Publications by authors named "Marcos Burgos"

29 Publications

  • Page 1 of 1

COVID-19 in Argentine teriflunomide-treated multiple sclerosis patients: First national case series.

Mult Scler Relat Disord 2021 May 30;53:103049. Epub 2021 May 30.

Centro de Esclerosis Múltiple de Buenos Aires, CABA; Argentina; Servicio de Neurología, Hospital Universitario CEMIC, Buenos Aires, Argentina.

We report COVID-19 presentation, course and outcomes in teriflunomide-treated MS patients in Argentina.

Methods: descriptive, retrospective, multicentre, study that included MS patients receiving teriflunomide who developed COVID-19, with clinical follow-up at reference MS centres, also listed in a nationwide registry.

Results: Eighteen MS patients on teriflunomide treatment, from eight MS centres developed COVID-19. The mean age was 41,2 years and 72% of them were female; 94% had diagnosis of relapsing-remitting MS and 6% presented a radiologically isolated syndrome. Median EDSS was 2 (range 0-5.5). The average time on teriflunomide therapy was 3 years. COVID-19 diagnosis was confirmed with nasal swab in 61%. None required hospitalization and they completely recovered from the acute-phase within 7-14 days. All the patients continued their teriflunomide therapy during COVID-19 course. No MS relapses occurred during or after COVID-19 course.

Conclusion: Our report adds to the evidence that COVID-19 is mild in patients receiving teriflunomide therapy and that continuing with teriflunomide therapy during Sars-CoV-2 infection is safe and advisable for MS patients.
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http://dx.doi.org/10.1016/j.msard.2021.103049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164731PMC
May 2021

Aggressive multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM.

J Clin Neurosci 2021 Jul 1;89:360-364. Epub 2021 Jun 1.

Neuroimmunology Unit, Department of Neuroscience, Hospital Aleman, Buenos Aires, Argentina.

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (aMS) as well as to compare clinical and radiological characteristics in aMS and non-aMS patients included in RelevarEM (NCT03375177).

Methods: The eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥ 6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥ 6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-aMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset.

Results: A total of 2158 patients with MS were included: 74 aMS and 2084 non-aMS. The prevalence of aMS in our cohort was 3.4% (95%CI 2.7-4.2). AMS were more likely to be male (p = 0.003), older at MS onset (p < 0.001), have primary progressive MS (PPMS) phenotype (p = 0.03), multifocal presentation (p < 0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p = 0.004 and p = 0.002, respectively).

Conclusion: 3.4% of our patient population could be considered aMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesions on MRI at clinical presentation all had higher odds of having aMS.
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http://dx.doi.org/10.1016/j.jocn.2021.05.047DOI Listing
July 2021

COVID-19 in multiple sclerosis and neuromyelitis optica spectrum disorder patients in Latin America: COVID-19 in MS and NMOSD patients in LATAM.

Mult Scler Relat Disord 2021 Jun 7;51:102886. Epub 2021 Mar 7.

Centro de esclerosis múltiple de Buenos Aires, Argentina.

Background: There is no data regarding COVID-19 in Multiple Sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients in Latin America.

Objective: The objective of this study was to describe the clinical characteristics and outcomes of patients included in RELACOEM, a LATAM registry of MS and NMOSD patients infected with COVID-19.

Methods: RELACOEM is a longitudinal, strictly observational registry of MS and NMOSD patients who suffer COVID-19 and Dengue in LATAM. Inclusion criteria to the registry were either: (1) a biologically confirmed COVID-19 diagnosis based on a positive result of a COVID-19 polymerase chain reaction (PCR) test on a nasopharyngeal swab; or (2) COVID-19-typical symptoms (triad of cough, fever, and asthenia) in an epidemic zone of COVID-19. Descriptive statistics were performed on demographic and clinical variables. The cohort was later stratified for MS and NMOSD and univariate and multivariate logistic regression analysis was performed to identify variables associated with hospitalizations/intensive critical units (ICU) admission.

Results: 145 patients were included in the registry from 15 countries and 51 treating physicians. A total of 129 (89%) were MS patients and 16 (11%) NMOSD. 81.4% patients had confirmed COVID-19 and 18.6% were suspected cases. 23 (15.8%) patients were hospitalized, 9 (6.2%) required ICU and 5 (3.4 %) died due to COVID-19. In MS patients, greater age (OR 1.17, 95% CI 1.05 - 1.25) and disease duration (OR 1.39, 95%CI 1.14-1.69) were associated with hospitalization/ICU. In NMOSD patients, a greater age (54.3 vs. 36 years, p=<0.001), increased EDSS (5.5 vs 2.9, p=0.0012) and disease duration (18.5 vs. 10.3 years, p=0.001) were significantly associated with hospitalization/ICU.

