Introduction: Despite management advances worldwide, tuberculosis still remains a serious uncontrolled disease. The absence of either a ‘gold’ standard diagnostic test, or a conventional rapid ‘reference’ laboratory test for asymptomatic Mycobacterium tuberculosis (MTB) carriers complicates disease control. Through mandatory screening of high-risk groups, early diagnosis of latent tuberculosis infection (LTBI) cases allows recognition and better control of the tuberculosis pandemic. Materials and Methods: The current tuberculosis screening guidelines as recommended by the World Health Organization, chest X-ray and tuberculin skin test were assessed and revealed rises in TB morbidity and fatality trends in the Kuwait population (low incidence country). In order to evaluate options for LTBI diagnosis, the current work implemented a 4-month prospective, observational, repeated-measure and randomly implemented survey on 180 new immigrants to Kuwait using a structured risk factor questionnaire whilst, simultaneously evaluating the performance of the two standard diagnostics (chest X-ray and tuberculin skin test) with the new biomarker interferon gamma release assays (T-SPOT .TB test and QuantiFERON Gold In-Tube test (QNF-GIT)); which detect the release of interferon gamma (INF-γ) released from sensitization to specific MTB antigens. Results: Associations between various epidemiological risk factors - such as socio-demographic status, smoking and environmental exposure-contact - were associated in the laboratory diagnosed LTBI participants. Positive identification of LTBI prevalence detected by two radiologists was 10.1% having ‘moderate’ inter-reader agreement (Kappa = 0.505), compared to no positives being detected by three pulmonologists. TST results were negative (less than 10-mm ‘cut-off’) even in the 86.1% Bacillus Calmette-Guérin vaccinated expatriates. Estimated LTBI using QNFGIT was 28.3% compared to 41.1% positive T-SPOT .TB test. Both interferon gamma assays revealed concordant ‘abnormal’ results in 26.1% with ‘good’ agreement (kappa = 0.627). Conclusion: Detection of latent tuberculosis infection can be facilitated by introducing evidence-based diagnostic classification depending on history taking of epidemiological-related risk factors and chest X-ray plus either interferon gamma assays.

Background: Migrant farmworkers are among the highest-risk populations for latent TB infection (LTBI) in the United States with numerous barriers to healthcare access and increased vulnerability to infectious diseases. LTBI is usually diagnosed on the border using the tuberculin skin test (TST). QuantiFERON-TB Gold In-Tube (QFT-GIT) also measures immune response against specific Mycobacterium tuberculosis antigens. The objective of this study is to assess the comparability of TST and QFT-GIT to detect LTBI among migrant farmworkers on the border, as well as to examine the effects of various demographic and clinical factors on test positivity. Methods: Participants were recruited using mobile clinics on the San Luis US-Mexico border and tested with QFT-GIT and TST. Demographic profiles and clinical histories were collected. Kappa coefficients assessed agreement between TST and QFT-GIT using various assay cutoffs. Logistic regression examined factors associated with positive TST or QFT-GIT results. Results: Of 109 participants, 59 of 108 (55 %) were either TST (24/71, 34 %) or QFT-GIT (52/106, 50 %) positive. Concordance between TST and QFT-GIT was fair (71 % agreement,kappa= 0.38, 95 % CI: 0.15, 0.61). Factors associated with LTBI positivity included smoking (OR = 1.26, 95 % CI-1.01-1.58) and diabetes/high blood sugar (OR = 0.70, 95 % CI = 0.51-0.98). Discussion: Test concordance between the two tests was fair, with numerous discordant results observed. Greater proportion of positives detected using QFT-GIT may help avoid LTBI under-diagnosis. Assessment of LTBI status on the border provides evidence whether QFT-GIT should replace the TST in routine practice, as well as identifies risk factors for LTBI among migrant populations.

Preventative interventions often demand that resources be consumed in the present in exchange for future benefits. Understanding these trade-offs, in a context of resource constraints, is essential for policy makers. Cost-effectiveness analysis is one tool to inform decision-making. Targeted testing and treatment (TTT) for latent tuberculosis infection (LTBI) consists in identifying people at high risk for LTBI for preventive treatment to decrease the risk that they will develop active tuberculosis disease (ATBD). The state of Tennessee began conducting TTT statewide in 2001. This study uses a decision tree to evaluate the cost and outcomes of TTT for LTBI in Tennessee, compared to passive ATBD case finding (PACF). Key event probabilities were obtained from the Tennessee TTT program and from the literature. Outcomes are measured in terms of Quality Adjusted Life Years (QALY). The cost-effectiveness threshold was set at $100,000/QALY saved. One-way sensitivity analyses around factors related to study design (exclusion of patient costs, secondary transmission, discount rate and analytical horizon), the program’s environment (prevalence of LTBI and drug resistance, ATBD treatment costs) and program performance (program maturity, treatment initiation and completion rate, testing in low-risk group, test characteristics, screening costs) were conducted, as was probabilistic sensitivity analysis (PSA) which takes into account the uncertainty in multiple parameters simultaneously. The base case, with a 25-year time horizon and 3% discount rate, shows that TTT prevents 47 ATBD cases, and saves 31 QALYs per 100,000 patients screened for LTBI at a societal cost of $12,579 (2011 US$) per QALY saved. Sensitivity analyses identified value thresholds that would trigger a change in preferred policy. PSA shows that the likelihood that TTT would be cost-effective is low. Decision makers interested in implementing TTT should carefully assess the characteristics of the local TB epidemic and expected program performance to determine whether TTT is preferable over PACF from a cost-effectiveness viewpoint.

