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Background: We sought to identify resistance patterns and key drivers of recent multidrug-resistant tuberculosis (MDR-TB) transmission in a TB-prevalent area in Peru. Methods: Cross-sectional study including MDR Mycobacterium tuberculosis complex (Mtbc) strains identified in Callao-Peru between April 2017 and February 2019. Mtbc DNA was extracted for whole genome sequencing which was used for phylogenetic inference, clustering, and resistance mutation analyses. Clusters indicative of recent transmission were defined based on a strain-to-strain distance of ≤5 (D5) single nucleotide polymorphisms (SNPs). Epidemiologic factors linked to MDR-TB clustering were analyzed using Poisson regression. Findings: 171 unique MDR-Mtbc strains were included; 22 (13%) had additional fluoroquinolone resistance and were classified as pre-XDR. Six strains (3.5%) harboured bedaquiline (BDQ) resistance mutations and were classified as MDR + BDQ. 158 (92%) Mtbc strains belonged to lineage 4 and 13 (8%) to lineage 2. Using a cluster threshold of ≤5 SNPs, 98 (57%) strains were grouped in one of the 17 D5 clusters indicative of recent transmission, ranging in size from 2 to the largest cluster formed by 53 4.3.3 strains (group_1). Lineage 4.3.3 strains showed the overall highest cluster rate (43%). In multivariate analyses, current or previous imprisonment was independently associated with being part of any MDR-TB transmission clusters (adjusted prevalence ratio [aPR], 1.45; 95% CI, 1.09-1.92). Interpretation: Pre-XDR-TB emerged in more than 10% of the MDR-TB strains investigated. Transmission of 4.3.3 Mtbc strains especially of the dominant group_1 clone is a major driver of the MDR-TB epidemic in Callao. Current or previous imprisonment was linked to recent MDR-TB transmissions, indicating an important role of prisons in driving the MDR-TB epidemic. Funding: This work was supported in part by the ERANet-LAC Network of the European Union, Latin America and the Caribbean Countries on Joint Innovation and Research Activities, and FONDECYT. Additional support was received from Leibniz Science Campus Evolutionary Medicine of the Lung, the Deutsche Forschungsgemeinschaft (German Research Foundation, under Germany's Excellence Strategy-EXC 2167 Precision Medicine in Inflammation), and the Research Training Group 2501 TransEvo.

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BACKGROUND: Preeclampsia is a multiorgan disorder associated with maternal and perinatal morbi-mortality. In Peru, incidence is 10% and accounts for 22% of maternal deaths. Genome and genetic epidemiological studies have found an association between preeclampsia and genetic polymorphisms. OBJECTIVE: To determine the association of the vascular endothelial growth factor (VEGF) +936 C/T and +405 G/C, interleukine-6 (IL-6) -174 G/C, IL-1ß-511 C/T, Apo A-1-75 G/A, Apo B-100 2488 C/T (Xbal) polymorphisms with preeclampsia in pregnant Peruvian women. METHODS: Were included preeclamptic and healthy (control) pregnant women. Maternal blood samples were subjected to DNA extraction, and molecular genetic analysis was conducted using the PCR-RFLP technique and following a specific protocol for each gene. Allele and genotypic frequencies in the cases and controls were compared. RESULTS: No association was found between the VEGF+936C/T and VEGF+405 polymorphisms and preeclampsia. The frequencies of the GG genotypes and the G allele of the -174 G/C polymorphism in the IL6 gene in preeclamptic and controls showed significant differences, with higher frequencies in cases. For the -511 C/T polymorphism of the IL-1ß gene, no significant differences were found in the frequencies of TT genotypes compared with CT+CC. The genotypes and alleles of the Apo-A1-75 G/A and Apo-B100 Xbal variants showed no significant differences between cases and controls. CONCLUSION: No association was found between the studied genetic markers and preeclampsia. However, in the -174G/C polymorphism of the IL-6 gene, significant differences were found mainly in the GG genotype and G allele.

