Role of the first WHO mutation catalogue in the diagnosis of antibiotic resistance in Mycobacterium tuberculosis in the Valencia Region, Spain: a retrospective genomic analysis.

BACKGROUND: In June, 2021, WHO published the most complete catalogue to date of resistance-conferring mutations in Mycobacterium tuberculosis. Here, we aimed to assess the performance of genome-based antimicrobial resistance prediction using the catalogue and its potential for improving diagnostics in a real low-burden setting. METHODS: In this retrospective population-based genomic study M tuberculosis isolates were collected from 25 clinical laboratories in the low-burden setting of the Valencia Region, Spain. Culture-positive tuberculosis cases reported by regional public health authorities between Jan 1, 2014, and Dec 31, 2016, were included. The drug resistance profiles of these isolates were predicted by the genomic identification, via whole-genome sequencing (WGS), of the high-confidence resistance-causing variants included in the catalogue and compared with the phenotype. We determined the minimum inhibitory concentration (MIC) of the isolates with discordant resistance profiles using the resazurin microtitre assay. FINDINGS: WGS was performed on 785 M tuberculosis complex culture-positive isolates, and the WGS resistance prediction sensitivities were: 85·4% (95% CI 70·8-94·4) for isoniazid, 73·3% (44·9-92·2) for rifampicin, 50·0% (21·1-78·9) for ethambutol, and 57·1% (34·0-78·2) for pyrazinamide; all specificities were more than 99·6%. Sensitivity values were lower than previously reported, but the overall pan-susceptibility accuracy was 96·4%. Genotypic analysis revealed that four phenotypically susceptible isolates carried mutations (rpoB Leu430Pro and rpoB Ile491Phe for rifampicin and fabG1 Leu203Leu for isoniazid) known to give borderline resistance in standard phenotypic tests. Additionally, we identified three putative resistance-associated mutations (inhA Ser94Ala, katG Leu48Pro, and katG Gly273Arg for isoniazid) in samples with substantially higher MICs than those of susceptible isolates. Combining both genomic and phenotypic data, in accordance with the WHO diagnostic guidelines, we could detect two new multidrug-resistant cases. Additionally, we detected 11 (1·6%) of 706 isolates to be monoresistant to fluoroquinolone, which had been previously undetected. INTERPRETATION: We showed that the WHO catalogue enables the detection of resistant cases missed in phenotypic testing in a low-burden region, thus allowing for better patient-tailored treatment. We also identified mutations not included in the catalogue, relevant at the local level. Evidence from this study, together with future updates of the catalogue, will probably lead in the future to the partial replacement of culture testing with WGS-based drug susceptibility testing in our setting. FUNDING: European Research Council and the Spanish Ministerio de Ciencia.

Population-based sequencing of Mycobacterium tuberculosis reveals how current population dynamics are shaped by past epidemics.

Transmission is a driver of tuberculosis (TB) epidemics in high-burden regions, with assumed negligible impact in low-burden areas. However, we still lack a full characterization of transmission dynamics in settings with similar and different burdens. Genomic epidemiology can greatly help to quantify transmission, but the lack of whole genome sequencing population-based studies has hampered its application. Here, we generate a population-based dataset from Valencia region and compare it with available datasets from different TB-burden settings to reveal transmission dynamics heterogeneity and its public health implications. We sequenced the whole genome of 785 Mycobacterium tuberculosis strains and linked genomes to patient epidemiological data. We use a pairwise distance clustering approach and phylodynamic methods to characterize transmission events over the last 150 years, in different TB-burden regions. Our results underscore significant differences in transmission between low-burden TB settings, i.e., clustering in Valencia region is higher (47.4%) than in Oxfordshire (27%), and similar to a high-burden area as Malawi (49.8%). By modeling times of the transmission links, we observed that settings with high transmission rate are associated with decades of uninterrupted transmission, irrespective of burden. Together, our results reveal that burden and transmission are not necessarily linked due to the role of past epidemics in the ongoing TB incidence, and highlight the need for in-depth characterization of transmission dynamics and specifically tailored TB control strategies.

