Methodology and Principal Findings To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis. Conclusions Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

Mutations at Amino Acid Position 315 of the katG Gene Are Associated with High-Level Resistance to Isoniazid, Other Drug Resistance, and Successful Transmission of Mycobacterium tuberculosis in The Netherlands

The prevalence of mutations at amino acid (aa) position 315 in the katG gene of isoniazid (INH)-resistant Mycobacterium tuberculosis isolates in The Netherlands and the mutations association with the level of INH resistance, multidrug resistance, and transmission were determined. Of 4288 M. tuberculosis isolates with available laboratory results, 295 (7%) exhibited INH resistance. Of 148 aa 315 mutants, 89% had MICs of 5-10 microg/mL, whereas 75% of the other 130 INH-resistant strains had MICs of 0.5-1 microg/mL. Of the aa 315 mutants, 33% exhibited monodrug resistance, compared with 69% of other INH-resistant strains (P<.0001). Multidrug resistance was found among 14% of the aa 315 mutants and 7% of the other INH-resistant strains (P>.05). The probability of being in an IS6110 DNA restriction fragment length polymorphism cluster was similar for aa 315 mutants and INH-susceptible strains, but the probability was reduced in other INH-resistant strains. Thus, aa 315 mutants lead to secondary cases of tuberculosis as often as INH-susceptible strains do.

Proportion of tuberculosis transmission that takes place in households in a high-incidence area

The prevalence of infection among household contacts of people with tuberculosis is high. This information frequently guides active case finding. We analysed DNA fingerprints of Mycobacterium tuberculosis from 765 tuberculosis patients in Ravensmead and Uitsig, adjacent suburbs of Cape Town, South Africa. In 129 households in which DNA fingerprints were available for more than one patient, we identified 313 patients, of whom 145 (46%) had a fingerprint pattern matching that of another member of the household. The proportion of transmission in the community that took place in the household was 19%, and therefore, in this high-incidence area, tuberculosis transmission occurs mainly outside the household.

Interventions to reduce tuberculosis mortality and transmission in low- and middle-income countries

Tuberculosis is among the top ten causes of global mortality and affects low-income countries in particular. This paper examines, through a literature review, the impact of tuberculosis control measures on tuberculosis mortality and transmission, and constraints to scaling-up. It also provides estimates of the effectiveness of various interventions using a model proposed by Styblo. It concludes that treatment of smear-positive tuberculosis using the WHO directly observed treatment, short-course (DOTS) strategy has by far the highest impact. While BCG immunization reduces childhood tuberculosis mortality, its impact on tuberculosis transmission is probably minimal. Under specific conditions, an additional impact on mortality and transmission can be expected through treatment of smear-negative cases, intensification of case-finding for smear-positive tuberculosis, and preventive therapy among individuals with dual tuberculosis-HIV infection. Of these interventions, DOTS is the most cost-effective at around US

Analysis of Rate of Change of IS6110 RFLP Patterns of Mycobacterium tuberculosis Based on Serial Patient Isolates

5-40 per disability-adjusted life year (DALY) gained. The cost for BCG immunization is likely to be under US

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts

50 per DALY gained. Treatment of smear-negative patients has a cost per DALY gained of up to US

Association between smoking and tuberculosis infection: a population survey in a high tuberculosis incidence area

100 in low-income countries, and up to US

Mycobacterium tuberculosis Beijing Genotype and Risk for Treatment Failure and Relapse, Vietnam

400 in middle-income settings. Other interventions, such as preventive therapy for HIV-positive individuals, appear to be less cost-effective. The major constraint to scaling up DOTS is lack of political commitment, resulting in shortages of funding and human resources for tuberculosis control. However, in recent years there have been encouraging signs of increasing political commitment. Other constraints are related to involvement of the private sector, health sector reform, management capacity of tuberculosis programmes, treatment delivery, and drug supply. Global tuberculosis control could benefit strongly from technical innovation, including the development of a vaccine giving good protection against smear-positive pulmonary tuberculosis in adults; simpler and shorter drug regimens for treatment of tuberculosis disease and infection; and improved diagnostics for tuberculosis infection and disease.