Conclusion: we found that in MS patients, age and disease duration was associated with hospitalization and ICU admission requirement, while age, disease duration and EDSS was associated in NMOSD.
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http://dx.doi.org/10.1016/j.msard.2021.102886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937038PMC
June 2021

What percentage of AQP4-ab-negative NMOSD patients are MOG-ab positive? A study from the Argentinean multiple sclerosis registry (RelevarEM).

Mult Scler Relat Disord 2021 Apr 7;49:102742. Epub 2021 Jan 7.

Hospital Central de Mendoza, Mendoza.

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-ab) have been described in aquaporin-4-antibodies(AQP4-ab)-negative neuromyelitis optica spectrum disorder (NMOSD) patients. We aimed to evaluate the percentage of AQP4-ab-negative NMOSD patients who are positive for MOG-ab in a cohort of Argentinean patients included in RelevarEM (Clinical Trials registry number NCT03375177).

Methods: RelevarEM is a longitudinal, strictly observational multiple sclerosis (MS) and NMOSD registry in Argentina. Of 3031 consecutive patients (until March 2020), 165 patients with phenotype of suspected NMOSD, whose relevant data for the purpose of this study were available, were included. Data on demographic, clinical, paraclinical and treatment in AQP4-ab (positive, negative and unknown) and MOG-ab (positive and negative) patients were evaluated.

Results: A total of 165 patients (79 AQP4-Ab positive, 67 AQP4-Ab negative and 19 unknown) were included. Of these, 155 patients fulfilled the 2015 NMOSD diagnostic criteria. Of 67 AQP4-Ab-negative patients, 36 (53.7%) were tested for MOG-Ab and 10 of them (27.7%) tested positive. Serum AQP4-ab levels were tested by means of cell-based assay (CBA) in 48 (35.2%), based on tissue-based indirect immunofluorescence assays in 58 (42.6%) and enzyme-linked immunosorbent assay in 4 (2.9%). All MOG-ab were tested by CBA. Optic neuritis (90%) was the most frequent symptom at presentation and optic nerve lesions the most frequent finding (80%) in neuroimaging of MOG-ab-associated disease. Of these, six (60%) patients were under immunosuppressant treatments at latest follow-up.

Conclusion: We observed that 27.7% (10/36) of the AQP4-ab-negative patients tested for MOG-ab were positive for this antibody, in line with results from other world regions.
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http://dx.doi.org/10.1016/j.msard.2021.102742DOI Listing
April 2021

Absence of latitudinal gradient in oligoclonal bands prevalence in Argentina.

Mult Scler Relat Disord 2020 Nov 13;46:102582. Epub 2020 Oct 13.

Servicio de Neurología - Hospital San Bernardo, Salta, Argentina.

Background: Like MS prevalence, oligoclonal bands (OCB) frequency seems to follow a latitudinal gradient. Argentina is extensive, latitude-wise, and previous studies have not found an MS prevalence latitudinal gradient. Our aim is to describe OCB prevalence in MS, clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) patients included in the Argentinean MS and NMOSD registry (RelevarEM) and to investigate if it follows a latitudinal gradient.

Methods: For each province, an average latitude was calculated, and OCB frequency was investigated. Multivariate logistical regression analysis and linear correlation were performed. Statistical analysis was repeated after excluding patients from centers using isoelectric focusing (IEF) in less than 95% of patients (CwIEF<95).

Results: We included 2866 patients. OCB where positive in 73.9% of patients. No association or correlation were found between OCB and latitude of residence, even after excluding patients from (CwIEF<95).

Conclusion: OCB positivity does not follow a latitudinal gradient in Argentina. Also, OCB positivity is lower than described in other world regions.
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http://dx.doi.org/10.1016/j.msard.2020.102582DOI Listing
November 2020

Essential Components of a Public Health Tuberculosis Prevention, Control, and Elimination Program: Recommendations of the Advisory Council for the Elimination of Tuberculosis and the National Tuberculosis Controllers Association.

MMWR Recomm Rep 2020 07 31;69(7):1-27. Epub 2020 Jul 31.