Preventative interventions often demand that resources be consumed in the present in exchange for future benefits. Cost-effectiveness analysis is a tool to understand these trade-offs, and inform decision-making under resource constraints. Targeted testing and treatment (TTT) for latent tuberculosis infection (LTBI) consists in identifying people at high risk for LTBI for preventive treatment to decrease the risk of active tuberculosis disease (ATBD). The state of Tennessee began conducting TTT statewide in 2001. This study uses a decision tree to evaluate the cost and outcomes of TTT for LTBI in Tennessee, compared to passive ATBD case finding (PACF). Key probabilities were obtained from the Tennessee TTT program and the literature. Outcomes are measured in terms of Quality Adjusted Life Years (QALY). The cost-effectiveness threshold was $100,000/QALY saved. One-way sensitivity analyses around factors related to study design, the program’s environment, and program performance were conducted, as was probabilistic sensitivity analysis (PSA) which takes into account the uncertainty in multiple parameters simultaneously. The base case, with a 25-year analytic horizon and 3% discount rate, shows that TTT prevents 47 ATBD cases, and saves 31 QALYs per 100,000 patients screened at a societal cost of $12,579 per QALY saved. Sensitivity analyses identified value thresholds that would trigger a change in preferred policy. PSA shows that the likelihood that TTT would be cost-effective is low. Decision makers should carefully assess the characteristics of the local TB epidemic and expected program performance to determine whether TTT is preferable over PACF from a cost-effectiveness viewpoint.

Latent tuberculosis infection (LTBI) is a global health issue that affects approximately one quarter of the world’s population. It refers to a state of persistent immune response to Mycobacterium tuberculosis without clinical evidence of active tuberculosis (TB). Latent tuberculosis infected individuals are asymptomatic and not contagious to others, however 5-15% of all infected individuals are at risk of developing active tuberculosis and become contagious, severely ill, or worse, die from active TB. There are identified risk groups that are targeted for identification, diagnosis and treatment of latent tuberculosis infection. These are human immunodeficiency virus (HIV) patients, children and adolescents, household or close contacts of active TB cases, migrants, refugees, prisoners and health care workers. The standard treatment used for treating LTBI is the isoniazid monotherapy. It has a high proven efficacy rate but is linked to poor acceptance and low completion rates, basically due to its long treatment duration and poor tolerability. A newer treatment regimen is the rifapentine plus isoniazid combination therapy. It is an effective regimen against LTBI and has a shorter treatment duration. The aim of this literature study was to evaluate the efficacy of rifapentine plus isoniazid combination therapy compared with the isoniazid monotherapy as treatment of latent tuberculosis infection. This thesis was based on five randomized clinical trials collected from PubMed database. The studies should have entailed an efficacy comparison between isoniazid monotherapy and rifapentine plus isoniazid combination therapy for the treatment of patients with latent tuberculosis. The studies showed lower rates of active TB and death in the rifapentine plus isoniazid combination group in comparison with the isoniazid monotherapy. The studies also proved that rifapentine plus isoniazid combination therapy was noninferior to the standard isoniazid monotherapy. The completion rates were significantly higher in the combination therapy arm. The safety profile between the two treatment regimens was similar, but with an increased hepatotoxicity rates in the isoniazid-only arm. The rifapentine plus isoniazid combination therapy is as efficacious as the isoniazid monotherapy. This shorter regimen could be used as first hand therapy as well for latent tuberculosis patients with high-risk of developing active TB as it has shown good tolerability and higher completion rates that is important to successfully treat LTBI and help eliminate TB worldwide. / Latent tuberkulos är ett globalt hälsoproblem som drabbar ungefär en fjärdedel av världens befolkning. Den definieras som ett tillstånd av immunreaktion mot Mycobacterium tuberculosis utan kliniska tecken på aktiv tuberkulos (TB). De infekterade individerna är asymtomatiska och inte smittsamma för andra, men 5–15% av alla infekterade individer riskerar att utveckla aktiv tuberkulos och bli smittsamma, bli allvarligt sjuka, eller värre, dö av aktiv tuberkulos. Personer med latent tuberkulos som tillhör riskgrupperna prioriteras för identifiering, diagnos och behandling av latent tuberkulos. Dessa riskgrupper är humant immunbristvirus (HIV)-patienter, barn och ungdomar, nära kontakter till personer med aktiva TB-fall, migranter, flyktingar, fångar och vårdpersonal. Standardbehandlingen mot latent tuberkulos är isoniazid monoterapi. Den har en högt beprövad effektivitetsgrad men är kopplad till dålig acceptans och låga kompletteringsgrader, på grund av framförallt den långa behandlingstiden och dålig tolerans. En nyare form av behandling är rifapentin kombinerat med isoniazid. Den är en effektiv