Allelic and genotypic frequencies of NAT2, CYP2E1, and AADAC genes in a cohort of Peruvian tuberculosis patients.

BACKGROUND: We determined the frequency of genetic polymorphisms in three anti-TB drug metabolic proteins previously reported: N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and arylacetamide deacetylase (AADAC) within a Peruvian population in a cohort of TB patients. METHODS: We genotyped SNPs rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2; rs3813867 and rs2031920 for CYP2E1; and rs1803155 for AADAC in 395 participants completed their antituberculosis treatment. RESULTS: Seventy-four percent of the participants are carriers of slow metabolizer genotypes: NAT2*5, NAT2*6, and NAT2*7, which increase the sensitivity of INH at low doses and increase the risk of drug-induced liver injuries. Sixty-four percent are homozygous for the wild-type CYP2E1*1A allele, which could increase the risk of hepatotoxicity. However, 16% had a NAT2 fast metabolizer phenotype which could increase the risk of acquiring resistance to INH, thereby increasing the risk of multidrug-resistant (MDR) or treatment failure. The frequency of rs1803155 (AADAC*2 allele) was higher (99.9%) in Peruvians than in European American, African American, Japanese, and Korean populations. CONCLUSIONS: This high prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru. These data will help the Peruvian National Tuberculosis Control Program develop new strategies for therapies.

Anti-tuberculosis chemotherapy alters TNFR2 expression on CD4+ lymphocytes in both drug-sensitive and -resistant tuberculosis: however, only drug-resistant tuberculosis maintains a pro-inflammatory profile after a long time.

BACKGROUND: Tuberculosis (TB) is an infectious disease. During TB, regulatory T cells (Treg) are related to poor prognosis. However, information about conventional and unconventional Treg (cTreg and uTreg, respectively) is limited. The tumour necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) are necessary for mycobacterial infection, and TNFR2 signalling is required to maintain Treg. METHODS: A blood sample of drug-susceptible (DS-TB) and drug-resistant tuberculosis (DR-TB) patients was obtained before (basal) and after 2 and 6 months of anti-TB therapy. Expression of TNF, TNFR1, and TNFR2 (transmembrane form, tm) on cTreg, uTreg, activated CD4+ (actCD4+), and CD4+ CD25- (CD4+) T cell subpopulations were evaluated. The main objective was to identify immunological changes associated with sensitive/resistant Mtb strains and with the use of anti-TB therapy. RESULTS: We found that after 6 months of anti-TB therapy, both DS- and DR-TB patients have decreased the frequency of cTreg tmTNF+, CD4+ tmTNFR1+ and CD4+ tmTNFR2+. Nevertheless, after 6 months of therapy, only DR-TB patients decreased the frequency of actCD4+ tmTNF+ and actCD4+ tmTNFR2+, exhibited a systemic inflammatory status (high levels of TNF, IFN-γ and IL-12), and their purified CD4+ T cells showed that TNF and TNFR2 are up-regulated at the transcriptional level. Moreover, DS- and DR-TB down-regulated TNFR1 and other proteins associated with Treg (FOXP3 and TGFß1) in response to the anti-TB therapy. CONCLUSION: These results partially explain the differences in the immune response of DS-TB vs DR-TB. The frequency of actCD4+ tmTNFR2+ cells and inflammatory status should be considered in the follow-up of therapy in DR-TB patients.

Prevalence of latent tuberculosis in patients with hematological neoplasms in a cancer referral hospital in Mexico City.

OBJECTIVE: To determine the prevalence of Latent Tuberculosis in patients with hematological neoplasms at the Instituto Nacional de Cancerología in Mexico City using the Tuberculin skin test (TST). METHODS: This retrospective study included all patients with a recent diagnosis of hematological neoplasms who were admitted for treatment from 2017 to 2018 and who were screened for latent tuberculosis with the TST. The prevalence of latent tuberculosis in this group, tolerance and therapeutic adherence in treated patients are described. RESULTS: The files of 446 patients with hematological malignancy who had a TST were reviewed. The prevalence of latent tuberculosis was 31.2% (n = 139). Ninety-three patients received isoniazid, 15.1% had some adverse reactions, but only 4 (4.3%) had to discontinue treatment. Two patients with latent tuberculosis under treatment with Isoniazid reactivated tuberculosis infection. CONCLUSIONS: The prevalence in our study was within the range of other similar Mexican populations. Isoniazid treatment had an adequate tolerance and adherence. Longer follow-up could offer more information on the risk of reactivation in both groups.

Latent and active tuberculosis infection in allogeneic hematopoietic stem cell transplant recipients: a prospective cohort study.