This report provides an introduction and reference tool for tuberculosis (TB) controllers regarding the essential components of a public health program to prevent, control, and eliminate TB. The Advisory Council for the Elimination of Tuberculosis and the National Tuberculosis Controllers Association recommendations in this report update those previously published (Advisory Council for the Elimination of Tuberculosis. Essential components of a tuberculosis prevention and control program. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep 1995;44[No. RR-11]). The report has been written collaboratively on the basis of experience and expert opinion on approaches to organizing programs engaged in diagnosis, treatment, prevention, and surveillance for TB at state and local levels.This report reemphasizes the importance of well-established priority strategies for TB prevention and control: identification of and completion of treatment for persons with active TB disease; finding and screening persons who have had contact with TB patients; and screening, testing, and treatment of other selected persons and populations at high risk for latent TB infection (LTBI) and subsequent active TB disease.Health departments are responsible for public safety and population health. To meet their responsibilities, TB control programs should institute or ensure completion of numerous responsibilities and activities described in this report: preparing and maintaining an overall plan and policy for TB control; maintaining a surveillance system; collecting and analyzing data; participating in program evaluation and research; prioritizing TB control efforts; ensuring access to recommended laboratory and radiology tests; identifying, managing, and treating contacts and other persons at high risk for Mycobacterium tuberculosis infection; managing persons who have TB disease or who are being evaluated for TB disease; providing TB training and education; and collaborating in the coordination of patient care and other TB control activities. Descriptions of CDC-funded resources, tests for evaluation of persons with TB or LTBI, and treatment regimens for LTBI are provided (Supplementary Appendices; https://stacks.cdc.gov/view/cdc/90289).
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http://dx.doi.org/10.15585/mmwr.rr6907a1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392523PMC
July 2020

Consensus recommendations for family planning and pregnancy in multiple sclerosis in argentina.

Mult Scler Relat Disord 2020 Aug 4;43:102147. Epub 2020 May 4.

Instituto Lennox/Clínica Reina Fabiola, Córdoba, Argentina.

Background: Multiple sclerosis (MS) is the most common chronic immune-mediated neurological disorder in young adults, more frequently found in women than in men. Therefore, pregnancy-related issues have become an object of concern for MS professionals and patients. The aim of this work was to review the existing data to develop the first Argentine consensus for family planning and pregnancy in MS patients.

Methods: A panel of expert neurologists from Argentina engaged in the diagnosis and care of MS patients met both virtually and in person during 2019 to carry out a consensus recommendation for family planning and pregnancy in MS. To achieve consensus, the procedure of the "formal consensus-RAND/UCLA method" was used.

Results: Recommendations were established based on published evidence and expert opinion focusing on pre-pregnancy counseling, pregnancy, and postpartum issues.

Conclusion: The recommendations of these consensus guidelines are intended to optimize the management and treatment of MS patients during their reproductive age in Argentina.
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http://dx.doi.org/10.1016/j.msard.2020.102147DOI Listing
August 2020

Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020.

MMWR Recomm Rep 2020 02 14;69(1):1-11. Epub 2020 Feb 14.

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States.The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (e.g., with low-quality evidence).These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M. tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9 months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens.In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9 month) isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances.
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http://dx.doi.org/10.15585/mmwr.rr6901a1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041302PMC
February 2020

Addressing Latent Tuberculosis Infection Treatment Through a Collaborative Care Model With Community Pharmacies and a Health Department.

Prev Chronic Dis 2020 02 13;17:E14. Epub 2020 Feb 13.

New Mexico Department of Health, Tuberculosis Program, Santa Fe, New Mexico.

Introduction: The objective of this study was to evaluate a novel collaborative care model using community pharmacies as additional access points for latent tuberculosis infection (LTBI) treatment for patients using combination weekly therapy with isoniazid and rifapentine (3HP) plus directly observed therapy for 12 weeks.

Methods: This prospective pilot study included adult patients diagnosed with LTBI. Patients were eligible for study participation if they spoke English or Spanish and were followed by the New Mexico Department of Health (NM DOH). Patients were excluded if they were pregnant, receiving concomitant HIV antiretroviral therapy, or had contraindications to 3HP due to allergy or drug interactions. Community pharmacy sites included chain, independent, and hospital outpatient pharmacies in Albuquerque and Santa Fe, New Mexico.

Results: A total of 40 patients initiated treatment with 3HP and were included. Most were female (55%) and had a mean age of 46 years (standard deviation, 12.6 y). A total of 75.0% of patients completed LTBI treatment with 3HP in a community pharmacy site. Individuals of Hispanic ethnicity were more likely to complete treatment (76.7% vs 40.0%, P = .04). Most patients (60%; n = 24) reported experiencing an adverse drug event (ADE) with 3HP therapy. Patients who completed treatment were less likely to experience an ADE than patients who discontinued treatment (50.0% vs 90.0%, P = .03). Pharmacists performed 398 LTBI treatment visits (40 initial visits, 358 follow-up visits), saving the NM DOH approximately 143 hours in patient contact time.