behandling mot latent tuberkulos med en kortare behandlingstid. Syftet med denna litteraturstudie var att utvärdera effekten av kombinationsterapi med rifapentin och isoniazid jämfört med isoniazid monoterapi för behandling av latent tuberkulos. Detta examensarbete baserades på fem randomiserade kliniska prövningar hämtade från PubMed-databasen. Samtliga fem studier innefattade effektivitetsjämförelse mellan isoniazid monoterapi och kombinationsterapi med rifapentin och isoniazid vid behandling av patienter med latent tuberkulos. Alla fem studier undersöktes visade lägre frekvens av aktiv TB och dödlighet i kombinationsterapi med rifapentin och isoniazid jämfört med isoniazid monoterapi. Resultatet bevisade också icke-underlägsenhet för kombinationsterapin jämfört med isoniazid monoterapin. Kompletteringsgraden var signifikant högre i kombinationsterapin. Säkerhetsprofilen mellan de två terapin var likartad, men med en ökad hepatotoxicitet i isoniazid monoterapi gruppen. Kombinationsterapi med rifapentin och isoniazid är lika effektiv som isoniazid monoterapi. Denna kortare behandling kan också användas som förstahandsbehandling för latent tuberkulos patienter med hög risk att utveckla till aktiv tuberkulos eftersom den har visat god tolerabilitet och högre kompletteringsgrad som är viktigt för att framgångsrikt behandla latent tuberkulos och hjälpa till att eliminera TB över hela världen.

No description available.

Most of the chemical reactions of living cells are catalyzed by protein enzymes. These enzymes are very efficient and display a high degree of specificity with respect to the reaction catalyzed. Cellular activities depend critically on the precise three-dimensional structure and function of thousands of enzymes. Many enzymes require binding of metal ions or small organic molecules for their function. The organic molecules that are indispensible components of catalysis by proteins are called coenzymes. Pyridoxal 5ʹ-phosphate (PLP) is a versatile coenzyme found in all living cells. PLP-dependent enzymes play a key role in the function of most of the enzymes catalyzing reactions in the metabolic pathways of amino acid synthesis and degradation. The enzyme pyridoxal kinase serves to make available the co-enzyme PLP to apo-PLP dependent enzymes. Because of their key role in cellular function and their medical importance, the structure and function of PLP-dependent enzymes have been extensively investigated. In the past decade, detailed investigations on the structure and function of several PLP-dependent enzymes have been carried out in our laboratory. The enzymes studied are B. subtilis serinehydroxymethyl transferase (SHMT), S. typhimurium acetylornithine aminotransferase (AcOAT), S. typhimurium and E. coli diaminopropionate ammonia lyase (DAPAL), S. typhimurium D-serine dehydratase (DSD), S. typhimurium D-cysteine desulfhydrase (DCyD) and S. typhimurium arginine decarboxylase (ArgD). The extensive studies conducted on PLP-dependent enzymes in our laboratory during the past decade has not only resulted in deeper understanding of their structure and function but also raised several new questions regarding substrate recognition, reaction specificity, role of active site residues in the catalytic reaction, mechanism of catalysis and potential applications of these enzymes. This thesis is an attempt to answer some of these questions. The thesis also presents the structure and function of a new protein, Salmonella typhimurium pyridoxal kinase, the enzyme that provides PLP for PLP-dependent enzymes. Single crystal X-ray diffraction technique is the most powerful tool currently available for the elucidation of the three-dimensional structures of proteins and other biological macromolecules and for revealing the relationship between their structure and function. X-ray diffraction studies have provided in depth understanding of the topology of secondary structural elements in the three-dimensional structures of proteins, the hierarchical organization of protein domains, structural basis for the substrate specificity of enzymes, intricate details of mechanisms of enzyme catalyzed reactions, allosteric regulation of enzyme activity, mechanisms of feed-back inhibition, structural basis of protein stability, symmetry of oligomeric proteins and their possible biological implications and a myriad of other biochemical and biophysical properties of proteins. The work reported in this thesis is primarily based on X-ray diffraction studies. X-ray crystal structure investigations are complemented by spectral and biochemical studies on the catalyzed reactions. The thesis begins with an introduction to PLP-dependent enzymes and presentation of a brief summary of the earlier work carried out in our laboratory on PLP-dependent enzymes (Chapter 1). A brief description of earlier functional classification of PLP-dependent enzymes and the more recent classification of these enzymes into the four groups based on their three-dimensional structure is provided. Although enzymes belonging to these four structural classes have evolved from independent evolutionary lineages, they share some common features near their active sites and in the mode of PLP binding. Earlier work carried out elsewhere on pyridoxal kinase and its key role in maintaining PLP at a low concentration in the cytosol is presented. Different mechanisms