Tuberculosis (TB) is a major infectious complication in hematopoietic stem cell transplant (HSCT) recipients in countries with high TB prevalence. Identifying and treating latent tuberculosis infection (LTBI) helps to prevent TB reactivation after transplantation. Few studies have compared the tuberculin skin test (TST) with interferon Gamma release assays (IGRA) to diagnose LTBI in HSCT candidates. We compared TST and QuantiFeron TB gold in tube (QTF-GIT) and prospectively evaluated the incidence of active tuberculosis in 126 HSCT candidates and 58 HSCT recipients with chronic GVHD followed at the outpatient clinic. TB was diagnosed by culture in Mycobacteria media and by commercial real-time PCR kit. Considering the positivity of any test, the prevalence of LTBI was 8.7% in HSCT candidates (11 out of 126) and 12.5% in HSCT recipients with chronic GVHD (6 out of 48). QTF-GIT indeterminate results were detected in 2.4% of the HSCT candidates. Fair to good agreement (K > 0.50) between tests was observed in both cohorts. Cumulative incidence of TB was 3% in the GVHD cohort. TB was diagnosed in 2 chronic GVHD recipients, both cases confirmed by positive culture and PCR. None of the 11 patients with LTBI diagnosed pre-HSCT who received INH prophylaxis developed TB.

Single-Nucleotide Variants in the AIM2 - Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis.

Tuberculosis (TB) remains a serious public health burden worldwide. TB is an infectious disease caused by the Mycobacterium tuberculosis Complex. Innate immune response is critical for controlling mycobacterial infection. NOD-like receptor pyrin domain containing 3/ absent in melanoma 2 (NLRP3/AIM2) inflammasomes are suggested to play an important role in TB. NLRP3/AIM2 mediate the release of pro-inflammatory cytokines IL-1ß and IL-18 to control M. tuberculosis infection. Variants of genes involved in inflammasomes may contribute to elucidation of host immune responses to TB infection. The present study evaluated single-nucleotide variants (SNVs) in inflammasome genes AIM2 (rs1103577), CARD8 (rs2009373), and CTSB (rs1692816) in 401 patients with pulmonary TB (PTB), 133 patients with extrapulmonary TB (EPTB), and 366 healthy control (HC) subjects with no history of TB residing in the Amazonas state. Quantitative Real Time PCR was performed for allelic discrimination. The SNV of AIM2 (rs1103577) is associated with protection for PTB (padj: 0.033, ORadj: 0.69, 95% CI: 0.49-0.97). CTSB (rs1692816) is associated with reduced risk for EPTB when compared with PTB (padj: 0.034, ORadj: 0.50, 95% CI: 0.27-0.94). Serum IL-1ß concentrations were higher in patients with PTB than those in HCs (p = 0,0003). The SNV rs1103577 of AIM2 appeared to influence IL-1ß release. In a dominant model, individuals with the CC genotype (mean 3.78 ± SD 0.81) appeared to have a higher level of IL-1ß compared to carriers of the T allele (mean 3.45 ± SD 0.84) among the patients with PTB (p = 0,0040). We found that SNVs of AIM2 and CTSB were associated with TB, and the mechanisms involved in this process require further study.

Malnutrition and tuberculosis: the gap between basic research and clinical trials.

Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB), an infectious disease that leads to numerous deaths worldwide. Malnutrition, smoking, alcohol abuse, Human Immunodeficiency Virus infection, and diabetes are some of the most important risk factors associated with TB development. At present, it is necessary to conduct studies on risk factors to establish new effective strategies and combat this disease. Malnutrition has been established as a risk factor since several years ago; although there is in vitro experimental evidence that reveals the importance of micronutrients in activating the immune response against M.tb, evidence from clinical trials is controversial. Currently, nutritional assessment is recommended in all TB patients upon diagnosis. However, there is insufficient evidence to indicate micronutrient supplementation as adjuvant therapy or prophylactic to prevent micronutrient depletion. Strengthening the interaction between basic and clinical research is necessary to carry out studies that will help establish adjuvant therapies to improve outcomes in TB patients. In this review, we discuss the experimental evidence, provided by basic research, regarding micronutrients in the TB field. However, when these studies are applied to clinical trials, the data are inconsistent, indicating that still missing mechanisms are necessary to propose alternatives to the treatment of TB patients.

Análise espacial e temporal da tuberculose entre pessoas em uso crônico de álcool, tabaco e ou drogas ilícitas no Estado do Paraná / Spatial and temporal analysis of tuberculosis among people with chronic use of alcohol, tobacco and/or illicit drugs in the state of Paraná