Conclusion: High completion rates and safe administration of LTBI treatment can be achieved in the community pharmacy setting.
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http://dx.doi.org/10.5888/pcd17.190263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021458PMC
February 2020

Multiple sclerosis and neuromyelitis optica spectrum disorders in Argentina: comparing baseline data from the Argentinean MS Registry (RelevarEM).

Neurol Sci 2020 Jun 20;41(6):1513-1519. Epub 2020 Jan 20.

Sección de Neuroinmunología y Enfermedades Desmielinizantes, Servicio de Neurología, Hospital de Clínicas José de San Martín, CABA, Argentina.

The objective of this study was to describe and compare the baseline epidemiological data of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients included in RelevarEM (Clinical Trials registry number NCT03375177).

Methods: RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. Epidemiological and comorbidity data from MS and NMOSD patients were described and compared. For comorbidities, the Charlson comorbidity index (CCI) was used to calculate the burden at entry. CCI was stratified in 0 and ≥ 1 and described for the entire cohort.

Results: A total of 1588 and 75 MS and NMOSD patients (respectively) were included. For MS patients, the mean age was 42 ± 7 years, female sex 65.3%, mean EDSS 2, and mean disease duration 8 ± 6 years. In NMOSD, the mean age was 40 ± 7 years, female sex 78.7%, mean disease duration 5 ± 3.5 years, and mean EDSS 2.5. The most frequent MS phenotype was RRMS in 82.4%. In MS, the CCI was 0 in 85.8.2% while ≥ 1 was in 14.2% of patients. Regarding phenotype stratification, CCI ≥ 1 was 3.9% in CIS, 13.5% in RRMS, 28.7% in SPMS, and 17.4% in PPMS (p < 0.001 between groups). In NMOSD, the CCI was 0 in 64% while ≥ 1 was in 36%. The MS/NMOSD ratio found was 21/1.

Conclusions: This is the first analysis of the longitudinal Argentinean registry of MS and NMOSD describing and comparing conditions that contributes to provide reliable real-world data in the country.
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http://dx.doi.org/10.1007/s10072-019-04230-6DOI Listing
June 2020

Consensus recommendations on the management of multiple sclerosis patients in Argentina.

J Neurol Sci 2020 Feb 2;409:116609. Epub 2019 Dec 2.

Institute of Neuroscience Buenos Aires - INEBA, Argentina.

Introduction: During the last 20 years, multiple sclerosis (MS) disease has seen major changes with new diagnostic criteria, a better identification of disease phenotypes, individualization of disease prognosis and the appearance of new therapeutic options in relapsing remitting as well as progressive MS. As a result, the management of MS patients has become more complex and challenging. The objective of these consensus recommendations was to review how the disease should be managed in Argentina to improve long-term outcomes in MS patients.

Methods: A panel of 36 experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2018 and 2019 to carry out a consensus recommendation on the management of MS patients in Argentina. To achieve consensus, the methodology of "formal consensus-RAND/UCLA method" was used.

Results: Recommendations focused on diagnosis, disease prognosis, tailored treatment, treatment failure identification and pharmacovigilance process.

Conclusions: The recommendations of these consensus guidelines attempt to optimize the health care and management of patients with MS in Argentina.
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http://dx.doi.org/10.1016/j.jns.2019.116609DOI Listing
February 2020

The Argentinean multiple sclerosis registry (RelevarEM): Methodological aspects and directions.

Mult Scler Relat Disord 2019 Jul 15;32:133-137. Epub 2019 May 15.

Centro de esclerosis múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Gascón 450,1181, Buenos Aires, Argentina.

Despite that different registries already exist in various countries in Europe and North America, no ongoing nationwide registry exists in Latin America (LATAM), a region where the disease behaves differently than in other regions. The objective of this document is to describe the methodology behind RelevarEM, the first nationwide MS registry in Argentina and LATAM. METHODS: In this article, we described the creation, implementation and data management of the nationwide MS registry in Argentina. The registry contains information on the structure, ethical aspects, implementation and variables of the registry (Clinical Trials registry number NCT NCT03375177). CONCLUSION: RelevarEM is the first MS nationwide registry in Argentina, as well as in LATAM, with the objective of providing reliable real-world data of MS in the country.
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http://dx.doi.org/10.1016/j.msard.2019.05.004DOI Listing
July 2019

Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients.