that have been proposed for the transfer of PLP from pyridoxal kinase to other apo PLP-dependent enzymes are briefly described. The experimental procedures and computational methods used during the course of these investigations to obtain the results reported in chapters 3-6 are presented in Chapter 2. Most of these methods are applicable to the isolation of plasmids, cloning, over expression, protein purification, mutant construction, crystallization, X-ray diffraction data collection and processing, structure elucidation and refinement, validation and structural analysis presented in the next three chapters. Various programs and protocols used for data processing, structure determination, refinement, model building, structure validation and analysis are also briefly described. In chapter 3, the role of a number of active site residues in the reaction catalyzed by EcDAPAL, a fold type II PLP-dependent enzyme, the structure of which was determined earlier in the laboratory is explored by mutational, biochemical and structural analyses. Earlier studies had established the probable role of Asp120 and Lys77 in the reaction leading to the breakdown of D-DAP and L-DAP, respectively (Bisht et al., 2012). To further validate the earlier observations, a number of active site mutants were generated for Asp 120 (D120N, D120C, D120S and D120T), Asp 189 (D189N, D189C, D189S and D189T), Lys77 (K77T, K77H, K77R and K77A), His 123 (H123L) and Tyr 168 (Y168F). The structure of D120N mutant crystal obtained after soaking in crystallization cocktail containing D-DAP revealed the presence of an intact external aldimine complex at the active site supporting the earlier proposal that Asp120 is the base abstracting the Cα proton from the D-isomer of DAP. Biochemical and structural observations suggested that none of the Asp189 mutants may bind PLP and were catalytically inactive suggesting an essential role for Asp189 in catalysis. In contrast to type I PLP-dependent enzymes, none of the Lys 77 mutants of EcDAPAL could bind PLP either covalently or non-covalently and were inactive with both the isomers of DAP. Thus, Lys77 appears to be important for both PLP binding and catalysis. H123L mutant formed an external aldimine with D-DAP and a gem-diamine complex with L-DAP indicating that this residue is also crucial for catalysis. These studies have provided additional support to the catalytic mechanism of EcDAPAL proposed earlier. The next Chapter 4 explores the structure, function and catalytic mechanism of Salmonella typhimurium DAPAL (StDAPAL). The protein was purified from a construct carrying a hexa-histidine tag at the C-terminus by Ni-NTA chromatography. The purified protein was demonstrated to be homogeneous by SDS-PAGE and MALDI-TOF. Crystals of StDAPAL belonging to the C-centred monoclinic space group (C121) with four molecules in the asymmetric unit were obtained by the micro batch method and used for collecting X-ray diffracting data. The crystal structure was determined by molecular replacement using the homologous enzyme from E. coli (PDB code 4D9M, Bisht et al., 2012), which shares a sequence identity of 50% with the S. typhimurium enzyme as the phasing model in the program Phaser (McCoy et al., 2007) of the CCP4 suite. The model was refined with Refmac5 of CCP4 suite to R and Rfree values of 25.5% and 30.9%, respectively. A superposition of the structure so obtained over EcDAPAL revealed that the two structures are very similar. A sulfate molecule bound to the active site of StDAPAL could be located. The position of the sulfate corresponds to that of the carboxyl group of aminoacrylate intermediate of EcDAPAL (4D9M). The PLP was bound to Lys78 as an internal aldimine. Since the active sites of the two protomers in fold type II PLP-dependent enzymes are independent, it might be possible to obtain functional monomers of EcDAPAL. With this view, mutation of a conserved Trp (Trp399) present in the dimeric interface resulted in the destabilization of the dimeric interface and partial conversion of the dimeric protein to a monomeric protein. However, the monomeric species of EcDAPALW399R was unable to bind PLP and hence did not possess any catalytic activity. This highlights the importance of dimeric organization for efficient binding of PLP as well as for the activity of the enzyme. A remarkable difference between EcDAPAL and StDAPAL is the absence of a disulfide bond between residues Cys271 and Cys299 in StDAPAL equivalent to the bond formed between Cys265 and Cys291 in EcDAPAL. Mutation of Cys265 and Cys291 of EcDAPAL to Ser did not affect the activity of the enzyme towards either of the isomers of the substrate indicating that the disulfide bond is not crucial for enzyme activity. The stability of the loop corresponding residues 261-295 of EcDAPAL was believed to be promoted by the disulfide bond. However, the equivalent loop was found to be ordered in StDAPAL even though the disulfide bond is absent. In contrast to StDAPAL, EcDAPAL did not show any metal dependent activity. The previous two chapters dealt with fold type II PLP-dependent enzymes. In contrast, Chapter 5 deals with revisiting the structure and function of a fold type I PLP-dependent enzyme, Salmonella typhimurium arginine decarboxylase (StADC). ADC is a very large polypeptide in comparison with other fold type I enzymes. It is induced