Tuberculosis due to Resistant Haarlem Strain, Tunisia

Multidrug-resistant tuberculosis was diagnosed in 21 HIV-negative, nonhospitalized male patients residing in northern Tunisia. A detailed investigation showed accelerated transmission of a Mycobacterium tuberculosis clone of the Haarlem type in 90% of all patients. This finding highlights the epidemic potential of this prevalent genotype

MDR-TB Outbreak among HIV-Negative Tunisian Patients followed during 11 Years

<div><p>Background</p><p>Multidrug-resistant tuberculosis (MDR-TB) outbreaks that evolve, from the outset, in a context strictly negative for HIV infection deserve special consideration since they reflect the true intrinsic epidemic potential of the causative strain. To our knowledge, the long-term evolution of such exceptional outbreaks and the treatment outcomes for the involved patients has never been reported hitherto. Here we provide a thorough description, over an 11-year period, of an MDR-TB outbreak that emerged and expanded in an HIV-negative context, Northern Tunisia.</p><p>Methodology/Principal Findings</p><p>From October 2001 to June 2011, the MDR-TB outbreak involved 48 HIV-negative individuals that are mainly young (mean age 31.09 yrs; 89.6% male) and noninstitutionalized. Drug susceptibility testing coupled to mutational analysis revealed that initial transmission involved an isolate that was simultaneously resistant to isoniazid, rifampicin, ethambutol, and streptomycin. The causative Haarlem3-ST50 outbreak strain expanded mainly as an 11-banded IS<i>6110</i> RFLP profile (77.1%), from which a 12-banded subclone evolved. After undergoing a 2-year treatment with second-line drugs, 22 (45.8%) patients were cured and 3 (6.2%) completed treatment, thus yielding an overall treatment success rate of 52.1%. Among the patients that experienced unfavorable treatment outcomes, 10 (20.8%) failed treatment, 3 (6.2%) were lost to follow-up, 5 (10.4%) died, and 5 (10.4%) could not be evaluated. Poor adherence to treatment was found to be the main independent predictor of unfavorable outcomes (HR: 9.15; 95% CI 1.72–48.73; <i>P</i> = 0.014). Intriguingly, the evolved 12-banded subclone proved significantly associated with unfavorable outcomes (HR: 4.90; 95% CI 1.04–23.04, <i>P</i> = 0.044). High rate of fatality and relapse was further demonstrated at the long-term, since 70% of those whose treatment failed have died, and 24% among those deemed successfully treated have relapsed.</p><p>Conclusions/Significance</p><p>Taken together, the data obtained in this study indicate that MDR-TB clinical isolates could become fit enough to cause large and severe outbreaks in an HIV-negative context. Such MDR-TB outbreaks are characterized by low treatment success rates and could evolve towards increased severity, thus calling for early detection of cases and the necessity to raise the bar of surveillance throughout and beyond the treatment period.</p></div

Promoter and neck region length variation of DC-SIGN is not associated with susceptibility to tuberculosis in Tunisian patients.

International audienceThe C-type lectin DC-SIGN (CD209) is an important pathogen recognition receptor of the innate immune system. Recent studies showed that DC-SIGN is the major receptor of Mycobacterium tuberculosis on human dendritic cells and that polymorphisms in the DC-SIGN promoter region are associated with susceptibility to tuberculosis. In this light, we aimed to study the potential implication of DC-SIGN genetic variation in the predisposition to tuberculosis in a group of Tunisian patients. We thus performed an association study comprising 138 tuberculosis patients and 140 healthy controls. Sequencing of the DC-SIGN promoter region detected four polymorphisms (-939, -871, -601, and -336), but no differences in their allelic distribution were observed between the two groups. In addition, the analysis of length variation in the DC-SIGN neck region indicated extremely low levels of polymorphisms and, again, no differences between patients and controls. Our data showed therefore that neither promoter variants nor length variation in the neck region of DC-SIGN is associated with susceptibility to tuberculosis in Tunisian patients

Emergence and expansion scenario of the Tunisian Haarlem3 MDR-TB outbreak based on genotypic analyses and accumulation of mutations in drug resistance genes.

<p>Numbers 11 and 12 within the blue and red circles indicate the 11-banded and 12-banded RFLP profiles, respectively. Lanes in blue indicate outbreak strains that evolved as 11-banded IS<i>6110</i> RFLP profile, while lanes in red indicate those with the 12-banded IS<i>6110</i> RFLP profile. The number of strains (n =) with a particular genotypic and drug resistance mutation profile is indicated. The detailed MIRU-VNTR24 patterns of the outbreak strains (MIRU1 and MIRU2) are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153983#pone.0153983.s001" target="_blank">S1 Table</a>.</p

Kaplan–Meier plots and log-rank test for probability of unfavorable outcomes, according to AFP smear positivity (A), poor adherence to treatment (B), and IS<i>6110</i> RFLP pattern of the outbreak strain (C).

<p>Kaplan–Meier plots and log-rank test for probability of unfavorable outcomes, according to AFP smear positivity (A), poor adherence to treatment (B), and IS<i>6110</i> RFLP pattern of the outbreak strain (C).</p

Baseline demographic characteristics of the 48 MDR-TB outbreak-associated patients according to the IS<i>6110</i>-RFLP profile of their corresponding isolate.

<p>Baseline demographic characteristics of the 48 MDR-TB outbreak-associated patients according to the IS<i>6110</i>-RFLP profile of their corresponding isolate.</p

Clinical outcomes for the 41 Haarlem3 MDR-TB outbreak patients that had received a 2-year second line anti-TB chemotherapy.

<p>Clinical outcomes for the 41 Haarlem3 MDR-TB outbreak patients that had received a 2-year second line anti-TB chemotherapy.</p

Predictors of unfavorable outcomes for the MDR-TB outbreak patients that had received a 2-year second line anti-TB chemotherapy.

<p>Predictors of unfavorable outcomes for the MDR-TB outbreak patients that had received a 2-year second line anti-TB chemotherapy.</p

Temporal distribution of the 48 Haarlem3 MDR-TB outbreak cases, 2001–2011.

<p>Temporal distribution of the 48 Haarlem3 MDR-TB outbreak cases, 2001–2011.</p