Latent M. tuberculosis infection--pathogenesis, diagnosis, treatment and prevention strategies

One third of the earths population is infected with Mycobacterium tuberculosis (Mtb), but only 5-10% of the infected individuals develop active tuberculosis (TB) over their lifetime. The remaining 90-95% stay healthy and are called latently infected individuals. They are the biggest reservoir of the tubercle bacilli and identifying the cases of latent TB is a part of the global plan of TB control. From the clinical point of view detection of latent TB infections (LTBI) in individuals with the highest active TB risk including cases of HIV infection, autoimmune inflammatory diseases or cancer, is a priority. This review summarizes the recent findings in the pathogenesis of latent TB, its diagnosis, treatment and prevention.     

The prognosis of latent tuberculosis: can disease be predicted?

In humans, Mycobacterium tuberculosis persists for long periods in a clinically latent state, creating a huge reservoir of 'silent' tuberculosis (TB) (roughly one-third of the global population) from which new cases continually arise. A prognostic marker for active TB would enable targeted treatment of the small fraction of infected individuals who are most at risk of developing contagious TB, contributing greatly to TB control efforts. Here, we propose that TB-specific interferon-gamma release assays might be useful for identifying individuals with progressive infections who are likely to develop the disease. This might provide an unprecedented advantage for TB control, namely targeted preventive therapy for individuals who are most at risk of developing active contagious TB.     

Risk factors for reactivation of tuberculosis in Manitoba

Although rates of reported cases of active tuberculosis have been declining in Manitoba and throughout Canada over the past two decades, the percentage of active cases due to reactivated tuberculosis has remained relatively constant. From 1976 to 1981, 113 cases of reactivated tuberculosis were listed in the Manitoba tuberculosis registry. We found that 36 cases did not meet our criteria for reactivation, primarily because there was no 6-month period of inactivity; another 5 cases could not be verified. In more than half of the remaining 72 the initial episode had occurred before 1960. We also randomly selected from the registry as controls 118 age- and sex-matched cases of nonreactivated tuberculosis. We found that registered Indian status was significantly associated with risk of reactivation, especially when the initial disease had been extensive. Awareness of high-risk groups, earlier diagnosis and adequate treatment are needed to prevent reactivated tuberculosis.     

Domiciliary Treatment of Tuberculosis

In the present therapy of tuberculosis with antimicrobial agents, most patients receive the major part of their treatment at home, and a significant proportion of active cases never enter sanatorium or stop working during their treatment.Domiciliary treatment in Canada, with and without sanatorium admission, has been reviewed. At present, approximately 7500 patients are being treated on an outpatient basis. Most have had a period of sanatorium treatment for investigation and institution of antimicrobial therapy, but in one province up to 30% of new active cases of tuberculosis, and in another 12%, are treated entirely on an outpatient basis.The indications are that domiciliary treatment is successful and that the practice is expanding. This practice will probably continue to expand as more and better outpatient clinic facilities are developed to provide the necessary supervision and follow-up of tuberculous patients.     

Spectrum of tuberculosis in patients with HIV infection in British Columbia: report of 40 cases.

OBJECTIVE: To review the clinical features, treatment and outcome of all known cases of tuberculosis in patients with human immunodeficiency virus (HIV) infection in British Columbia between 1984 and 1990. DESIGN: Retrospective case review. SETTING: Provincial tuberculosis registry and university-affiliated HIV clinic. PATIENTS: All people with HIV infection in whom active tuberculosis was diagnosed during the study period. RESULTS: All 40 patients identified were men; their mean age was 38 years. Of the subjects 30 (75%) were homosexual, 6 (15%) were homosexual and used intravenous drugs, 2 (5%) just used intravenous drugs, and 1 (2%) had had heterosexual contact with prostitutes; for the remaining subject the risk factor for HIV infection was not established. In all cases cultures of specimens from 15 body sources yielded Mycobacterium tuberculosis. Thirty-five of the patients had acquired immunodeficiency syndrome (AIDS), and five had HIV infection uncomplicated except for tuberculosis. In 28 (70%) of the cases no AIDS-defining disease had previously been diagnosed, and in 23 (58%) extrapulmonary tuberculosis represented the AIDS-defining disease. Symptoms at presentation included weight loss (in 80% of the cases), fever (in 75%), cough (in 70%) and night sweats (in 55%). The mean CD4 lymphocyte count was 0.2 x 10(9)/L (in 15 cases). Tuberculin skin test results were positive in 8 of 16 cases. The most striking radiologic finding was intrathoracic adenopathy. All except one of the 36 patients who received appropriate treatment responded favourably at first. Adverse reactions necessitating changes in treatment occurred in 12 (33%) of the cases. Relapse occurred after completion of therapy in two cases (one at 3 weeks and the other at 9 months after treatment was stopped). Tuberculosis was the cause of death in five cases. CONCLUSIONS: Tuberculosis in people with HIV infection commonly presents as extrapulmonary disease and precedes or coincides with other AIDS-defining opportunistic infections. In most cases tuberculosis is the AIDS-defining disease. Even though radiologic findings are often unusual physicians should suspect tuberculosis. A careful examination for evidence of disease at multiple sites should be done. The duration and choice of therapy must be adequate to avoid relapse.     