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Abstract Background: Preeclampsia is a multiorgan disorder associated with maternal and perinatal morbi-mortality. In Peru, incidence is 10% and accounts for 22% of maternal deaths. Genome and genetic epidemiological studies have found an association between preeclampsia and genetic polymorphisms. Objective: To determine the association of the vascular endothelial growth factor (VEGF) +936 C/T and +405 G/C, interleukine-6 (IL-6) -174 G/C, IL-1β-511 C/T, Apo A-1-75 G/A, Apo B-100 2488 C/T (Xbal) polymorphisms with preeclampsia in pregnant Peruvian women. Methods: Were included preeclamptic and healthy (control) pregnant women. Maternal blood samples were subjected to DNA extraction, and molecular genetic analysis was conducted using the PCR-RFLP technique and following a specific protocol for each gene. Allele and genotypic frequencies in the cases and controls were compared. Results: No association was found between the VEGF+936C/T and VEGF+405 polymorphisms and preeclampsia. The frequencies of the GG genotypes and the G allele of the -174 G/C polymorphism in the IL6 gene in preeclamptic and controls showed significant differences, with higher frequencies in cases. For the -511 C/T polymorphism of the IL-1β gene, no significant differences were found in the frequencies of TT genotypes compared with CT+CC. The genotypes and alleles of the Apo-A1-75 G/A and Apo-B100 Xbal variants showed no significant differences between cases and controls. Conclusion: No association was found between the studied genetic markers and preeclampsia. However, in the -174G/C polymorphism of the IL-6 gene, significant differences were found mainly in the GG genotype and G allele.

Resumen Antecedentes: La preeclampsia es un trastorno multiorgánico asociado con la morbi-mortalidad materna y perinatal. En el Perú, su incidencia es del 10% y causa el 22% de las muertes maternas. Se encontró una asociación entre la preeclampsia y ciertos polimorfismos. Objetivo: Determinar asociación entre los polimorfismos genéticos del factor de crecimiento endotelial vascular (VEGF) +936 C/T y +405 G/C, interleucina-6 (IL-6) -174G/C, IL-1β -511 C/T, Apo A-1 -75 G/A, Apo B-100 2488 C/T (Xbal), y preeclampsia en gestantes peruanas. Métodos: Se incluyeron gestantes preeclámpticas y sanas (controles). Las muestras de sangre fueron procesadas para extracción del ADN, y el análisis se realizó con la técnica PCR-RFLP con protocolos específicos para cada gen y confirmación con secuenciamiento Sanger. Se compararon las frecuencias alélicas y genotípicas en los casos (preeclampsia) y los controles. Resultados: No se halló asociación entre los polimorfismos VEGF+936-C/T y VEGF+405 y la preeclampsia. Las frecuencias de los genotipos GG y el alelo G del polimorfismo -174-G/C en el gen IL6 en preeclámpticas y controles, mostraron diferencias significativas, con frecuencias más altas en los casos. Para el polimorfismo -511-C/T del gen IL-1β, no se encontraron diferencias significativas en las frecuencias de genotipos TT comparados con CT+CC. Los genotipos y alelos de las variantes Apo-A1-75-G/A y Apo-B100 Xbal no mostraron diferencias significativas entre los grupos Conclusión: No se encontró asociación entre los marcadores genéticos estudiados y la preeclampsia. Sin embargo, el polimorfismo -174-G/C en el gen IL6 mostró diferencias significativas principalmente en el genotipo GG y el alelo G.

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In this study, we aimed to assess the relationship between tuberculosis case rate and COVID-19 case fatality rate (CFR) among districts within a tuberculosis-endemic metropolitan area. We analyzed data from 43 districts in Lima, Peru. We used districts as the units of observation. Linear regressions were used to investigate the relationship between COVID-19 CFRs and tuberculosis case rates. The mean COVID-19 CFR in each district for reporting Weeks 5-32 was used as the dependent variable. Independent variable was the mean rate of confirmed pulmonary tuberculosis cases for 2017-2019 period. Analyses were adjusted by population density, socioeconomic status, crowded housing, health facility density, and case rates of hypertension, diabetes mellitus, and HIV infection. The mean COVID-19 CFR in Lima was 4.0% ± 1.1%. The mean tuberculosis rate was 16.0 cases per 10,000 inhabitants. In multivariate analysis, tuberculosis case rate was associated with COVID-19 CFR (ß = 1.26; 95% confidence interval: 0.24-2.28; p = .02), after adjusting for potential confounders. We found that Lima districts with a higher burden of tuberculosis exhibited higher COVID-19 CFRs, independent of socioeconomic, and morbidity variables.