[Vaccination against hepatitis B in patients with inflammatory bowel disease: immune response and associated factors.] / Vacunación frente a hepatitis B en pacientes con enfermedad inflamatoria intestinal: respuesta inmunitaria y factores asociados.

OBJECTIVE: Patients with Inflammatory Bowel Disease (IBD) are at increased risk of hepatitis B virus (HBV) infection as well as a lower response to vaccination. This study aimed to analyze the immune response after vaccination against HBV in patients diagnosed with IBD and its associated factors. METHODS: A retrospective observational study was conducted on patients with IBD treated at the vaccination clinic for at-risk patients at the Complejo Hospitalario Universitario de Albacete during the period 2011-2018. Immune response after vaccination and associated factors were determined using logistic regression models. RESULTS: 231 patients were included. HBV Vaccination had an optimal immune response in 82.7% of the patients. The likelihood of response to vaccination increased in those diagnosed with ulcerative colitis (OR 2.90; 95% CI 1.11-7.61) and decreased with age (80% lower in those aged 40-55 years (OR 0.20; 95% CI 0.05-0.83) and 88% lower in those over 55 years of age (OR 0.12; 95% CI 0.03-0.53) compared to those under 40 years of age) and pharmacological immunosuppression (OR 0.20; 95% CI 0.58-0.71). CONCLUSIONS: The decrease in the immunogenicity of the vaccine against hepatitis B in patients with IBD after the beginning of immunosuppressive treatment, as well as with age, make early vaccination a priority in this kind of patients.

OBJETIVO: Los pacientes con Enfermedad Inflamatoria Intestinal (EII) tienen más riesgo de infección por el virus de la hepatitis B (VHB) así como menor respuesta frente a la vacunación. El objetivo de este estudio fue analizar la respuesta inmunitaria tras la vacunación frente al VHB en los pacientes diagnosticados de EII y sus factores asociados. METODOS: Se realizó un estudio observacional retrospectivo sobre los pacientes con EII atendidos en la consulta de vacunas de pacientes de riesgo en el Complejo Hospitalario Universitario de Albacete durante el período 2011-2018. Se determinó la respuesta serológica tras la vacunación y los factores asociados mediante modelos de regresión logística. RESULTADOS: Se incluyeron 231 pacientes. La vacunación frente al VHB tuvo una respuesta inmunitaria óptima en un 82,7% de los pacientes. La probabilidad de respuesta a la vacunación aumentó en aquellos diagnosticados de colitis ulcerosa (OR 2,90; IC95% 1,11-7,61) y se redujo con la edad (80% menor en los de 40-55 años (OR 0,20; IC95% 0,05-0,83) y 88% menor en mayores de 55 años (OR 0,12; IC95% 0,03-0,53) frente a los menores de 40 años) y con la inmunosupresión farmacológica (OR 0,20; IC95% 0,58-0,71). CONCLUSIONES: La disminución de la inmunogenicidad de la vacuna frente a la hepatitis B en los pacientes con EII tras el inicio del tratamiento inmunosupresor, así como con la edad, hacen prioritaria la vacunación temprana en este tipo de pacientes.

Vacunación frente a hepatitis B en pacientes con enfermedad inflamatoria intestinal: respuesta inmunitaria y factores asociados / Vaccination against hepatitis B in patients with inflammatory bowel disease: immune response and associated factors