Analysis of a mathematical model for tuberculosis: What could be done to increase case detection

This paper presents qualitative and quantitative study of a TB mathematical model to test results from a survey carried out in Benin City, Nigeria. The purpose of the survey was to determine factors that could enhance the case detection rate of tuberculosis. Results from the survey identified four key factors that must be combined for an effective control of TB and increase the case detection rate: effective awareness programme, active cough identification, associated cost factor for treatment of identified cases and effective treatment. The overall effect of these factors on the basic reproduction number under treatment, R_T, of the TB model was considered. In all, a serious concentration on tuberculosis awareness programmes and active cough identification as a marker for someone having TB was shown to significantly reduce the value of the reproduction number, hereby reducing the severity of the disease in the presence of treatment.     

A Theoretical Assessment of the Effects of Smoking on the Transmission Dynamics of Tuberculosis

Smoking has long being associated with tuberculosis. We present a tuberculosis dynamics model taking into account the fact that some people in the population are smoking in order to assess the effects of smoking on tuberculosis transmission. The epidemic thresholds known as the reproduction numbers and equilibria for the model are determined and stabilities analyzed. Qualitative analysis of the model including positivity and persistence of solutions are presented. The model is numerically analyzed to assess the effects of smoking on the transmission dynamics of tuberculosis. Numerical simulations of the model show that smoking enhances tuberculosis transmission, progression to active disease and in a population of smokers, tuberculosis cannot be controlled even when treatment success is assumed to be as high as 88%. Further, analysis of the reproduction numbers indicates that the number of active tuberculosis cases increases as the number of smokers increase.     

New approaches in the diagnosis and treatment of latent tuberculosis infection

With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with isoniazid for nine months. Other options include therapy with rifampicin for 4 months or isoniazid + rifampicin for 3 months or rifampicin + pyrazinamide for 2 months or isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence.     

Rational use of antibiotics in mucoviscidosis pediatric cases with an account of local microbiological monitoring]

The results of local microbiological monitoring of bronchial secretion in 482 children with mucoviscidosis observed within 2000-2004 in the Republican Centre of Mucoviscidosis are presented. The results provided development of recommendations for rational use of antibiotics in the treatment of infectious processes in pediatric patients with mucoviscidosis. Since the emergence of MRSA in such patients is low, it is recommended to use antistaphylococcal betalactams (oxacillin, cefazolin, amoxycillin/clavulanate) for the treatment of infections due to S. aureus. For the treatment of infections due to some other pathogens, except S. maltophilia, the most active betalactams were carbapenems (imipenem and meropenem). Ciprofloxacin was active against numerous etiological agents causing low respiratory tract infections in children with mucoviscidosis except S. maltophila and A. xylosoxidans subsp. xylosoxidans. For the treatment of infections due to P. aeruginosa, P. aeruginosa muc. and K. pneumoniae the most active aminoglycosides were amikacin and tobramycin (for P. aeruginosa and P. aeruginosa muc.), while gentamicin was not active in such cases. As for antibiotics of other groups, high activity against S. aureus in the treatment of children with mucoviscidosis was recarded with the use of vancomycin, fusidic acid and rifampicin. Azithromycin and co-trimoxazole were active against H. influenzae. Chloramphenicol was active against S. maltophilia, B. cepacia and H. influenzae in the treatment of such patients.     

Skeletal Lesions in Human Tuberculosis May Sometimes Heal: An Aid to Palaeopathological Diagnoses

In three to five percent of active cases of tuberculosis, skeletal lesions develop. Typically, these occur on the vertebrae and are destructive in nature. In this paper, we examined cases of skeletal tuberculosis from a skeletal collection (Galler Collection) with focus on the manifestation of bony changes due to tuberculosis in various body regions in association with antibiotic introduction. This skeletal collection was created in 1925–1977 by a pathologist at the University Hospital in Zürich, Ernst Galler. It includes the remains of 2426 individuals with documented clinical histories as well as autopsies. It contained 29 cases of skeletal tuberculosis lesions. We observed natural healing of vertebral lesions through several processes including fusion of vertebrae, bone deposition and fusion of posterior elements. In these cases, we observed a higher frequency and proportion of bone deposition and fusion of posterior vertebral elements where pharmacological agents were used. There were also four cases of artificial healing through surgically induced posterior spinal fusion. With the introduction of pharmaceutical treatments, the number of individuals with multiple tuberculous foci decreased from 80% to 25% when compared to individuals who did not receive any drug therapy. Investigation of comorbidities showed that pneumonia, pleuritis and being underweight were consistently present, even with pharmaceutical treatment. Our results have applications in palaeopathological diagnoses where healing and consequent bone deposition may complicate differential diagnoses.     