J Neurol Sci 2018 02 4;385:217-224. Epub 2018 Jan 4.

Hospital de Clínicas Ntra Sra del Carmen, San Miguel de Tucumán, Argentina.

One of the biggest challenges in multiple sclerosis (MS) is the definition of treatment response/failure in order to optimize treatment decisions in affected patients. The objective of this consensus was to review how disease activity should be assessed and to propose recommendations on the identification of treatment failure in RRMS patients in Argentina.

Methods: A panel of experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2016 and 2017 to carry out a consensus recommendation on the identification of treatment failure in RRMS patients. To achieve consensus, the methodology of "formal consensus-RAND/UCLA method" was used.

Results: Recommendations were established based on published evidence and the expert opinion. Recommendations focused on disease management, disease activity markers and treatment failure identification were determined. Main consensus were: ≥2 relapses during the first year of treatment and/or ≥3 new or enlarged T2 or T1 GAD+ lesions and/or sustained increase of ≥2 points in EDSS or ≥100% in T25FW defines treatment failure in RRMS patients.

Conclusions: The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Argentina.
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http://dx.doi.org/10.1016/j.jns.2018.01.004DOI Listing
February 2018

Virulence of Mycobacterium tuberculosis after Acquisition of Isoniazid Resistance: Individual Nature of katG Mutants and the Possible Role of AhpC.

PLoS One 2016 28;11(11):e0166807. Epub 2016 Nov 28.

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.

In the last decade, there were 10 million new tuberculosis cases per year globally. Around 9.5% of these cases were caused by isoniazid resistant (INHr) Mycobacterium tuberculosis (Mtb) strains. Although isoniazid resistance in Mtb is multigenic, mutations in the catalase-peroxidase (katG) gene predominate among the INHr strains. The effect of these drug-resistance-conferring mutations on Mtb fitness and virulence is variable. Here, we assessed differences in bacterial growth, immune response and pathology induced by Mtb strains harboring mutations at the N-terminus of the katG gene. We studied one laboratory and one clinically isolated Mtb clonal pair from different genetic lineages. The INHr strain in each pair had one and two katG mutations with significantly reduced levels of the enzyme and peroxidase activity. Both strains share the V1A mutation, while the double mutant clinical INHr had also the novel E3V katG mutation. Four groups of C57BL/6 mice were infected with one of the Mtb strains previously described. We observed a strong reduction in virulence (reduced bacterial growth), lower induction of proinflammatory cytokines and significantly reduced pathology scores in mice infected with the clinical INHr strain compared to the infection caused by its INHs progenitor strain. On the other hand, there was a subtle reduction of bacteria growth without differences in the pathology scores in mice infected with the laboratory INHr strain. Our results also showed distinct alkyl-hydroperoxidase C (AhpC) levels in the katG mutant strains, which could explain the difference in the virulence profile observed. The difference in the AhpC levels between clonal strains was not related to a genetic defect in the gene or its promoter. Cumulatively, our results indicate that the virulence, pathology and fitness of INHr strains could be negatively affected by multiple mutations in katG, lack of the peroxidase activity and reduced AhpC levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125630PMC
June 2017

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Eur Respir J 2016 10 1;48(4):1160-1170. Epub 2016 Sep 1.

Institute of Tropical Medicine, Antwerp, Belgium.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045442PMC
http://dx.doi.org/10.1183/13993003.00462-2016DOI Listing
October 2016

Tuberculosis screening using ability to provide sputum in an endemic emergency department.

Eur Respir J 2016 Jan 22;47(1):330-3. Epub 2015 Oct 22.

TB Centre and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.

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http://dx.doi.org/10.1183/13993003.00877-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703042PMC
January 2016

First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea.

Infect Genet Evol 2015 Jul 21;33:314-9. Epub 2015 May 21.

Institute of Tropical Medicine (ITM), Antwerp, Belgium; Medical Research Council (MRC), Fajara, Gambia; New York University (NYU), New York, United States.

In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs.
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http://dx.doi.org/10.1016/j.meegid.2015.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503999PMC
July 2015

Social and clinical predictors of drug-resistant tuberculosis in a public hospital, Monterrey, Mexico.

Ann Epidemiol 2014 Oct 10;24(10):771-5. Epub 2014 Jul 10.

Department of Anthropology, University of New Mexico, Albuquerque.