Introdução: A tuberculose é uma doença infectocontagiosa causada pelo Mycobacterium tuberculosis, que tem estreita relação com as desigualdades sociais, atingindo principalmente pessoas em exclusão social, e por vezes, em uso abusivo de álcool, tabaco e drogas ilícitas. Objetivo: Analisar a distribuição espacial e tendência temporal dos casos diagnosticados por tuberculose entre alcoolistas, tabagistas e usuários de drogas ilícitas no Estado do Paraná, Sul do Brasil. Métodos: Tratou-se de um estudo ecológico, desenvolvido nos 399 munícipios do Estado do Paraná. A população do estudo consistiu de casos diagnosticados de tuberculose no Sistema de Informação de Agravos de Notificação, entre o período de 2008 a 2018 com declaração de alcoolismo, tabagismo e uso de drogas ilícitas. Recorreu-se à análise exploratória dos dados por meio da estatística descritiva com o cálculo de medidas de frequências absolutas e relativas. Para a identificação de clusters, recorreu-se à técnica denominada Getis-Ord Gi*. Para a detecção dos aglomerados de risco espacial aplicou-se a Estatística de Varredura Puramente Espacial e o Spatial Variation in Temporal Trends. E nas séries temporais utilizou o método de autorregressão Prais-Winsten e a decomposição de séries temporais denominado Seasonal-Trend by Loess. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo. Resultados: Foram diagnosticados 29.499 casos de TB desses, 32,41% (n=9.529) faziam uso de algum tipo de substância psicoativa, sendo o alcoolismo o mais prevalente 20,4% (n=6.013), seguido do tabagismo 14,2% (n=4.185) e drogas ilícitas 9,8% (n=2.893). Quanto à detecção dos aglomerados de risco espacial, entre os que faziam uso do álcool, observou-se incidência de 5,4 casos/100 mil habitantes e um crescimento anual de 0,58%. Quanto ao tabagismo, verificou-se incidência de 3,8 casos por 100.000 habitantes, e um crescimento anual de 37,08% já as outras drogas, uma incidência de 2,6 casos/100.000 habitantes. Observou-se que 1.099 casos eram populações privadas de liberdade, sendo que a maioria era tabagista (n=460;41,8%), seguido por usuários de drogas ilícitas (n=451;41,0%) e alcoolistas (n=179;16,3%). Dentre esses casos, observou-se uma tendência temporal decrescente e hotspost para alcoolismo, tabagismo e drogas ilícitas nas quatro macrorregionais do Estado. Entre os casos de TB levantados, 560 eram de pessoas em situação de rua, tendo-se que a situação de alcoolismo foi a mais prevalente (n=420; 36,30%), seguido pelo tabagismo (n=382; 33,02%) e outras drogas ilícitas (n=355; 30,68%). Ao aplicar a tendência temporal também apresentou um cenário crescente no estado para todas as categorias analisadas. E ao identificar os hotspost entre a população nota-se que, houve associação espacial local apenas na macrorregional Leste na região metropolitana de Curitiba para alcoolismo, tabagismo e outras drogas ilícitas. Conclusão: O estudo avança no conhecimento ao evidenciar a problemática do uso de drogas entre pessoas com diagnóstico de TB, evidenciando uma tendência de crescimento desses eventos. Além disso, o estudo também evidenciou a problemática dessa situação em populações privadas de liberdade e em situação de rua. Apesar do Sul ser considerado região de grande riqueza, o estudo evidencia o contraste, da situação de desigualdade que aflige essa população, exprimindo a situação da TB, uso nocivo de drogas e da exclusão social. Os resultados advindos com o estudo evidenciam os desafios do país em se avançar no fim da TB, e serve de base de evidência para nutrir políticas publicas e desenvolvimento de ações estratégicas em territórios e grupos vulneráveis.

Introduction: Tuberculosis is an infectious and contagious disease caused by Mycobacterium tuberculosis, which is closely related to social inequalities, affecting mainly people in social exclusion, and sometimes in the abuse of alcohol, tobacco and illicit drugs. Objective: To analyze the spatial distribution and temporal trend of cases diagnosed with tuberculosis among alcoholics, smokers and illicit drug users in the state of Paraná, southern Brazil. Methods: This was an ecological study, developed in 399 municipalities in the state of Paraná. The study population consisted of diagnosed cases of tuberculosis in the Notifiable Diseases Information System, between 2008 and 2018, with declarations of alcoholism, smoking and use of illicit drugs. Exploratory data analysis was used through descriptive statistics with the calculation of absolute and relative frequency measures. For the identification of clusters, the technique called Getis-Ord Gi* was used. For the detection of spatial risk clusters, the Purely Spatial Scan Statistics and the Spatial Variation in Temporal Trends were applied. And in the time series used the Prais-Winsten autoregression method and the decomposition of time series called Seasonal-Trend by Loess. The study was approved by the Research Ethics Committee of the University of São Paulo at Ribeirão Preto College of Nursing. Results: Of these, 29,499 cases of TB were diagnosed, 32.41% (n=9,529) were using some type of psychoactive substance, with alcoholism being the most prevalent 20.4% (n=6,013), followed by smoking 14.2 % (n=4,185) and illegal drugs 9.8% (n=2,893). As for the detection of clusters of spatial risk, among those who used alcohol, there was an incidence of 5.4 cases/100 thousand inhabitants and an annual growth of 0.58%; As for smoking, there was an incidence of 3.8 cases per 100,000 inhabitants, and an annual growth of 37.08%, as for other drugs, an incidence of 2.6 cases/100,000 inhabitants. It was observed that 1,099 cases were populations deprived of liberty, with the majority being smokers (n=460;41.8%), followed by illicit drug users (n=451;41.0%) and alcoholics (n= 179;16.3%). Among these cases, there was a decreasing temporal trend and hotspot for alcoholism, smoking and illicit drugs in the four macro-regions of the state. Among the TB cases surveyed, 560 were homeless, with the situation of alcoholism being the most prevalent (n=420; 36.30%), followed by smoking (n=382; 33.02 %) and other illegal drugs (n=355; 30.68%). When applying the temporal trend, it also presented a growing scenario in the state for all categories analyzed. And when identifying the hotsposts among the population, it is noted that there was a local spatial association only in the East macro-region in the metropolitan region of Curitiba for alcoholism, smoking and other illicit drugs. Conclusion: The study advances in knowledge by highlighting the problem of drug use among people diagnosed with TB, showing a growing trend of these events. In addition, the study also highlighted the problem of this situation in populations deprived of liberty and on the streets. Although the South is considered a region of great wealth, the study highlights the contrast, the inequality that afflicts this population, expressing the situation of TB, harmful use of drugs and social exclusion. The results arising from the study highlight the country's challenges in moving towards the end of TB, and serve as an evidence base to nurture public policies and the development of strategic actions in territories and vulnerable groups.

Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas.

The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant rs10754558 in the NLRP3 gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in NLRC4 significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their "household contacts" (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed "exhausted" in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.

Las posibles causas del aumento de la incidencia de la tuberculosis en Chile / Possible causes of the increase in tuberculosis incidence in Chile

La tuberculosis continúa siendo una de las principales causas de morbimortalidad a nivel mundial. En Chile, luego de un período de estancamiento, se ha observado un aumento de casos en los últimos dos años, llegando a una tasa de incidencia de 15,7 casos por 100.000 habitantes en 2018. El estudio busca dilucidar si este aumento es generalizado o si se produce en grupos específicos de la población, y en qué medida corresponde a cambios epidemiológicos u operacionales del programa. Se realizó un estudio descriptivo utilizando datos de fuentes secundarias oficiales para analizar los cambios en el número de casos de tuberculosis en los últimos dos años según áreas geográficas y grupos vulnerables. Además, se analizó el comportamiento de las actividades de pesquisa y diagnóstico de la enfermedad. Se observó aumento de casos en 6 regiones del país, siendo los extranjeros los que aumentan en mayor medida respecto a los otros grupos vulnerables, aunque la incidencia de tuberculosis en este grupo no afecta la incidencia entre los chilenos. La importancia de los extranjeros en el aumento de los casos se produce fundamentalmente en la Región Metropolitana, en cambio en las otras regiones son otros los grupos vulnerables prioritarios. En cuanto a la pesquisa y los métodos diagnósticos, éste puede ser un factor que colabora al aumento de casos en algunas regiones, pero en general no tiene un peso relevante. En conclusión, el aumento de casos de tuberculosis está focalizado a algunas áreas específicas lo que refuerza la importancia de los análisis locales y la definición de estrategias diferenciadas.

Tuberculosis (TB) continues to be one of the leading causes of morbidity and mortality worldwide. In Chile, after a period of stagnation, an increase in cases has been observed in the last two years, reaching an incidence rate of 15.7 per 100,000 inhabitants in 2018. The study seeks to elucidate whether this increase is widespread or if it occurs in specific groups, also if it corresponds to epidemiological or operational changes. A descriptive study was carry on using data from official secondary sources to analyze changes in the number of cases in the last two years according to geographic areas and risk groups. In addition, case finding and diagnosis activities of TB program was analyzed. Increase in cases was observed in 6 regions of the country and foreigner people had the largest increase compared to other risk groups, although the incidence among Chilean is not affected for this fact. The importance of foreigners in the increase of cases occurs mainly in metropolitan region, while in the other regions there are other priority risk groups. Case finding and diagnosis activities may be contribute to increase of cases in some regions, but it does not have a relevant weight in general. In conclusion, the increase of tuberculosis cases is focused on some specific areas, which reinforces the importance of local analysis and the definition of differentiated strategies.

Incidence of tuberculosis in patients receiving anti-TNF therapy for rheumatic diseases: a systematic review.