Fundamentos: Los pacientes con Enfermedad Inflamatoria Intestinal (EII) tienen más riesgo de infección por el virus de la hepatitis B (VHB) así como menor respuesta frente a la vacunación. El objetivo de este estudio fue analizar la respuesta inmunitaria tras la vacunación frente al VHB en los pacientes diagnosticados de EII y sus factores asociados. Métodos: Se realizó un estudio observacional retrospectivo sobre los pacientes con EII atendidos en la consulta de vacunas de pacientes de riesgo en el Complejo Hospitalario Universitario de Albacete durante el período 2011-2018. Se determinó la respuesta serológica tras la vacunación y los factoresasociados mediante modelos de regresión logística. Resultados: Se incluyeron 231 pacientes. La vacunación frente al VHB tuvo una respuesta inmunitaria óptima en un 82,7% de los pacientes. La probabilidad de respuesta a la vacunación aumentó en aquellos diagnosticados de colitis ulcerosa (OR 2,90; IC95% 1,11-7,61) y se redujo con la edad (80% menor en los de 40-55 años (OR 0,20; IC95% 0,05-0,83) y 88% menor en mayores de 55 años (OR 0,12; IC95% 0,03-0,53) frente a los menores de 40 años) y con la inmunosupresión farmacológica (OR 0,20; IC95% 0,58-0,71). Conclusiones: La disminución de la inmunogenicidad de la vacuna frente a la hepatitis B en los pacientes con EII tras el inicio del tratamiento inmunosupresor, así como con la edad, hacen prioritaria la vacunación temprana en este tipo de pacientes.(AU)

Background: Patients with Inflammatory Bowel Disease (IBD) are at increased risk of hepatitis B virus (HBV) infection as well as a lower response to vaccination. This study aimed to analyze the immune response after vaccination against HBV in patients diagnosed with IBD and its associated factors. Methods: A retrospective observational study was conducted on patients with IBD treated at the vaccination clinic for at-risk patients at the Complejo Hospitalario Universitario de Albacete during the period 2011-2018. Immune response after vaccination and associated factors were determined using logistic regression models. Results: 231 patients were included. HBV Vaccination had an optimal immune response in 82.7% of the patients. The likelihood of response to vaccination increased in those diagnosed with ulcerative colitis (OR 2.90; 95% CI 1.11-7.61) and decreased with age (80% lower in those aged 40- 55 years (OR 0.20; 95% CI 0.05-0.83) and 88% lower in those over 55 years of age (OR 0.12; 95% CI 0.03-0.53) compared to those under 40 years of age) and pharmacological immunosuppression (OR 0.20; 95% CI 0.58-0.71). Conclusions: The decrease in the immunogenicity of the vaccine against hepatitis B in patients with IBD after the beginning of immunosuppressive treatment, as well as with age, make early vaccination a priority in this kind of patients.(AU)

[Outbreak of epidemic keratoconjunctivitis caused by human adenovirus serotype 8 in a nursing home.] / Brote de queratoconjuntivitis epidémica por adenovirus humano serotipo 8 en una residencia de mayores.

OBJECTIVE: Ocular infections caused by human adenovirus are highly contagious and can cause outbreaks, especially in nursing homes. In this work, we describe the epidemiological and analytical research as well as the control measures carried out for a conjunctivitis outbreak. METHODS: Descriptive epidemiological study. Cases with a symptom onset date prior to oficial communication were analyzed retrospectively. The rest was analyzed prospectively. Conjunctival smears were collected for microbiological study. Virological analysis was performed by detecting adenovirus by PCR and genotyping. A data questionnaire that collected clinical and epidemiological information was designed. Possible risk factors associated with infection were studied by calculating the Odds Ratio. RESULTS: On June 11, 2019, the Epidemiological Surveillance Section of the Provincial Health Department of Albacete was notified of the existence of a large number of cases of conjunctivitis in a geriatric center. 54 cases were declared: 43 internal residents, 3 day center assistants and 8 workers. Attack rates were 35.8%, 12.5% and 8.4% respectively. Three risk factors were associated with the disease: patient´s lack of autonomy, being a resident at the nursing home and having their room assigned on the first floor. Human adenovirus serotype 8 was detected in the patients' samples. CONCLUSIONS: A high attack rate was observed in internal residents and the disease was associated with patient´s lack of autonomy and having their room assigned on the first floor of the nursing home. The outbreak was caused by human adenovirus serotype 8.