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BACKGROUND: Tuberculosis (TB) has been linked to an increased risk of atherosclerotic cardiovascular disease (ASCVD). We assessed whether latent TB infection (LTBI) is associated with subclinical coronary atherosclerosis in 2 TB-prevalent areas. METHODS: We analyzed cross-sectional data from studies conducted in Lima, Peru, and Kampala, Uganda. Individuals ≥40 years old were included. We excluded persons with known history of ASCVD events or active TB. Participants underwent QuantiFERON-TB (QFT) testing to define LTBI and computed tomography angiography to examine coronary atherosclerosis. A Coronary Artery Disease-Reporting Data System (CAD-RADS) score ≥3 defined obstructive CAD (plaque causing ≥50% stenosis). RESULTS: 113 and 91 persons with and without LTBI, respectively, were included. There were no significant differences between LTBI and non-LTBI participants in terms of age (median [interquartile range]; 56 [51-62] vs 55 [49-64] years; P = .829), male sex (38% vs 42%; P = .519), or 10-year ASCVD risk scores (7.1 [3.2-11.7] vs 6.1 [2.8-1.8]; P = .533). CAD prevalence (any plaque) was similar between groups (29% vs 24%; P = .421). Obstructive CAD was present in 9% of LTBI and 3% of non-LTBI individuals (P = .095). LTBI was associated with obstructive CAD after adjusting for ASCVD risk score, HIV status, and study site (adjusted OR, 4.96; 95% CI, 1.05-23.44; P = .043). Quantitative QFT TB antigen minus Nil interferon-γ responses were associated with obstructive CAD (adjusted OR, 1.2; 95% CI, 1.03-1.41; P = .022). CONCLUSIONS: LTBI was independently associated with an increased likelihood of subclinical obstructive CAD. Our data indicate that LTBI is a nontraditional correlate of ASCVD risk.

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BACKGROUND: We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru. METHODS: We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis. RESULTS: Data from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5-52.8 vs. 6.5 pg/mL, 4.5-15; P<0.01). LTBI remained associated with higher unstimulated interferon-gamma levels after controlling for age, sex, recent AMI, history of hypertension, diabetes mellitus, dyslipidemia, end stage renal disease, malignancy, obesity, and tobacco use (adjusted odds ratio, 2.93; 95% confidence interval, 1.8-4.9). In a sensitivity analysis that excluded participants with AMI, the association between unstimulated interferon-gamma and LTBI remained present (adjusted odds ratio; 3.93; 95% confidence interval, 1.9-8.2). CONCLUSIONS: LTBI was associated with higher unstimulated interferon-gamma levels. These data suggest ongoing immune activation in LTBI.

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Background: Tuberculosis has been associated with an increased risk of cardiovascular disease (CVD), including acute myocardial infarction (AMI). We investigated whether latent tuberculosis infection (LTBI) is associated with AMI. Methods: We conducted a case-control study in 2 large national public hospital networks in Lima, Peru, between July 2015 and March 2017. Case patients were patients with a first time diagnosis of type 1 (spontaneous) AMI. Controls were patients without a history of AMI. We excluded patients with known human immunodeficiency virus infection, tuberculosis disease, or prior LTBI treatment. We used the QuantiFERON-TB Gold In-Tube assay to identify LTBI. We used logistic regression modeling to estimate the odds ratio (OR) of LTBI in AMI case patients versus non-AMI controls. Results: We enrolled 105 AMI case patients and 110 non-AMI controls during the study period. Overall, the median age was 62 years (interquartile range, 56-70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08-3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05-3.45). Conclusions: LTBI was independently associated with AMI. Our results suggest a potentially important role of LTBI in CVD.

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Introducción: El diagnóstico prenatal temprano de anomalías cromosómicas requiere de técnicas invasivas, como la biopsia de vellosidades coriales (BVC) y la amniocentesis (AMC), con el fin de obtener células fetales, cultivarlas y obtener el cariotipo en los fetos con riesgo alto para estas anomalías, identificadas mediante marcadores ecográficos y bioquímicos desde las 11 semanas. Reportamos nuestra experiencia hasta junio del año 2016. Diseño: Estudio descriptivo longitudinal. Institución: Instituto Latinoamericano de Salud Reproductiva (ILSAR), Lima, Perú. Participantes: Fetos de primer y segundo trimestres del embarazo. Intervenciones: Se analizó los resultados del estudio de 400 fetos que cursaban el primer y segundo trimestre y que tenían riesgo alto para anomalías cromosómicas (mayor de 1/270 inicialmente y 1/100 desde el año 2012), resultado cuantificado utilizando la base de datos del Fetal Test de España más el resultado de los marcadores bioquímicos (riesgo combinado). El análisis del cariotipo fetal se realizó en muestras obtenidas por medio de 338 amniocentesis genéticas y 62 biopsias de vellosidades coriales realizadas durante el período comprendido de enero 2003 a junio 2016 en nuestro centro ILSAR. Principales medidas de resultados: Presencia de arcadores ecográficos y normalidad de los cariotipos. Resultados: Los marcadores ecográficos encontrados con mayor frecuencia fueron: higroma quístico (35,8%), translucencia nucal aumentada (13%), ductus venoso con onda de velocidad de flujo anormal (8,5%), dos o más marcadores asociados a anomalías fetales (13,7%). De 400 muestras estudiadas, 141 (35%) fueron cariotipos anormales: 64 (45%) T21, 35 (25%) T18, 21 (15%) 45X, 7 (5%) T13, 14 (10%) otras anomalías. No hubo complicación importante alguna atribuida al procedimiento invasivo. Conclusiones: En los fetos con riesgo alto para anomalías cromosómicas estudiados, el 35% tuvo cariotipo anormal, siendo las más frecuentes las trisomías de los cromosomas 21 y 18, seguidas de la monosomía del cromosoma X. El higroma quístico, la translucencia nucal aumentada y la presencia de 2 o más marcadores asociados a anomalías fetales fueron los hallazgos más frecuentes en la determinación del riesgo ecográfico. El higroma quístico mostró el mayor valor predictivo para anomalías cromosómicas.