INTRODUCTION: The TNF inhibitors were the first immunobiologicals used to treat rheumatic diseases, but their use is associated with an increased risk of tuberculosis. The primary objective is to estimate the incidence of tuberculosis in patients with rheumatic diseases exposed to anti-TNF therapy. The secondary objectives are to evaluate the incidence of tuberculosis by region and subgroups of diseases, to review the presentation of tuberculosis in these patients, and to assess the time elapsed between onset of anti-TNF therapy and development of active granulomatous disease. METHODS: A systematic review of the literature was conducted in MEDLINE, the Cochrane Library, and LILACS. The primary endpoint was described as incidence and secondary outcomes, through subgroup analyses and comparisons of means. RESULTS: We included 52 observational studies. Among the exposed patients, 947 cases of tuberculosis were documented (62.2% pulmonary), with a cumulative incidence of 9.62 cases per 1000 patients exposed. TB incidence across different continents was distributed as follows: South America, 11.75 cases/1000 patients exposed; North America, 4.34 cases/1000 patients exposed; Europe, 6.28 cases/1000 patients exposed; and Asia, 13.47 cases/1000 patients exposed. There were no significant differences in TB incidence among the described diseases. The mean time elapsed from start of anti-TNF therapy until the endpoint was 18.05 months. CONCLUSION: The incidence of TB in patients with rheumatic diseases exposed TNF inhibitor considering all countries was 9.62 cases per 1000 patients exposed. TB incidence was higher in South America and Asia compared with North America and Europe. Most cases occurred in the first XX months of use, and the pulmonary form predominated.Key Points• Higher incidence of tuberculosis in patients exposed to anti-TNF compared with the general population.• Higher incidence of TB in countries of South America and Asia compared with North America and Europe.

Multiple cavitary lung lesions on CT: imaging findings to differentiate between malignant and benign etiologies.

OBJECTIVE: To determine the CT findings of multiple cavitary lung lesions that allow the differentiation between benign and malignant etiologies. METHODS: We reviewed CT scans, including patients with two or more cavitary lung lesions. We evaluated the number of cavitary lesions, their location, cavity wall thickness, and additional findings, correlating the variables with the diagnosis of a benign or malignant lesion. RESULTS: We reviewed the chest CT scans of 102 patients, 58 (56.9%) of whom were male. The average age was 50.5 ± 18.0 years. Benign and malignant lesions were diagnosed in 74 (72.6%) and 28 (27.4%) of the patients, respectively. On the CT scans, the mean number of cavities was 3, the mean wall thickness of the largest lesions was 6.0 mm, and the mean diameter of the largest lesions was 27.0 mm. The lesions were predominantly in the upper lobes, especially on the right (in 43.1%). In our comparison of the variables studied, a diagnosis of malignancy was not found to correlate significantly with the wall thickness of the largest cavity, lymph node enlargement, emphysema, consolidation, bronchiectasis, or bronchial obstruction. The presence of centrilobular nodules correlated significantly with the absence of malignant disease (p < 0.05). In contrast, a greater number of cavities correlated significantly with malignancy (p < 0.026). CONCLUSIONS: A larger number of cavitary lung lesions and the absence of centrilobular nodules may be characteristic of a malignant etiology. However, on the basis of our evaluation of the lesions in our sample, we cannot state that wall thickness is a good indicator of a benign or malignant etiology.

Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial.

Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.

[Disseminated infection caused by the bacillus Calmette-Guérin vaccine and SARS-CoV-2 coinfection in a patient with IL-12 receptor ß1 subunit deficiency]. / Infección diseminada por vacuna con bacilo de Calmette-Guérin y coinfección por SARS-CoV-2 en paciente con deficiencia de la subunidad ß1 del receptor de IL-12.

BACKGROUND: Inborn errors of immunity manifest with a greater susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, or malignancies. One of these is the mendelian susceptibility to mycobacterial disease. The most frequent etiology is the complete autosomal recessive deficiency of the ß1 subunit of the interleukin 12 receptor. CASE REPORT: A female patient who, by the age of six months, started with a nodular lesion in the right shoulder and ipsilateral axillary adenitis after the bacillus Calmette-Guérin vaccine was applied. Later, she developed a cutaneous fistula in the anterior thorax, the inframammary region, and chronic recidivant suppurative lymphadenitis. A disseminated infection caused by Mycobacterium bovis was diagnosed, therefore, individualized pharmacological treatment was required due to failure with the primary treatment. The patient was diagnosed with deficiency in the ß1 subunit of the interleukin 12 receptor at age six. During her last hospitalization, she presented fever, cough, and tachypnea, and SARS-CoV-2 was detected by quantitative polymerase chain reaction. The patient has had a favorable evolution. CONCLUSION: In patients with disseminated infections caused by bacillus Calmette-Guérin vaccination or by environmental mycobacteria, there should be suspicion of an inborn error of immunity and the patient should be referred to a third level hospital for an early immunological assessment.

Antecedentes: Los errores innatos de la inmunidad se manifiestan con una mayor susceptibilidad a infecciones, autoinmunidad, enfermedades autoinflamatorias, alergia o malignidad. Uno de estos es la susceptibilidad mendeliana a infecciones micobacterianas. La etiología más frecuente es la deficiencia completa autosómica recesiva de la subunidad ß1 del receptor de interleucina 12. Caso clínico: Paciente que comenzó a los seis meses de edad con una lesión nodular en hombro derecho y adenitis axilar ipsolateral posterior a la vacuna con bacilo de Calmette-Guérin. Posteriormente desarrolló una fistula cutánea en tórax anterior, región inframamaria y linfadenitis supurativa crónica recidivante. Se diagnosticó infección diseminada por Mycobacterium bovis, por lo que requirió tratamiento farmacológico individualizado debido al fracaso con el tratamiento primario. La paciente fue diagnosticada con deficiencia de la subunidad ß1 del receptor de interleucina 12 a los seis años. Durante su última hospitalización presentó fiebre, tos y taquipnea, detectándose SARS-CoV-2 por reacción en cadena de la polimerasa cuantitativa. La paciente evolucionó favorablemente. Conclusión: En los pacientes con infecciones diseminadas por la vacuna con bacilo de Calmette-Guérin o micobacterias ambientales, debe sospecharse un error innato de la inmunidad y derivarlos a tercer nivel de atención para la evaluación inmunológica temprana.