Purpose: Drug-resistant tuberculosis (DRTB) is steadily increasing in Mexico, but little is known of patient risk factors in the Mexico-United States border region. This preliminary case-control study included 95 patients with active pulmonary TB with drug susceptibility results attending the José E. González University Hospital in the urban hub of Nuevo León-the Monterrey Metropolitan Area. We report potential social and clinical risk factors of DRTB among this hospital-based sample.

Methods: We collected data through face-to-face interviews and medical record reviews from 25 cases with DRTB and 70 drug-sensitive controls. DNA was collected to assess an effect of genetic ancestry on DRTB by using a panel of 291,917 genomic markers. We calculated crude and multivariate logistic regression.

Results: After adjusting for potential confounding factors, we found that prior TB treatment (odds ratio, 4.5; 95% confidence interval, 0.9-21.1) and use of crack cocaine (odds ratio, 4.6; 95% confidence interval, 1.1-18.7) were associated with DRTB. No other variables, including genetic ancestry and comorbidities, were predictive.

Conclusions: Health care providers may benefit from recognizing predictors of DRTB in regions where routine drug susceptibility testing is limited. Prior TB treatment and illicit drug use, specifically crack cocaine, may be important risk factors for DRTB in this region.
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http://dx.doi.org/10.1016/j.annepidem.2014.07.001DOI Listing
October 2014

ENCOMS: Argentinian survey in cost of illness and unmet needs in multiple sclerosis.

Arq Neuropsiquiatr 2014 May;72(5):337-43

Novartis, Argentina.

Unlabelled: The objective of the study was to assess the cost of multiple sclerosis (MS) patients in Argentina categorized by disease severity using a societal perspective.

Method: Cross-sectional study including MS patients from 21 MS centers in 12 cities of Argentina. Patients were stratified by disease severity using the expanded disability status scale (EDSS) (group 1 with EDSS score between 0 and 3; group 2 with EDSS >3 and <7; group 3 with EDSS ≥7). Direct and indirect costs were analyzed for the second quarter of 2012 from public sources and converted to US Dollars.

Results: 266 patients were included. Mean annual cost per MS patient was USD 36,025 (95%CI 31,985-38,068) for patients with an EDSS between 0-3; USD 40,705 (95%CI 37,199-46,300) for patients with EDSS >3 and <7, and USD 50,712 (95%CI 47,825-62,104) for patients with EDSS ≥7.

Conclusions: This is the first Argentine study evaluating the costs of MS considering disease severity.
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http://dx.doi.org/10.1590/0004-282x20140016DOI Listing
May 2014

The effects of socioeconomic status, clinical factors, and genetic ancestry on pulmonary tuberculosis disease in northeastern Mexico.

PLoS One 2014 11;9(4):e94303. Epub 2014 Apr 11.

University of New Mexico, Department of Anthropology, Albuquerque, New Mexico, United States of America.

Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB susceptibility in parental populations may contribute to variation in disease susceptibility in the region.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094303PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984129PMC
January 2015

Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampin-resistant, rpoB mutant Mycobacterium tuberculosis.

J Bacteriol 2012 Dec 21;194(23):6441-52. Epub 2012 Sep 21.

Division of Infectious Diseases, Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Multidrug-resistant tuberculosis has emerged as a major threat to tuberculosis control. Phylogenetically related rifampin-resistant actinomycetes with mutations mapping to clinically dominant Mycobacterium tuberculosis mutations in the rpoB gene show upregulation of gene networks encoding secondary metabolites. We compared the expressed proteomes and metabolomes of two fully drug-susceptible clinical strains of M. tuberculosis (wild type) to those of their respective rifampin-resistant, rpoB mutant progeny strains with confirmed rifampin monoresistance following antitubercular therapy. Each of these strains was also used to infect gamma interferon- and lipopolysaccharide-activated murine J774A.1 macrophages to analyze transcriptional responses in a physiologically relevant model. Both rpoB mutants showed significant upregulation of the polyketide synthase genes ppsA-ppsE and drrA, which constitute an operon encoding multifunctional enzymes involved in the biosynthesis of phthiocerol dimycocerosate and other lipids in M. tuberculosis, but also of various secondary metabolites in related organisms, including antibiotics, such as erythromycin and rifamycins. ppsA (Rv2931), ppsB (Rv2932), and ppsC (Rv2933) were also found to be upregulated more than 10-fold in the Beijing rpoB mutant strain relative to its wild-type parent strain during infection of activated murine macrophages. In addition, metabolomics identified precursors of phthiocerol dimycocerosate, but not the intact molecule itself, in greater abundance in both rpoB mutant isolates. These data suggest that rpoB mutation in M. tuberculosis may trigger compensatory transcriptional changes in secondary metabolism genes analogous to those observed in related actinobacteria. These findings may assist in developing novel methods to diagnose and treat drug-resistant M. tuberculosis infections.
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http://dx.doi.org/10.1128/JB.01013-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497527PMC
December 2012

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

PLoS Med 2012 28;9(8):e1001300. Epub 2012 Aug 28.