Introduction: Early prenatal diagnosis of chromosomal abnormalities requires invasive techniques, including chorionic villous sampling (CVS) and amniocentesis (AMC) in order to acquire, culture and kayotype cells from fetuses at high risk for these abnormalities based on sonographic and biochemical markers present after week 11. We report our experience through June 2016.Design: Descriptive, longitudinal study. Setting: Instituto Latinoamericano de Salud Reproductiva (ILSAR), Lima, Peru. Participants: First and second trimester of pregnancy fetuses. Interventions: Results of the study of 400 first and second trimester fetuses at high risk for chromosomal abnormalities (greater than 1/270 initially or 1/100 starting in 2012) based on Spain Fetal Test database and the results of biochemical markers (combined risk). Fetal karyotype analysis was performed on samples obtained from 338 genetic AMC and 62 CVS from January 2003 to June 2016. Main outcomes measures: Presence of ultrasound markers and normality of karyotypes. Results: The sonographic markers of complications identified most frequently were the following: cystic hygroma (35.8%), increased nuchal translucency (13%), abnormal ductus venosus waveforms (8.5%), two or more markers associated with fetal anomalies (13.7%). Out of the 400 samples studied, 141 (35%) had abnormal karyotypes: 64 (45%) trisomy 21, 35 (25%) trisomy 18, 21 (15%) monosomy X, 7 (5%) trisomy 13, and 14 (10%) other abnormalities. No major complications were attributed to the invasive procedure. Conclusions: Among these fetuses at high risk for chromosomal abnormalities, 35% had an abnormal karyotype. The most frequent chromosomal abnormalities were trisomies 21 and 18, followed by monosomy X. Cystic hygroma, increased nuchal translucency, and the presence of 2 or more markers associated with fetal anomalies were the most common findings in determining the sonographic risk of abnormalities. Cystic hygroma showed the highest predictive value for chromosomal abnormalities.

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Introducción: El diagnóstico prenatal temprano de anomalías cromosómicas requiere de técnicas invasivas, como la biopsia de vellosidades coriales (BVC) y la amniocentesis (AMC), con el fin de obtener células fetales, cultivarlas y obtener el cariotipo en los fetos con riesgo alto para estas anomalías, identificadas mediante marcadores ecográficos y bioquímicos desde las 11 semanas. Reportamos nuestra experiencia hasta junio del año 2016. Diseño: Estudio descriptivo longitudinal. Institución: Instituto Latinoamericano de Salud Reproductiva (ILSAR), Lima, Perú. Participantes: Fetos de primer y segundo trimestres del embarazo. Intervenciones: Se analizó los resultados del estudio de 400 fetos que cursaban el primer y segundo trimestre y que tenían riesgo alto para anomalías cromosómicas (mayor de 1/270 inicialmente y 1/100 desde el año 2012), resultado cuantificado utilizando la base de datos del Fetal Test de España más el resultado de los marcadores bioquímicos (riesgo combinado). El análisis del cariotipo fetal se realizó en muestras obtenidas por medio de 338 amniocentesis genéticas y 62 biopsias de vellosidades coriales realizadas durante el período comprendido de enero 2003 a junio 2016 en nuestro centro ILSAR. Principales medidas de resultados: Presencia de arcadores ecográficos y normalidad de los cariotipos. Resultados: Los marcadores ecográficos encontrados con mayor frecuencia fueron: higroma quístico (35,8%), translucencia nucal aumentada (13%), ductus venoso con onda de velocidad de flujo anormal (8,5%), dos o más marcadores asociados a anomalías fetales (13,7%). De 400 muestras estudiadas, 141 (35%) fueron cariotipos anormales: 64 (45%) T21, 35 (25%) T18, 21 (15%) 45X, 7 (5%) T13, 14 (10%) otras anomalías. No hubo complicación importante alguna atribuida al procedimiento invasivo. Conclusiones: En los fetos con riesgo alto para anomalías cromosómicas estudiados, el 35% tuvo cariotipo anormal, siendo las más frecuentes las trisomías de los cromosomas 21 y 18, seguidas de la monosomía del cromosoma X. El higroma quístico, la translucencia nucal aumentada y la presencia de 2 o más marcadores asociados a anomalías fetales fueron los hallazgos más frecuentes en la determinación del riesgo ecográfico. El higroma quístico mostró el mayor valor predictivo para anomalías cromosómicas.