Multiple cavitary lung lesions on CT: imaging findings to differentiate between malignant and benign etiologies / Lesões escavadas pulmonares múltiplas em TC: achados de imagem para diferenciação entre etiologia maligna e benigna

ABSTRACT Objective: To determine the CT findings of multiple cavitary lung lesions that allow the differentiation between benign and malignant etiologies. Methods: We reviewed CT scans, including patients with two or more cavitary lung lesions. We evaluated the number of cavitary lesions, their location, cavity wall thickness, and additional findings, correlating the variables with the diagnosis of a benign or malignant lesion. Results: We reviewed the chest CT scans of 102 patients, 58 (56.9%) of whom were male. The average age was 50.5 ± 18.0 years. Benign and malignant lesions were diagnosed in 74 (72.6%) and 28 (27.4%) of the patients, respectively. On the CT scans, the mean number of cavities was 3, the mean wall thickness of the largest lesions was 6.0 mm, and the mean diameter of the largest lesions was 27.0 mm. The lesions were predominantly in the upper lobes, especially on the right (in 43.1%). In our comparison of the variables studied, a diagnosis of malignancy was not found to correlate significantly with the wall thickness of the largest cavity, lymph node enlargement, emphysema, consolidation, bronchiectasis, or bronchial obstruction. The presence of centrilobular nodules correlated significantly with the absence of malignant disease (p < 0.05). In contrast, a greater number of cavities correlated significantly with malignancy (p < 0.026). Conclusions: A larger number of cavitary lung lesions and the absence of centrilobular nodules may be characteristic of a malignant etiology. However, on the basis of our evaluation of the lesions in our sample, we cannot state that wall thickness is a good indicator of a benign or malignant etiology.

RESUMO Objetivo: Determinar os achados tomográficos de lesões escavadas pulmonares múltiplas que contribuem para a diferenciação entre etiologia benigna e maligna. Métodos: Foram revisados exames de TC, sendo incluídos pacientes com duas ou mais lesões pulmonares escavadas. Avaliaram-se a quantidade de lesões escavadas, sua localização, espessura parietal das lesões e achados adicionais, correlacionando as variáveis com a presença de diagnóstico de benignidade ou de malignidade. Resultados: Foram revisadas TCs de tórax de 102 pacientes, sendo 58 (56,9%) desses do sexo masculino. A média de idade foi de 50,5 ± 18,0 anos. Lesões benignas e malignas foram diagnosticadas em 74 pacientes (72,6%) e em 28 (27,4%), respectivamente. Quanto aos achados tomográficos, a média do número de cavidades foi 3, a da espessura média da parede da maior lesão foi de 6,0 mm, e a do diâmetro da maior lesão foi de 27,0 mm. Houve predomínio das lesões em lobos superiores, especialmente no direito (43,1%). Após a comparação das variáveis estudadas, a espessura parietal da maior escavação, assim como a presença de linfonodomegalia, enfisema, consolidação, bronquiectasias e obstrução brônquica, não apresentaram diferenças estatisticamente significativas para o diagnóstico de malignidade. A presença de nódulos centrolobulares correlacionou-se significativamente com a ausência de doença maligna (p < 0,05). Observou-se também que um número maior de cavidades se correlacionou significativamente com malignidade (p < 0,026). Conclusões: Um maior número de lesões pulmonares escavadas e a ausência de nódulos centrolobulares podem ser características relacionadas à etiologia maligna. Por outro lado, a espessura parietal não permitiu a diferenciação entre etiologia benigna e maligna das lesões em nossa amostra.

A population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment.

INTRODUCTION: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The advent of immunobiologic therapy with TNF inhibitors agents, has been associated with a significant increase in incident cases of tuberculosis in this population. OBJECTIVE: To estimate the incidence of tuberculosis in patients receiving TNF inhibitors therapy for rheumatic diseases. As secondary objectives, we sought to evaluate mortality and the clinical impact of screening for latent tuberculosis infection. METHODS: This retrospective study included patients with rheumatic diseases of Public Health System from the Brazilian state, a high TB incidence area, who received prescriptions of TNF inhibitors agents between 2006 and 2016. RESULTS: A total of 5853 rheumatic disease patients were included. Patients were predominantly women (68.7%) aged 49.5 (± 14.7) years old. Forty-three cases of TB were found (2.86 cases per 1000 person-years; 18 times higher than in the general population). Adalimumab and certolizumab users presented a higher risk for TB development compared to etanercept users (RR: 3.11, 95%CI 1.16-8.35; 7.47, 95%CI 1.39-40.0, respectively). In a subgroup of patients, screening for latent tuberculosis infection was performed in 86% of patients, and 30.2% had a positive tuberculin skin test. Despite latent TB treatment, TB was diagnosed in 2 out of 74 (2.7%) patients. Overall, TB diagnosis did not increase mortality. CONCLUSION: In this population-based study of rheumatic disease patients from a high incident area, TNF inhibitor exposure was associated with an 18-time increased TB incidence. Adalimumab and certolizumab were associated with greater and earlier TB diagnosis compared to etanercept.