Bureau of Tuberculosis, New York, New York, United States of America.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.

Methods And Findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]).

Conclusions: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.
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http://dx.doi.org/10.1371/journal.pmed.1001300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429397PMC
December 2012

Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlled trial.

JAMA 2011 Apr;305(14):1415-23

Clinical Trial Division, International Union Against Tuberculosis and Lung Disease, Paris, France.

Context: Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance.

Objective: To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis.

Design, Setting, And Patients: The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis.

Interventions: Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n = 798 patients) or separately (n = 787) in the 8-week intensive phase of treatment.

Main Outcome Measure: Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%.

Results: In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups.

Conclusions: Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations.

Trial Registration: clinicaltrials.gov Identifier: NCT00216333.
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http://dx.doi.org/10.1001/jama.2011.436DOI Listing
April 2011

Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis.

PLoS Pathog 2006 Jun 16;2(6):e61. Epub 2006 Jun 16.

Division of Infectious Diseases and Geographic Medicine, Stanford University Medical Center, Stanford, California, USA.

Understanding the ecology of drug-resistant pathogens is essential for devising rational programs to preserve the effective lifespan of antimicrobial agents and to abrogate epidemics of drug-resistant organisms. Mathematical models predict that strain fitness is an important determinant of multidrug-resistant Mycobacterium tuberculosis transmission, but the effects of strain diversity have been largely overlooked. Here we compared the impact of resistance mutations on the transmission of isoniazid-resistant M. tuberculosis in San Francisco during a 9-y period. Strains with a KatG S315T or inhA promoter mutation were more likely to spread than strains with other mutations. The impact of these mutations on the transmission of isoniazid-resistant strains was comparable to the effect of other clinical determinants of transmission. Associations were apparent between specific drug resistance mutations and the main M. tuberculosis lineages. Our results show that in addition to host and environmental factors, strain genetic diversity can influence the transmission dynamics of drug-resistant bacteria.
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http://dx.doi.org/10.1371/journal.ppat.0020061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1479046PMC
June 2006

Treatment of multidrug-resistant tuberculosis in San Francisco: an outpatient-based approach.

Clin Infect Dis 2005 Apr 2;40(7):968-75. Epub 2005 Mar 2.

Department of Internal Medicine, Division of Infectious Diseases, University of New Mexico, Albuquerque, New Mexico 87131-5271, USA.

Background: Treatment of patients with multidrug-resistant tuberculosis requires prolonged therapy, often involving long hospital stays. Despite intensive and costly therapy, cure rates are relatively low.

Methods: We reviewed the outcomes for all patients with multidrug-resistant tuberculosis treated in San Francisco, California, during 1982-2000 and identified billing charges for patients treated during 1995-2000. Mycobacterium tuberculosis isolates were genotyped by IS6110-based restriction fragment-length polymorphism analysis.

Results: Forty-eight cases were identified with resistance to a median of 3 drugs (range, 2-9 drugs). The median age of the patients was 49.5 years (range, 22-78 years); 36 (75%) of 48 patients were foreign born, 11 (23%) were human immunodeficiency virus (HIV) seropositive, and 45 (94%) had pulmonary tuberculosis. Thirty-two (97%) of the 33 HIV-seronegative patients were cured, with only 1 relapse occurring 5 years after treatment. All 11 HIV-seropositive patients died during observation. Twenty-one patients (44%) required hospitalization, with a median duration of stay of 14 days (range, 3-74 days). The estimated inpatient and outpatient aggregate cost for the 11 patients treated after 1994 was $519,928, with a median cost of $27,752 per patient. No secondary cases of multidrug-resistant tuberculosis were identified through population-based genotyping.

Conclusions: Treatment of multidrug-resistant tuberculosis in HIV-seronegative patients largely on an outpatient basis was feasible and was associated with high cure rates and lower cost than in other published studies. Patients with underlying HIV infection had very poor outcomes.
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http://dx.doi.org/10.1086/428582DOI Listing
April 2005

Molecular epidemiology of tuberculosis: methodology and applications.