Does the onset of tuberculosis in AIDS predict shorter survival? Results of a cohort study in 17 European countries over 13 years. AIDS in Europe Study Group.

OBJECTIVE--To assess the impact of tuberculosis on mortality in patients with AIDS. DESIGN--Community based cohort study. SETTING--52 centres in 17 countries (AIDS in Europe study). SUBJECTS--5249 patients who were alive and free of tuberculosis one month after the diagnosis of AIDS, enrolled between 1979 and 1989, and followed up until 1992. MAIN OUTCOME MEASURES--Onset of clinically active tuberculosis or death, or both. RESULTS--During a mean follow up period of 15 months 201 (4%) patients developed tuberculosis and 3889 (74%) died. Patients who developed tuberculosis survived significantly longer (median 22 months) than those who did not (median 16 months). This apparent survival advantage was due to patients who survived longer having more opportunity to develop tuberculosis (or any other disease). In models that took into account the time at which tuberculosis was diagnosed, the onset of tuberculosis was associated with a significant increase in mortality (adjusted relative hazard of death 1.34; 95% confidence interval 1.12 to 1.60). CONCLUSIONS--The onset of tuberculosis in patients with AIDS predicts a substantial increase in mortality. Whether this increased mortality is directly attributable to the tuberculosis remains uncertain. If the association is causal preventive chemotherapy and aggressive treatment of tuberculosis could improve survival in AIDS.     

Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology

14alpha-Demethylase (CYP51) is a key enzyme in all sterol biosynthetic pathways (animals, fungi, plants, protists, and some bacteria), catalyzing the removal of the C-14 methyl group following cyclization of squalene. Based on mutations found in CYP51 genes from Candida albicans azole-resistant isolates obtained after fluconazole treatment of fungal infections, and using site-directed mutagenesis, we have found that fluconazole binding and substrate metabolism vary among three different CYP51 isoforms: human, fungal, and mycobacterial. In C. albicans, the Y132H mutant from isolates shows no effect on fluconazole binding, whereas the F145L mutant results in a 5-fold increase in its IC(50) for fluconazole, suggesting that F145 (conserved only in fungal 14alpha-demethylases) interacts with this azole. In C. albicans, F145L accounts, in part, for the difference in fluconazole sensitivity reported between mammals and fungi, providing a basis for treatment of fungal infections. The C. albicans Y132H and human Y145H CYP51 mutants show essentially no effect on substrate metabolism, but the Mycobacterium tuberculosis F89H CYP51 mutant loses both its substrate binding and metabolism. Because these three residues align in the three isoforms, the results indicate that their active sites contain important structural differences, and further emphasize that fluconazole and substrate binding are uncoupled properties.     

Implications of partial immunity on the prospects for tuberculosis control by post-exposure interventions

One-third of the world population (approximately 2 billion individuals) is currently infected with Mycobacterium tuberculosis, the vast majority harboring a latent infection. As the risk of reactivation is around 10% in a lifetime, it follows that 200 million of these will eventually develop active pulmonary disease. Only therapeutic or post-exposure interventions can tame this vast reservoir of infection. Treatment of latent infections can reduce the risk of reactivation, and there is accumulating evidence that combination with post-exposure vaccines can reduce the risk of reinfection. Here we develop mathematical models to explore the potential of these post-exposure interventions to control tuberculosis on a global scale. Intensive programs targeting recent infections appear generally effective, but the benefit is potentially greater in intermediate prevalence scenarios. Extending these strategies to longer-term persistent infections appears more beneficial where prevalence is low. Finally, we consider that susceptibility to reinfection is altered by therapy, and explore its epidemiological consequences. When we assume that therapy reduces susceptibility to subsequent reinfection, catastrophic dynamics are observed. Thus, a bipolar outcome is obtained, where either small or large reductions in prevalence levels result, depending on the rate of detection and treatment of latent infections. By contrast, increased susceptibility after therapy may induce an increase in disease prevalence and does not lead to catastrophic dynamics. These potential outcomes are silent unless a widespread intervention is implemented.     