OBJETIVO: Las infecciones oculares causadas por adenovirus humanos son altamente contagiosas y pueden causar brotes, especialmente en residencias de ancianos. El objetivo de este trabajo fue exponer las investigaciones epidemiológicas y analíticas realizadas para el estudio del brote de queratoconjuntivitis epidémica y las medidas establecidas para su control. METODOS: Se realizó un estudio epidemiológico descriptivo. Se analizaron de forma retrospectiva los casos con fecha de inicio de síntomas anterior a la comunicación oficial, y de forma prospectiva el resto. Se recogieron frotis conjuntivales para estudio microbiológico. El análisis virológico fue realizado mediante la detección de adenovirus por PCR y genotipado. Se diseñó un cuestionario de datos que recogía información clínica y epidemiológica. Se estudiaron posibles factores de riesgo asociados a la infección mediante el cálculo de la Odds Ratio. RESULTADOS: El 11 de junio de 2019 se notificó a la Sección de Vigilancia Epidemiológica de la Dirección Provincial de Sanidad de Albacete la existencia de un número elevado de casos de conjuntivitis en un centro geriátrico. Se declararon 54 casos: 43 entre residentes internos, 3 entre asistentes del centro de día y 8 entre personal laboral. Las tasas de ataque fueron del 35,8%, 12,5% y 8,4%, respectivamente. La falta de autonomía, el ser residente interno y estar ubicado en la primera planta fueron factores asociados a la enfermedad. Se detectó adenovirus humano serotipo 8 en las muestras correspondientes a enfermos. CONCLUSIONES: Se observó una elevada tasa de ataque en residentes internos y la enfermedad se asoció con la falta de autonomía y la localización en la primera planta. El brote fue causado por adenovirus humano serotipo 8.

Brote de queratoconjuntivitis epidémica por adenovirus humano serotipo 8 en una residencia de mayores / Outbreak of epidemic keratoconjunctivitis caused by human adenovirus serotype 8 in a nursing home

OBJETIVO: Las infecciones oculares causadas por adenovirus humanos son altamente contagiosas y pueden causar brotes, especialmente en residencias de ancianos. El objetivo de este trabajo fue exponer las investigaciones epidemiológicas y analíticas realizadas para el estudio del brote de queratoconjuntivitis epidémica y las medidas establecidas para su control. MÉTODOS: Se realizó un estudio epidemiológico descriptivo. Se analizaron de forma retrospectiva los casos con fecha de inicio de síntomas anterior a la comunicación oficial, y de forma prospectiva el resto. Se recogieron frotis conjuntivales para estudio microbiológico. El análisis virológico fue realizado mediante la detección de adenovirus por PCR y genotipado. Se diseñó un cuestionario de datos que recogía información clínica y epidemiológica. Se estudiaron posibles factores de riesgo asociados a la infección mediante el cálculo de la Odds Ratio. RESULTADOS: El 11 de junio de 2019 se notificó a la Sección de Vigilancia Epidemiológica de la Dirección Provincial de Sanidad de Albacete la existencia de un número elevado de casos de conjuntivitis en un centro geriátrico. Se declararon 54 casos: 43 entre residentes internos, 3 entre asistentes del centro de día y 8 entre personal laboral. Las tasas de ataque fueron del 35,8%, 12,5% y 8,4%, respectivamente. La falta de autonomía, el ser residente interno y estar ubicado en la primera planta fueron factores asociados a la enfermedad. Se detectó adenovirus humano serotipo 8 en las muestras correspondientes a enfermos. CONCLUSIONES: Se observó una elevada tasa de ataque en residentes internos y la enfermedad se asoció con la falta de autonomía y la localización en la primera planta. El brote fue causado por adenovirus humano serotipo 8