when the bacterium is subjected to low pH and plays a major role in protecting the cells from acid stress. The structure of StADC was determined but not satisfactorily refined by Dr. S. R. Bharat earlier. The X-ray diffraction data collected by Bharat needed to be improved and the structure needed to be further refined and compared with the homologous E. coli enzyme. Therefore, the entire process of data processing, structure solution and refinement was repeated. The refined structure of StADC was found to correspond to the apo form of the enzyme with only a phosphate molecule occupying the position equivalent to that of 5’ phosphate of PLP observed in EcADC holo enzyme structure. This allowed examination of structural changes that accompany PLP binding and formation of an internal aldimine. The apo to holo transition in StADC involves the movement and ordering of two loops consisting of residues 151-164 and 191-196 which are in the linker and PLP binding domains of the protein, respectively. Phosphate binding by itself appears to be insufficient for these structural changes. These two loops are close to the PLP binding site of the other protomer of the dimer. Hence, these movements are probably important for the catalytic function of the enzyme. Holo ADC has been found as a decamer in other studies. The decameric form of the apo-StADC suggests that PLP binding may not be essential for the oligomeric state of the protein. ADC appears to reduce proton concentration inside the cell in two ways; (i) by surface charge neutralization and (ii) by arginine decarboxylation by extracting a proton from the cytoplasm. The resulting product agmatine is exchanged for extra cellular arginine by arginine-agmatine antiporter. The low sequence identity and lack of structural similarity of the inducible and constitutive forms of ADC from S. typhimurium shows that these are unlikely to be products of divergent evolution. The final chapter 6 of the thesis presents the work carried out on S. typhimurium pyridoxal kinase (PLK). In the salvage pathway of pyridoxal 5’phosphate (PLP), PLP is produced as the product of the reaction catalyzed by PLK using PL, PN and PM as substrates. Thus, PLK plays the critical role of ensuring availability of PLP to the large number of PLP-dependent enzymes. S. typhimurium PLK was purified to homogeneity, crystallized in its native as well as ligand bound forms. It was necessary to circumvent an unusual problem caused by spots arising from a contaminant crystal to obtain the structure of the native crystals of PLK that belonged to the P212121 space group with two protomers in the crystal asymmetric unit. It was then straight forward to determine the ligand bound structures of StPLK (space group P43212) obtained by co-crystallization with ATP, PL and Mg2+ by molecular replacement using the wild type structure as the phasing model. The structures obtained by co-crystallization revealed the presence of ADP, Mg2+ and a PL bound to the active site Lys233 via a Schiff base (internal aldimine). This is the first structure in which the presence of an internal aldimine in the active site of PLK has been observed. Formation of the internal aldimine might be one way to prevent the release of excess PLP and protecting the cell from PLP induced toxicity. The enzyme was shown to be inhibited by the product which will also help in maintaining PLP concentration at low levels. It was also demonstrated that PLK interacts with apo-PLP-dependent enzymes. This observation supports possible direct transfer of PLP from PLK to PLP-dependent enzymes. The thesis ends with an appendix where the work carried out during the course of the thesis work but not as part of the thesis is briefly described.

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One of the strategies recommended for the control of tuberculosis is the identification and early treatment of individuals with latent M. tuberculosis infection (ILTB). In Brazil, ILTB is not part of the compulsory notification aggravations, but there is a recommendation for States to create instruments for notification and follow-up of cases. In Goiás, a notification form for ILTB was developed in 2012 by the State Department of Health. The objective of the research is to analyze the epidemiological profile of ILTB cases and to characterize the surveillance processes related to the diagnosis and treatment of this disease in this state. The reports of ILTB cases treated between 2013 and 2015 were analyzed. A database linking was carried out considering the cases of tuberculosis reported in the SINAN NET Notification System and the ILTB records. To evaluate the technical and structure aspects of ILTB control services, a structured questionnaire was applied to the supervisors of health surveillance in the 18 health regions of the State. A descriptive and exploratory data analysis was carried out using software SPSS 13.0 and TABWIN 1.6 EPI INFO. 345 cases of ILTB were reported in the study period. The patients' ages ranged from 0 to 92 years (median age 38 years); 65.2% were adults and 10.1% were up to 10 years. Five municipalities (Goiânia, Aparecida de Goiânia, Jataí, Anápolis and Formosa) reported 77.7% of the cases. In 24.6% of the cases, the criterion for treatment of ILTB was the result of Tuberculin Test (TT)> 10mm. In this group all cases were asymptomatic and 