HIV and tuberculosis in India

The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time. The World Health Organization (WHO) reports 9.2 million new cases of TB in 2006 of whom 7.7% were HIV-infected. Tuberculosis is the most common opportunistic infection in HIV-infected patients as well as the leading cause of death. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. The diagnosis of TB is based on sputum smear microscopy, a 100-year old technique and chest radiography, which has problems of specificity. Extra-pulmonary, disseminated and sputum smear negative manifestations are more common in patients with advanced immunosuppression. Newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-poor settings. Treatment of HIV-TB co-infection is complex and associated with high pill burden, overlapping drug toxicities, risk of immune reconstitution inflammatory syndrome (IRIS) and challenges related to adherence. From a programmatic point of view, screening of all HIV-infected persons for tuberculosis and vice-versa will help identify co-infected patients who require treatment for both infections. This requires good coordination and communication between the TB and AIDS control programs, in India.     

多层螺旋CT对肺结核合并肺癌患者的诊断价值

目的:研究多层螺旋CT对肺结核合并肺癌的鉴别诊断价值。方法:选择2013年3月至2015年9月在我院确诊的肺结核合并肺癌患者32例和单纯肺结核患者39例应用多层螺旋CT扫描患者肺部病变情况。结果:肺结核合并肺癌组:陈旧性肺结核28例、活动性肺结核4例;病灶位置经典部位29例、非经典部位3例,合并鳞癌11例、腺癌13例、小细胞癌5例、未分化癌3例;10例结核病灶与肺癌病灶不同侧、13例结核病灶与肺癌病灶同侧不同叶、9例结核病灶于肺癌病灶同侧同叶。单纯性肺结核组胨旧性肺结核36例、活动性肺结核3例;病灶位置经典部位34例(上叶尖段11例、后段9例、下叶背段14例)、非经典部位5例。肺结核合并肺癌组患者分叶征、毛刺征、胸膜凹陷征、阻塞性肺炎及肺不张以及棘状突起比例高于单纯肺结核组,而空泡影比例低于单纯肺结核组,差异具有统计学意义(P0.05);两组钙化、斑片条索影、结节影以及空洞或空腔比较,差异无统计学意义(P0.05)。结论:多层螺旋CT对肺结核合并肺癌具有较高的临床鉴别诊断价值。     

Longitudinal study of tuberculosis outcomes among immunologically naive Aché natives of Paraguay

This study documents the course of a tuberculosis epidemic in an immunologically naive group of South American Indians within fewer than 20 years after first sustained contact with outsiders. Groups of Northern Aché (ah-CHAY) of eastern Paraguay were contacted and settled on reservations between 1971-1979. Not surprisingly, the Aché are very susceptible to tuberculosis, and the epidemiological characteristics of the disease are quite different from those of populations that have had tuberculosis for centuries. Within 6 years of the first detected case of tuberculosis among the Aché, the prevalence rate of active tuberculosis cases reached 18.2%, and of infected cases among adults, 64.6%, some of the highest rates ever reported for any human group. Remarkably, males and females are equally likely to have been diagnosed with active tuberculosis, Aché children between birth and 5 years of age are least vulnerable to tuberculosis, high nutritional and socioeconomic status do not decrease the risk of disease or infection, and children immunized with BCG are less responsive to tuberculin challenge than are other children. Moreover, similar to the Yanomam?, but unlike populations of European or African descent, a high percentage of Aché with active disease test negative on tuberculin challenge tests (purified protein derivative; PPD). These differences may be due to a high prevalence of diminished cell-mediated immunity, and T-helper 2 dominance. We also hypothesize that these immunological characteristics, low genetic diversity, hostile intergroup interactions, and behavioral noncompliance to treatment protocols together contribute to the high rates of active disease observed. Existing tuberculosis control programs are poorly equipped to handle the impact of these causal complexities on the course of recent tuberculosis epidemics that have quickly spread throughout native communities of Latin America during the last decade.     

Rational antimicrobial pharmacotherapy of secondary infections in patients with pulmonary tuberculosis]

The results of 3-year (2002-2004) local microbiological monitoring of secondary infections due to opportunistic microflora that complicated the treatment of the main disease in patients of a regional (Moscow) tuberculosis hospital are presented. The monitoring revealed the leading microorganisms, the etiological agents of the secondary lower respiratory tract infection in the patients with pulmonary tuberculosis. The level of their resistance to the up-to-date antimicrobials was determined. Recommendations for optimization of antibacterial therapy of patients with pulmonary tuberculosis complicated by secondary lower respiratory tract infection due to opportunistic microorganisms were developed and validated.