Natural History Of Tuberculosis Research Articles

Transcriptomics for child and adolescent tuberculosis.

SummaryTuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is estimated that 70 million children (<15 years) are currently infected with Mtb, with 1.2 million each year progressing to disease. Of these, a quarter die. The risk of progression from Mtb infection to disease and from disease to death is dependent on multiple pathogen and host factors. Age is a central component in all these transitions. The natural history of TB in children and adolescents is different to adults, leading to unique challenges in the development of diagnostics, therapeutics, and vaccines. The quantification of RNA transcripts in specific cells or in the peripheral blood, using high‐throughput methods, such as microarray analysis or RNA‐Sequencing, can shed light into the host immune response to Mtb during infection and disease, as well as understanding treatment response, disease severity, and vaccination, in a global hypothesis‐free manner. Additionally, gene expression profiling can be used for biomarker discovery, to diagnose disease, predict future disease progression and to monitor response to treatment. Here, we review the role of transcriptomics in children and adolescents, focused mainly on work done in blood, to understand disease biology, and to discriminate disease states to assist clinical decision‐making. In recent years, studies with a specific pediatric and adolescent focus have identified blood gene expression markers with diagnostic or prognostic potential that meet or exceed the current sensitivity and specificity targets for diagnostic tools. Diagnostic and prognostic gene expression signatures identified through high‐throughput methods are currently being translated into diagnostic tests.

Phylogeography and transmission of M. tuberculosis in Moldova: A prospective genomic analysis.

The incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible tuberculosis (TB), is the main driver of incident MDR-TB in these countries. We conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of Mycobacterium tuberculosis. Of 2,236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. Moreover, 92% of multidrug-resistant M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified 3 large clades that were comprised nearly uniformly of MDR-TB: 2 of these clades were of Beijing lineage, and 1 of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity. Our study lasted for only 2 years, a relatively short duration compared with the natural history of TB, and, thus, the ability to infer the full extent of transmission is limited. The MDR-TB epidemic in Moldova is associated with the local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.

Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.

Breaking Transmission with Vaccines: The Case of Tuberculosis.

Members of the Mycobacterium tuberculosis complex (MTBC) have evolved causing tuberculosis (TB) in different mammalian hosts. MTBC ecotypes have adapted to diverse animal species, with M. bovis being the most common cause of TB in livestock. Cattle-to-human transmission of M. bovis through ingestion of raw milk was common before introduction of the pasteurization process. TB in humans is mainly caused by M. tuberculosis. This bacterium is considered a genetically clonal pathogen that has coevolved with humans due to its ability to manipulate and subvert the immune response. TB is a major public health problem due to airborne person-to-person transmission of M. tuberculosis. The essential yet unanswered question on the natural history of TB is when M. tuberculosis decides to establish latent infection in the host (resambling the lysogenic cycle of lambda phage) or to cause pulmonary disease (comparable to the lytic cycle of lambda phage). In this latter case, M. tuberculosis kills the host with the aim of achieving transmission to new hosts. Combating the TB epidemic requires stopping transmission. M. bovis BCG, the present vaccine against TB, is derived from M. bovis and only protects against disseminated forms of TB. Thus, a priority in TB research is development of new effective vaccines to prevent pulmonary disease. Attenuated vaccines based on M. tuberculosis as MTBVAC are potential candidates that could contribute to break the TB transmission cycle.

Clustured regularly interspersed short palindromic repeats (CRISPR) genetic diversity studies as a mean to reconstruct the evolution of the Mycobacterium tuberculosis complex

The natural history of tuberculosis may be tackled by various means, among which the record of molecular scars that have been registered by the Mycobacterium tuberculosis complex (MTBC) genomes transmitted from patient to patient for tens of thousands years and possibly more. Recently discovered polymorphic loci, the CRISPR sequences, are indirect witnesses of the historical phage-bacteria struggle, and may be related to the time when the ancestor of today's tubercle bacilli were environmental bacteria, i.e. before becoming intracellular parasites. In this article, we present what are CRISPRs and try to summarize almost 20 years of research results obtained using the genetic diversity of the CRISPR loci in MTBC as a perspective for studying new models. We show that the study of the diversity of CRISPR sequences, thanks to «spoligotyping», has played a great role in our global understanding of the population structure of MTBC.

Translating basic science insight into public health action for multidrug- and extensively drug-resistant tuberculosis.

Multidrug (MDR)- and extensively drug-resistant (XDR) tuberculosis (TB) impose a heavy toll of human suffering and social costs. Controlling drug-resistant TB is a complex global public health challenge. Basic science advances including elucidation of the genetic basis of resistance have enabled development of new assays that are transforming the diagnosis of MDR-TB. Molecular epidemiological approaches have provided new insights into the natural history of TB with important implications for drug resistance. In the future, progress in understanding Mycobacterium tuberculosis strain-specific human immune responses, integration of systems biology approaches with traditional epidemiology and insight into the biology of mycobacterial persistence have potential to be translated into new tools for diagnosis and treatment of MDR- and XDR-TB. We review recent basic sciences developments that have contributed or may contribute to improved public health response.

Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review.