78.8% had contact with active tuberculosis. It was identified that 39 cases were HIV positive, corresponding to 12.7% of indications for ILTB treatment. According to health surveillance supervisors, all 246 municipalities had a Tuberculosis Control Program. Concerning the specific training on ILTB, 74 municipalities (30.1%) received this training, reaching 141 health professionals. In relation to the specific training for the application of TT, only three (16.7%) health regions were trained, of which two managed to decentralize this training to some of their jurisdictions. Eleven regional health (61.1%) reported that the number of TT provided by the State Department of Health was inadequate to meet the demands of municipalities. According to supervisors, 88.2% of the municipalities in Goiás do not have the tools to monitor cases of co-infection with HIV. The present study contributed to the knowledge of the epidemiological profile of the reported cases of ILTB, as well as to the process of control of this aggravation in the State. Failures were identified in the ILTB control process in the different regions of the State of Goiás. This study is expected to support effective actions to control tuberculosis in the State. / A tuberculose ainda é um grande problema de saúde global. Uma das estratégias preconizada para controle da tuberculose consiste na identificação e tratamento precoce dos indivíduos com infecção latente pelo M. tuberculosis (ILTB). No Brasil, a ILTB não faz parte dos agravos de notificação compulsória, porém existe recomendação para que os Estados criem instrumentos para notificação e acompanhamento dos casos. Em Goiás, uma ficha de notificação para ILTB foi desenvolvida em 2012 pela Secretaria de Estadual da Saúde. O objetivo da pesquisa consiste em analisar o perfil epidemiológico dos casos de ILTB e caracterizar os processos de vigilância relacionados ao diagnóstico e tratamento dessa doença neste estado. Foram analisadas as notificações de casos de ILTB tratados entre 2013 e 2015. Foi realizada a vinculação de base de dados considerando os casos de tuberculose notificados no Sistema de Informação de Agravos de Notificação (SINAN NET) e os registros de ILTB. Para avaliar aspectos técnicos e de estrutura de serviços de controle de ILTB foi aplicado questionário estruturado para os supervisores de vigilância em saúde das 18 regiões de saúde do Estado. Foi realizada análise descritiva e exploratória de dados por meio dos softwares SPSS 13.0 e TABWIN 1.6 EPI INFO. 345 casos de ILTB foram notificados, no período de estudo. A idade dos pacientes variou de 0 a 92 anos (mediana de 38 anos); 65,2% eram adultos e 10,1% tinham até 10 anos. 05 municípios (Goiânia, Aparecida de Goiânia, Jataí, Anápolis e Formosa) notificaram 77,7% dos casos. Em 24,6% dos casos, o critério para tratamento da ILTB foi o resultado do Teste Tuberculínico (TT) >10mm. Nesse grupo todos os casos eram assintomáticos e 78,8% tinham contato com caso de tuberculose ativa. Identificou-se que 39 casos eram HIV positivos, correspondendo a 12,7% das indicações para tratamento ILTB. De acordo com os supervisores de vigilância em saúde, todos os 246 municípios contavam com Programa de Controle da Tuberculose. 74 municípios (30,1%), receberam treinamento sobre ILTB, alcançando 141 profissionais de saúde. Em relação ao treinamento especifico para aplicação do TT apenas 03 (16,7%) regiões de saúde foram capacitadas, das quais duas conseguiram descentralizar esta capacitação para alguns de seus municípios jurisdicionados. 11 regionais de saúde (61,1%) informaram que o número de TT disponibilizado pela Secretaria de Estado da Saúde foi inadequado para atender as demandas dos municípios. Ainda segundo os supervisores, 88,2% dos municípios goianos não dispõem de ferramentas para acompanhamento dos casos de co-infecção com HIV. O presente estudo contribuiu para o conhecimento do perfil epidemiológico dos casos notificados de ILTB, bem como para o processo de controle desse agravo no Estado. Foram identificadas falhas no processo de controle da ILTB, nas diferentes regiões de Saúde do Estado de Goiás. Espera-se que esse estudo possa subsidiar ações efetivas para o controle da tuberculose no Estado.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os profissionais da área da saúde formam um dos grupos mais vulneráveis à infecção pelo Mycobacterium tuberculosis (Mtb). Segundo estimativas da Organização Mundial de Saúde (OMS), 8,8 milhões de pessoas estavam infectadas pelo Mtb e ocorreram 1,4 milhão de óbitos por tuberculose (TB) em 2010. A identificação de pessoas com Infecção Latente Tuberculosa (ILTB) é considerada pela OMS como uma prioridade no controle da doença, especialmente em países em desenvolvimento em que a incidência da doença ativa tem apresentado redução. O objetivo do presente trabalho foi avaliar, no Brasil, o custo-efetividade dos testes Prova Tuberculínica (PT) e Quantiferon TB Gold-In-Tube (QTF-GIT) no diagnóstico e tratamento da ILTB em profissionais de saúde atuantes na atenção básica, sob a perspectiva do Sistema Único de Saúde (SUS), comparando cinco estratégias que incluem o QTF-GIT, distintos pontos de corte para a PT e uso sequencial dos dois testes; e analisar o impacto do tabagismo sobre o risco de ILTB entre os profissionais de saúde, destacando-se a categoria da Enfermagem. Foi realizada uma avaliação