OBJECTIVE: Ocular infections caused by human adenovirus are highly contagious and can cause outbreaks, especially in nursing homes. In this work, we describe the epidemiological and analytical research as well as the control measures carried out for a conjunctivitis outbreak. METHODS: Descriptive epidemiological study. Cases with a symptom onset date prior to oficial communication were analyzed retrospectively. The rest was analyzed prospectively. Conjunctival smears were collected for microbiological study. Virological analysis was performed by detecting adenovirus by PCR and genotyping. A data questionnaire that collected clinical and epidemiological information was designed. Possible risk factors associated with infection were studied by calculating the Odds Ratio. RESULTS: On June 11, 2019, the Epidemiological Surveillance Section of the Provincial Health Department of Albacete was notified of the existence of a large number of cases of conjunctivitis in a geriatric center. 54 cases were declared: 43 internal residents, 3 day center assistants and 8 workers. Attack rates were 35.8%, 12.5% and 8.4% respectively. Three risk factors were associated with the disease: patient's lack of autonomy, being a resident at the nursing home and having their room assigned on the first floor. Human adenovirus serotype 8 was detected in the patients' samples. CONCLUSIONS: A high attack rate was observed in internal residents and the disease was associated with patient's lack of autonomy and having their room assigned on the first floor of the nursing home. The outbreak was caused by human adenovirus serotype 8

High-resolution mapping of tuberculosis transmission: Whole genome sequencing and phylogenetic modelling of a cohort from Valencia Region, Spain.

BACKGROUND: Whole genome sequencing provides better delineation of transmission clusters in Mycobacterium tuberculosis than traditional methods. However, its ability to reveal individual transmission links within clusters is limited. Here, we used a 2-step approach based on Bayesian transmission reconstruction to (1) identify likely index and missing cases, (2) determine risk factors associated with transmitters, and (3) estimate when transmission happened. METHODS AND FINDINGS: We developed our transmission reconstruction method using genomic and epidemiological data from a population-based study from Valencia Region, Spain. Tuberculosis (TB) incidence during the study period was 8.4 cases per 100,000 people. While the study is ongoing, the sampling frame for this work includes notified TB cases between 1 January 2014 and 31 December 2016. We identified a total of 21 transmission clusters that fulfilled the criteria for analysis. These contained a total of 117 individuals diagnosed with active TB (109 with epidemiological data). Demographic characteristics of the study population were as follows: 80/109 (73%) individuals were Spanish-born, 76/109 (70%) individuals were men, and the mean age was 42.51 years (SD 18.46). We found that 66/109 (61%) TB patients were sputum positive at diagnosis, and 10/109 (9%) were HIV positive. We used the data to reveal individual transmission links, and to identify index cases, missing cases, likely transmitters, and associated transmission risk factors. Our Bayesian inference approach suggests that at least 60% of index cases are likely misidentified by local public health. Our data also suggest that factors associated with likely transmitters are different to those of simply being in a transmission cluster, highlighting the importance of differentiating between these 2 phenomena. Our data suggest that type 2 diabetes mellitus is a risk factor associated with being a transmitter (odds ratio 0.19 [95% CI 0.02-1.10], p < 0.003). Finally, we used the most likely timing for transmission events to study when TB transmission occurred; we identified that 5/14 (35.7%) cases likely transmitted TB well before symptom onset, and these were largely sputum negative at diagnosis. Limited within-cluster diversity does not allow us to extrapolate our findings to the whole TB population in Valencia Region. CONCLUSIONS: In this study, we found that index cases are often misidentified, with downstream consequences for epidemiological investigations because likely transmitters can be missed. Our findings regarding inferred transmission timing suggest that TB transmission can occur before patient symptom onset, suggesting also that TB transmits during sub-clinical disease. This result has direct implications for diagnosing TB and reducing transmission. Overall, we show that a transition to individual-based genomic epidemiology will likely close some of the knowledge gaps in TB transmission and may redirect efforts towards cost-effective contact investigations for improved TB control.