[Worsening situation of tuberculosis in Chile]. / El deterioro de la tuberculosis en Chile.

BACKGROUND: Recent data suggest an increase in tuberculosis (TB) incidence in Chile. AIM: To evaluate recent epidemiological trends, geographic extension and potential factors associated with TB reemergence in Chile. MATERIAL AND METHODS: Data analysis from official sources and trend analysis. RESULTS: TB incidence rate increased from 12.3 (2014) to 14.7 (2017) per 100,000 inhabitants. Morbidity rates also increased in nine out of 15 regions. The proportion of TB cases in specific groups has also increased in the last six years: HIV/AIDS (68%), immigrants (118%), drug users/alcoholics (267%) and homeless people (370%). Several indicators of the national TB program performance have deteriorated including TB case detection, HIV co-infection study and contact tracing activities. Overall results indicate a higher than expected case-fatality ratio (> 3%), high rates of loss from follow-up (> 5%), and low percentage of cohort healing rate (< 90%). This decline is associated with a Control Program with scarce human resources whose central budget decreased by 90% from 2008 to 2014. New molecular diagnostic tools and liquid media culture were only recently implemented. CONCLUSIONS: TB trends and overall program performance indicators have deteriorated in recent years in Chile and several factors appear to be involved. Multiple strategies will be required to rectify this situation.

Diagnosis and clinical outcomes of extrapulmonary tuberculosis in antiretroviral therapy programmes in low- and middle-income countries: a multicohort study.

INTRODUCTION: Extrapulmonary tuberculosis (EPTB) is difficult to confirm bacteriologically and requires specific diagnostic capacities. Diagnosis can be especially challenging in under-resourced settings. We studied diagnostic modalities and clinical outcomes of EPTB compared to pulmonary tuberculosis (PTB) among HIV-positive adults in antiretroviral therapy (ART) programmes in low- and middle-income countries (LMIC). METHODS: We collected data from HIV-positive TB patients (≥16 years) in 22 ART programmes participating in the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium in sub-Saharan Africa, Asia-Pacific, and Caribbean, Central and South America regions between 2012 and 2014. We categorized TB as PTB or EPTB (EPTB included mixed PTB/EPTB). We used multivariable logistic regression to assess associations with clinical outcomes. RESULTS AND DISCUSSION: We analysed 2695 HIV-positive TB patients. Median age was 36 years (interquartile range (IQR) 30 to 43), 1102 were female (41%), and the median CD4 count at TB treatment start was 114 cells/µL (IQR 40 to 248). Overall, 1930 had PTB (72%), and 765 EPTB (28%). Among EPTB patients, the most frequently involved sites were the lymph nodes (24%), pleura (15%), abdomen (11%) and meninges (6%). The majority of PTB (1123 of 1930, 58%) and EPTB (582 of 765, 76%) patients were diagnosed based on clinical criteria. Bacteriological confirmation (using positive smear microscopy, culture, Xpert MTB/RIF, or other nucleic acid amplification tests result) was obtained in 897 of 1557 PTB (52%) and 183 of 438 EPTB (42%) patients. EPTB was not associated with higher mortality compared to PTB (adjusted odd ratio (aOR) 1.0, 95% CI 0.8 to 1.3), but TB meningitis was (aOR 1.9, 95% CI 1.0 to 3.1). Bacteriological confirmation was associated with reduced mortality among PTB patients (aOR 0.7, 95% CI 0.6 to 0.8) and EPTB patients (aOR 0.3 95% CI 0.1 to 0.8) compared to TB patients with a negative test result. CONCLUSIONS: Diagnosis of EPTB and PTB at ART programmes in LMIC was mainly based on clinical criteria. Greater availability and usage of TB diagnostic tests would improve the diagnosis and clinical outcomes of both EPTB and PTB.

[Distant bacillus Calmette-Guérin disease in an infant. Case report]. / Enfermedad por bacilo de Calmette-Guérin a distancia en un lactante. Presentación de un caso.