econômica completa do tipo custo-efetividade, conduzida considerando uma coorte hipotética de 10.000 profissionais de saúde atuantes na atenção básica, com horizonte temporal restrito a um ano. Um modelo analítico de decisão, caracterizado por uma árvore de probabilidades de eventos, foi desenvolvido utilizando o software TreeAge ProTM 2013 para simular os resultados clínicos e impactos econômicos em saúde da nova tecnologia diagnóstica (QTF-GIT) versus a PT tradicional. Esse modelo simulou cinco estratégias diagnósticas para detecção e tratamento da ILTB: (a) PT, usando ponto de corte de 5mm; (b) PT, usando ponto de corte de 10 mm; (c) teste QTF-GIT; (d) PT, com ponto de corte de 5mm, seguida de teste QTF-GIT quando PT positiva; (e) PT, com ponto de corte de 10mm, seguida de teste QTF-GIT quando PT positiva. Foi realizada análise de sensibilidade determinística univariada. Na determinação dos fatores associados à ILTB, foi elaborado um modelo de regressão logística múltipla com seleção hierarquizada, utilizando o software Stata. A estratégia mais custo-efetiva foi a PT no ponto de corte ≥10mm, considerando como medida de desfecho tanto o número de indivíduos corretamente classificados pelos testes assim como o número de casos de TB evitados. A utilização isolada do QTF-GIT revelou-se a estratégia de menor eficiência, com RCEI= R$ 343,24 por profissional corretamente classificado pelo teste. Encontrou-se risco à ILTB significantemente maior para sexo masculino [OR=1,89; IC 95%:1,11-3,20], idade ≥ 41 anos [OR=1,56; IC 95%: 1.09-2,22], contato próximo com familiar com TB [OR=1,55; IC 95%: 1.02-2,36], status do tabagismo fumante [OR=1,75; IC 95%: 1.03-2,98] e categoria profissional da Enfermagem [OR=1,44; IC 95%: 1.02-2,03]. Concluiu-se que a PT no ponto de corte de 10mm é a estratégia diagnóstica mais custo-efetiva para ILTB entre os profissionais de saúde na atenção básica e que a ILTB está associada ao hábito do tabagismo e à categoria profissional de Enfermagem. / Health professionals form one of the groups most vulnerable to infection by Mycobacterium tuberculosis (Mtb). According to estimates by the World Health Organization (WHO), 8.8 million people were infected with Mtb and were 1.4 million deaths from TB in 2010. The identification of persons with Latent Tuberculosis Infection (LTBI) is considered by WHO as a priority in the control of disease, especially in developing countries where the incidence of active disease has shown reduction. The aim of this study was to evaluate, in Brazil, the cost-effectiveness of tests Tuberculin Skin Test (TST) and Quantiferon TB Gold-In-Tube (QFT-GIT) in the diagnosis and treatment of LTBI in health professionals working in primary care from the perspective of SUS, comparing five strategies that include the QFT -GIT, different cutoff points for TST and sequential use of two tests; and analyze the impact of smoking on the risk of LTBI among health professionals, highlighting the category of Nursing. A full economic assessment of the type cost-effectiveness was performed, conducted considering a hypothetical cohort of 10,000 health professionals working in primary care, with limited time horizont of one year. A decision analytical model, characterized by a tree of probabilities of events, was developed using the TreeAge ProTM software 2013 (TreeAge Software Inc, Williamstown, MA, USA) to simulate the clinical and economic impacts on health of new diagnostic technology (QFT -GIT) versus the traditional TST. This model simulated five diagnostic strategies for detection and treatment of LTBI (a) TST, using a cut-off of 5 mm; (B) TST, using 10 mm cut-off currently recommended by the TNP; (C) QFT-GIT test; (D) TST, with a cut-off of 5 mm, followed by QFT-GIT test when positive TST; (E) TST, with a cut-off point of 10 mm, followed by QFT-GIT test when positive TST. Univariate deterministic sensitivity analysis was performed to assess the robustness of the results. In determining the factors associated with LTBI, a multiple logistic regression model with hierarchical selection was made, using the Stata software. TST strategy at the cut-off ≥ 10mm was the most cost-effective strategy, while the QFT-GIT alone was the most effective strategy, but showed higher cost. It was found to significantly greater risk for LTBI male [OR = 1.89; 95% CI: 1.11 to 3.20], age ≥ 41 years [OR = 1.56; 95% CI: 1.09-2,22], close contact with a family with TB [OR = 1.55; 95% CI: 1.02-2,36], the smoker smoking status [OR = 1.75; 95% CI: 1.03-2,98] and professional nursing category [OR = 1.44; 95% CI: 1.02-2,03]. It was concluded that TST in 10mm cut-off is the diagnostic strategy more cost-effective for LTBI among health professionals in primary care and that LTBI is associated with the smoke and professional category nurse.