Biomedica 2004 Jun;24 Supp 1:188-201

Division of Infectious Diseases, University of New Mexico, Health Sciences Center, Department of Internal Medicine, Albuquerque, NM, USA.

The resurgence of tuberculosis around the world has renewed interest in understanding the epidemiology and pathogenesis of this disease. A revolutionary advance in the field of tuberculosis research has been the development of molecular techniques that permit identification and tracking of individual strains of Mycobacterium tuberculosis. With these techniques, molecular epidemiology has been established as a new discipline that adds another dimension to the classical epidemiology of tuberculosis and has increased our understanding of the transmission dynamics of M. tuberculosis. The increased epidemiological knowledge has led to discovery of inadequacies in tuberculosis control programs; this information has helped garner resources for program improvement and has highlighted the need for the continuous surveillance of tuberculosis. Additional genetic methods are being developed based on the knowledge of the genome sequence of M. tuberculosis. These simpler and less costly genotyping techniques promise to expand the application of molecular epidemiology to developing nations (where 90% of the disease burden occurs) in support of national tuberculosis programs. Furthermore, these tools permit ever more effective probes into the dynamics of transmission, the population structure, evolution and pathogenesis of M. tuberculosis.
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June 2004

Mycobacteria inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection.

Infect Immun 2004 May;72(5):2872-8

Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-0620, USA.

Inducible nitric oxide synthase (iNOS) is a cytoplasmic protein responsible for the generation of nitric oxide (NO. ) in macrophages. In this work, we hypothesized that the intracellular localization of iNOS is significant for effective delivery of NO. to phagosomes containing ingested microorganisms. Using immunofluorescence microscopy and Western blot analysis, iNOS was shown to localize in the vicinity of phagosomes containing latex beads in stimulated macrophages. iNOS also localized to phagosomes containing Escherichia coli. The colocalization of iNOS with ingested latex beads was an actin-dependent process, since treatment with the actin microfilament disrupter cytochalasin D prevented iNOS recruitment to latex bead phagosomes. In contrast to E. coli and inert particle phagosomes, mycobacterial phagosomes did not colocalize with iNOS. This study demonstrates that (i). iNOS can be recruited to phagosomes; (ii). this recruitment is dependent on a functional actin cytoskeleton; (iii). certain microorganisms have the ability to prevent or reduce colocalization with iNOS; and (iv). spatial exclusion of iNOS may play a role in Mycobacterium tuberculosis pathogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC387846PMC
http://dx.doi.org/10.1128/IAI.72.5.2872-2878.2004DOI Listing
May 2004

Effect of drug resistance on the generation of secondary cases of tuberculosis.

J Infect Dis 2003 Dec 9;188(12):1878-84. Epub 2003 Dec 9.

Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University Medical Center, Stanford, California, USA.

Background: The results of animal studies suggest that isoniazid-resistant strains of Mycobacterium tuberculosis are less pathogenic than isoniazid-susceptible strains. Here, we assess the relative pathogenicity of drug-resistant and drug-susceptible strains, in a human population.

Methods: We linked IS6110 genotype patterns of M. tuberculosis strains with drug-susceptibility test results and epidemiologic information for 85% of culture-positive incident cases of tuberculosis (TB) in San Francisco during 1991-1999. We assumed that drug-susceptible and drug-resistant strains were transmitted to secondary case patients if the drug-resistance and genotype patterns were identical. We calculated the number of secondary cases for each drug-resistance pattern and determined the relative secondary-case rate ratio (SR) of drug-resistant TB to drug-susceptible TB.

Results: There were 1800 patients with culture-positive TB, drug-susceptibility test results, and genotyping results. The overall SR of drug-resistant to drug-susceptible TB cases was 0.51 (95% confidence interval [CI], 0.37-0.69). The SR was 0.29 (95% CI, 0.15-0.57) for isoniazid-resistant strains, 0.10 (95% CI, 0.02-0.42) for strains resistant to both isoniazid and streptomycin, and 0.88 (95% CI, 0.53-1.47) for streptomycin-resistant strains. There were no secondary cases caused by multidrug-resistant (MDR) TB. The SR for rifampin-resistant cases was 2.33 (95% CI, 1.04-5.25). Seventy-eight percent (7/9) of the patients with rifampin-resistant secondary cases of TB were seropositive for human immunodeficiency virus.

Conclusion: In the context of an effective TB program in San Francisco, strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drug-susceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases.
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http://dx.doi.org/10.1086/379895DOI Listing
December 2003
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