The bacillus Calmette-Guérin vaccine is an attenuated vaccine historically used to prevent severe forms of tuberculosis. It is applied to all newborns in countries with high prevalence of tuberculosis. Local complications, such as suppuration or regional adenopathies, may occur after application. Disease due to the spread of the bacillus is infrequent, usually occurring in a patient with an underlying immune alteration. We present the case of a 5-month-old child who was admitted due to a 2-month evolution with weight loss and subcutaneous nodules. Disease was suspected to be due to bacillus Calmette- Guérin dissemination, being diagnosed by biopsy of the lesions. Treatment was carried out with three antituberculous drugs, evolving towards clinical recovery. Although immunological studies were carried out, no immunodeficiency could be demonstrated as a predisposing condition.

La vacuna con el bacilo de Calmette-Guérin es una vacuna atenuada utilizada para prevenir formas graves de tuberculosis. Se aplica a los recién nacidos en países con alta prevalencia de tuberculosis. Pueden presentarse, después de su aplicación, complicaciones a nivel local, como supuración o adenopatías regionales. La enfermedad por diseminación del bacilo es infrecuente y ocurre, por lo general, en pacientes con alteraciones inmunitarias subyacentes. Se presenta el caso de un niño de 5 meses que ingresó por un cuadro de 2 meses de evolución con detención del aumento de peso y nódulos subcutáneos. Se sospechó enfermedad por diseminación del bacilo y se diagnosticó por la biopsia de las lesiones. Se realizó el tratamiento con tres drogas antituberculosas, y se recuperó clínicamente. Si bien se realizaron estudios inmunológicos, no logró demostrarse ninguna inmunodeficiencia como afección predisponente.

Fatores predisponentes de tuberculose em indivíduos privados de liberdade: revisão integrativa / Predisposing factors of tuberculosis in liberty-deprived: an integrative review

Introdução: O ambiente prisional proporciona predisposição de diversas doenças, como é o caso da tuberculose, cujo risco de adoecimento aumenta em 28 vezes no interior das prisões. Objetivo: Integrar os fatores causadores de tuberculose em indivíduos privados de liberdade, mencionados na literatura nacional e internacional. Materiais e Métodos: Trata-se de uma revisão integrativa realizada nas bases de dados LILACS, MEDLINE e PUBMED nos meses de abril a junho de 2017. Resultados: A amostra foi constituída por 12 estudos. Os resultados permitiram constatar que o uso de drogas ilícitas injetáveis, o tempo de encarceramento, o compartilhamento de cela com outros detentos e a coinfecção HIV/TB foram os principais fatores relacionados ao adoecimento por tuberculose na população penitenciária. Ademais, a tuberculose pulmonar foi o principal achado dentro do ambiente prisional, seguida pela infecção latente por tuberculose. Conclusão: O controle da tuberculose é uma necessidade urgente na sociedade. O desenvolvimento de programas de controle desta, bem como a instalação de serviços de saúde efetivos, que promovam um cuidado integral e a prevenção e promoção, assim como a reabilitação da saúde das pessoas privadas de liberdade constitui-se em uma necessidade imperiosa no contexto prisional.

Introduction: The prison environment provides a predisposition for several diseases, such as tuberculosis. The risk of getting infected is increased by 28 times within prisons. Objective: To integrate the causative factors of tuberculosis in liberty-deprived individuals reported in both national and international literature. Materials and Methods: A literature review was performed to identify published studies from April to June 2017. Published studies were identified using an initial search of the LILACS, MEDLINE, and PUBMED database. Results: The literature search resulted in the identification of 12 studies. The results showed that injecting drug use, incarceration time, cell sharing with other inmates, and HIV/TB coinfection were the main factors related to tuberculosis in prison population. In addition, pulmonary tuberculosis was the main finding within the prison environment, followed by latent tuberculosis infection. Conclusion: Tuberculosis control is an urgent need in society. The development of programs to control it, as well as the establishment of effective health services that deliver integral health care, prevention and promotion of health care. Furthermore, the rehabilitation of prisoners' health constitutes a compelling need in the prisoner context.

El deterioro de la tuberculosis en Chile / Worsening situation of tuberculosis in Chile

Background: Recent data suggest an increase in tuberculosis (TB) incidence in Chile. Aim: To evaluate recent epidemiological trends, geographic extension and potential factors associated with TB reemergence in Chile. Material and Methods: Data analysis from official sources and trend analysis. Results: TB incidence rate increased from 12.3 (2014) to 14.7 (2017) per 100,000 inhabitants. Morbidity rates also increased in nine out of 15 regions. The proportion of TB cases in specific groups has also increased in the last six years: HIV/AIDS (68%), immigrants (118%), drug users/alcoholics (267%) and homeless people (370%). Several indicators of the national TB program performance have deteriorated including TB case detection, HIV co-infection study and contact tracing activities. Overall results indicate a higher than expected case-fatality ratio (> 3%), high rates of loss from follow-up (> 5%), and low percentage of cohort healing rate (< 90%). This decline is associated with a Control Program with scarce human resources whose central budget decreased by 90% from 2008 to 2014. New molecular diagnostic tools and liquid media culture were only recently implemented. Conclusions: TB trends and overall program performance indicators have deteriorated in recent years in Chile and several factors appear to be involved. Multiple strategies will be required to rectify this situation.