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os profissionais da área da saúde formam um dos grupos mais vulneráveis à infecção pelo Mycobacterium tuberculosis (Mtb). Segundo estimativas da Organização Mundial de Saúde (OMS), 8,8 milhões de pessoas estavam infectadas pelo Mtb e ocorreram 1,4 milhão de óbitos por tuberculose (TB) em 2010. A identificação de pessoas com Infecção Latente Tuberculosa (ILTB) é considerada pela OMS como uma prioridade no controle da doença, especialmente em países em desenvolvimento em que a incidência da doença ativa tem apresentado redução. O objetivo do presente trabalho foi avaliar, no Brasil, o custo-efetividade dos testes Prova Tuberculínica (PT) e Quantiferon TB Gold-In-Tube (QTF-GIT) no diagnóstico e tratamento da ILTB em profissionais de saúde atuantes na atenção básica, sob a perspectiva do Sistema Único de Saúde (SUS), comparando cinco estratégias que incluem o QTF-GIT, distintos pontos de corte para a PT e uso sequencial dos dois testes; e analisar o impacto do tabagismo sobre o risco de ILTB entre os profissionais de saúde, destacando-se a categoria da Enfermagem. Foi realizada uma avaliação econômica completa do tipo custo-efetividade, conduzida considerando uma coorte hipotética de 10.000 profissionais de saúde atuantes na atenção básica, com horizonte temporal restrito a um ano. Um modelo analítico de decisão, caracterizado por uma árvore de probabilidades de eventos, foi desenvolvido utilizando o software TreeAge ProTM 2013 para simular os resultados clínicos e impactos econômicos em saúde da nova tecnologia diagnóstica (QTF-GIT) versus a PT tradicional. Esse modelo simulou cinco estratégias diagnósticas para detecção e tratamento da ILTB: (a) PT, usando ponto de corte de 5mm; (b) PT, usando ponto de corte de 10 mm; (c) teste QTF-GIT; (d) PT, com ponto de corte de 5mm, seguida de teste QTF-GIT quando PT positiva; (e) PT, com ponto de corte de 10mm, seguida de teste QTF-GIT quando PT positiva. Foi realizada análise de sensibilidade determinística univariada. Na determinação dos fatores associados à ILTB, foi elaborado um modelo de regressão logística múltipla com seleção hierarquizada, utilizando o software Stata. A estratégia mais custo-efetiva foi a PT no ponto de corte ≥10mm, considerando como medida de desfecho tanto o número de indivíduos corretamente classificados pelos testes assim como o número de casos de TB evitados. A utilização isolada do QTF-GIT revelou-se a estratégia de menor eficiência, com RCEI= R$ 343,24 por profissional corretamente classificado pelo teste. Encontrou-se risco à ILTB significantemente maior para sexo masculino [OR=1,89; IC 95%:1,11-3,20], idade ≥ 41 anos [OR=1,56; IC 95%: 1.09-2,22], contato próximo com familiar com TB [OR=1,55; IC 95%: 1.02-2,36], status do tabagismo fumante [OR=1,75; IC 95%: 1.03-2,98] e categoria profissional da Enfermagem [OR=1,44; IC 95%: 1.02-2,03]. Concluiu-se que a PT no ponto de corte de 10mm é a estratégia diagnóstica mais custo-efetiva para ILTB entre os profissionais de saúde na atenção básica e que a ILTB está associada ao hábito do tabagismo e à categoria profissional de Enfermagem. / Health professionals form one of the groups most vulnerable to infection by Mycobacterium tuberculosis (Mtb). According to estimates by the World Health Organization (WHO), 8.8 million people were infected with Mtb and were 1.4 million deaths from TB in 2010. The identification of persons with Latent Tuberculosis Infection (LTBI) is considered by WHO as a priority in the control of disease, especially in developing countries where the incidence of active disease has shown reduction. The aim of this study was to evaluate, in Brazil, the cost-effectiveness of tests Tuberculin Skin Test (TST) and Quantiferon TB Gold-In-Tube (QFT-GIT) in the diagnosis and treatment of LTBI in health professionals working in primary care from the perspective of SUS, comparing five strategies that include the QFT -GIT, different cutoff points for TST and sequential use of two tests; and analyze the impact of smoking on the risk of LTBI among health professionals, highlighting the category of Nursing. A full economic assessment of the type cost-effectiveness was performed, conducted considering a hypothetical cohort of 10,000 health professionals working in primary care, with limited time horizont of one year. A decision analytical model, characterized by a tree of probabilities of events, was developed using the TreeAge ProTM software 2013 (TreeAge Software Inc, Williamstown, MA, USA) to simulate the clinical and economic impacts on health of new diagnostic technology (QFT -GIT) versus the traditional TST. This model simulated five diagnostic strategies for detection and treatment of LTBI (a) TST, using a cut-off of 5 mm; (B) TST, using 10 mm cut-off currently recommended by the TNP; (C) QFT-GIT test; (D) TST, with a cut-off of 5 mm, followed by QFT-GIT test when positive TST; (E) TST, with a cut-off point of 10 mm, followed by QFT-GIT test when positive TST. Univariate deterministic sensitivity analysis was performed to assess the robustness of the results. In determining the factors associated with LTBI, a multiple logistic regression model with hierarchical selection was made, using the Stata software. TST strategy at the cut-off ≥ 10mm was the most cost-effective strategy, while the QFT-GIT alone was the most effective strategy, but showed higher cost. It was found to significantly greater risk for LTBI male [OR = 1.89; 95% CI: 1.11 to 3.20], age ≥ 41 years [OR = 1.56; 95% CI: 1.09-2,22], close contact with a family with TB [OR = 1.55; 95% CI: 1.02-2,36], the smoker smoking status [OR = 1.75; 95% CI: 1.03-2,98] and professional nursing category [OR = 1.44; 95% CI: 1.02-2,03]. It was concluded that TST in 10mm cut-off is the diagnostic strategy more cost-effective for LTBI among health professionals in primary care and that LTBI is associated with the smoke and professional category nurse.