Introduction: Early prenatal diagnosis of chromosomal abnormalities requires invasive techniques, including chorionic villous sampling (CVS) and amniocentesis (AMC) in order to acquire, culture and kayotype cells from fetuses at high risk for these abnormalities based on sonographic and biochemical markers present after week 11. We report our experience through June 2016.Design: Descriptive, longitudinal study. Setting: Instituto Latinoamericano de Salud Reproductiva (ILSAR), Lima, Peru. Participants: First and second trimester of pregnancy fetuses. Interventions: Results of the study of 400 first and second trimester fetuses at high risk for chromosomal abnormalities (greater than 1/270 initially or 1/100 starting in 2012) based on Spain Fetal Test database and the results of biochemical markers (combined risk). Fetal karyotype analysis was performed on samples obtained from 338 genetic AMC and 62 CVS from January 2003 to June 2016. Main outcomes measures: Presence of ultrasound markers and normality of karyotypes. Results: The sonographic markers of complications identified most frequently were the following: cystic hygroma (35.8%), increased nuchal translucency (13%), abnormal ductus venosus waveforms (8.5%), two or more markers associated with fetal anomalies (13.7%). Out of the 400 samples studied, 141 (35%) had abnormal karyotypes: 64 (45%) trisomy 21, 35 (25%) trisomy 18, 21 (15%) monosomy X, 7 (5%) trisomy 13, and 14 (10%) other abnormalities. No major complications were attributed to the invasive procedure. Conclusions: Among these fetuses at high risk for chromosomal abnormalities, 35% had an abnormal karyotype. The most frequent chromosomal abnormalities were trisomies 21 and 18, followed by monosomy X. Cystic hygroma, increased nuchal translucency, and the presence of 2 or more markers associated with fetal anomalies were the most common findings in determining the sonographic risk of abnormalities. Cystic hygroma showed the highest predictive value for chromosomal abnormalities.

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BACKGROUND: Isoniazid and rifampicin are the two most efficacious first-line agents for tuberculosis (TB) treatment. We assessed the prevalence of isoniazid and rifampicin mono-resistance, associated risk factors, and the association of mono-resistance on treatment outcomes. METHODS: A prospective, observational cohort study enrolled adults with a first episode of smear-positive pulmonary TB from 34 health facilities in a northern district of Lima, Peru, from March 2010 through December 2011. Participants were interviewed and a sputum sample was cultured on Löwenstein-Jensen (LJ) media. Drug susceptibility testing was performed using the proportion method. Medication regimens were documented for each patient. Our primary outcomes were treatment outcome at the end of treatment. The secondary outcome included recurrent episodes among cured patients within two years after completion of the treatment. RESULTS: Of 1292 patients enrolled, 1039 (80%) were culture-positive. From this subpopulation, isoniazid mono-resistance was present in 85 (8%) patients and rifampicin mono-resistance was present in 24 (2%) patients. In the multivariate logistic regression model, isoniazid mono-resistance was associated with illicit drug use (adjusted odds ratio (aOR) = 2.10; 95% confidence interval (CI): 1.1-4.1), and rifampicin mono-resistance was associated with HIV infection (aOR = 9.43; 95%CI: 1.9-47.8). Isoniazid mono-resistant patients had a higher risk of poor treatment outcomes including treatment failure (2/85, 2%, p-value<0.01) and death (4/85, 5%, p<0.02). Rifampicin mono-resistant patients had a higher risk of death (2/24, 8%, p<0.01). CONCLUSION: A high prevalence of isoniazid and rifampicin mono-resistance was found among TB patients in our low HIV burden setting which were similar to regions with high HIV burden. Patients with isoniazid and rifampicin mono-resistance had an increased risk of poor treatment outcomes.

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