BackgroundThe prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data.Methodology and Principal FindingsTo estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis.ConclusionsCurrent models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

Childhood Tuberculosis Challenges and Way Forward

Despite the increased global attention, funding and achieve-ments in the control of tuberculosis over the past decade,children have been largely ignored and have not benefitedfrom the advances in diagnosis and treatment. Childrenyounger than 15 years contribute 15–20% of the global TBdisease burden, although accurate data are scarce due tochallenges in case ascertainment and lack of surveillance inthis age group [1]. Tuberculosis transmission to childrennot only indicates inadequate control in the community, butcreates a pool of latently infected individuals who form thefountainhead of adult disease at some time in the future.Elimination of TB by 2050, a goal of the worldwide TBscientific community requires attention to diagnosis, treat-ment and prevention of TB in adults and childrensimultaneously, though the approaches would need to bequite different [2]. Further, young children are at high riskfor disease progression and high mortality as well as long-term sequelae, if the disease is not diagnosed and treatedappropriately. The needs for research are substantial and itis hoped that the research community and funders will payincreasing attention to these priorities. New diagnosticsincluding liquid culture methods, the MODS assay, nucleicacid amplification techniques, line probe assays and othermolecular techniques need to be tested and validated on anumber of different clinical specimens that may be obtainedfrom children. Randomized trials and high quality pharma-cokinetic and observational studies are required to evaluatethe efficacy and safety of currently recommended dosagesas well as length of anti-TB treatment for the differentforms of pulmonary and extra-pulmonary TB [3]. Asseveral new drugs enter the pipeline for the first time indecades, studies in children need to be urgently initiated ifthey are not to be excluded from the benefits of theseadvances. Surveys to estimate the burden of TB andprevalence of drug resistance should include children inan effort to generate baseline data and monitor progress ofcontrol efforts. While trials to determine the best regimenfor prevention among contacts of multi-drug resistant TBare needed, implementation research addressing barriers torapid scale up of contact tracing and chemoprophylaxisshould take priority for TB control programs.Indian journal of pediatrics (IJP) publishes updatedreviews on clinical problems faced by pediatricians indaily clinical practice. A symposium on tuberculosisaddressing the state of the art on various aspects isappearing in two parts. The articles are written byexperts in the field and geared towards practicingpediatricians while highlighting gaps in knowledge. Inthis issue four articles on various aspects of childhoodtuberculosis are included. In recent years with analysis ofepidemiological aspects of childhood tuberculosis, thereis better understanding of natural history of childtuberculosis. An article by Marais et al [4] discusses theepidemiology and natural history of tuberculosis. The chang-ing trends in clinical manifestations, diagnostic approach and

Childhood Tuberculosis: Epidemiology and Natural History of Disease

Despite previous misperceptions that childhood tuberculosis (TB) is less relevant, since children tend to develop mild disease, contribute little to transmission and do not impact epidemic control, awareness is growing that TB is an important preventable cause of disease and death among children in TB endemic areas. At an operational level there remains an urgent need for feasible and implementable policies to guide management in resource limited settings. This manuscript reviews the epidemiology and natural history of TB in children in order to improve understanding of the various disease entities encountered and to provide the rationale for different management approaches.

Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD

Tuberculosis (TB), smoking, HIV and chronic obstructive pulmonary disease (COPD) are burgeoning epidemics in developing countries. The link between TB and HIV is well established. Less well recognised is the strong relationship between tobacco smoking and the development and natural history of TB. These associations are of considerable relevance to public health and disease outcomes in individuals with TB. Moreover, tobacco smoking, a modifiable risk factor, is associated with poorer outcomes in HIV-associated opportunistic infections, of which TB is the commonest in developing countries. It is now also becoming clear that TB, like tobacco smoke, besides its known consequences of bronchiectasis and other pulmonary morbidity, is also a significant risk factor for the development of COPD. Thus, there is a deleterious and synergistic interaction between TB, HIV, tobacco smoking and COPD in a large proportion of the world's population. Further work, specifically mechanistic and epidemiological studies, is required to clarify the role of tobacco smoke on the progression of TB and HIV infection, and to assess the impact of smoking cessation interventions. These interactions deserve urgent attention and have major implications for coordinated public health planning and policy recommendations in the developing world.

Commentary: Kristian Feyer Andvord's studies on the epidemiology of tuberculosis and the origin of generation cohort analysis

Accepted 3 April 2008The Norwegian physician Kristian Feyer Andvord(1855–1934) who had no training in epidemiology,observed differences in mortality rates from tuber-culosis between counties in Norway late 19th centuryand started in the 1890s to speculate on why the ratesdiffered between counties and had fallen for infantsbut not adults. This triggered him to spend his careeron the natural history of tuberculosis by means ofpopulation data and made him suggest that primaryinfection with tuberculosis mainly takes place inchildhood and that falling mortality rates at thetime of observation was a reflection of exposure earlyin life.

Nouveaux outils du diagnostic de l’infection tuberculeuse latente

Until recently, the tuberculin skin test was the only test for detecting latent tuberculosis (TB) infection with a lack of specificity and reliability. Since 2005, new tests are available. Those tests are based on interferon gamma released (IGRAs) by T lymphocytes after mycobacterium tuberculosis antigen specific exposure. The new tests are able to modify our understanding of natural history of tuberculosis. Longitudinal studies are needed to define the predictive value of IGRAs.

Tuberculosis in children

<h3>Key points</h3> Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. Children with TB are markers of recent disease transmission, usually from infectious adults. The 1 million cases of TB in children registered each year is likely to be a gross underestimate. The diagnosis is challenging and often presumed rather than confirmed. Symptoms, if present, are nonspecific. TB infection occurs when a previously uninfected child inhales an infected aerosol droplet. At this stage, the child usually shows no symptoms, the infection passes undetected and the primary focus heals. In most cases the infection is controlled by the body9s immune system and the organisms remain dormant. This is called latent TB. TB disease can develop either then or at a later stage when the organism multiplies, overpowering the host defences. At this stage, symptoms develop and there may be radiological or microbiological evidence of disease. "More bugs require more drugs". In TB infection, the organism load is small and therefore drug-resistant mutations are rare: hence simpler drug regimes are effective. In TB disease, the number of organisms is greater, so a combination of ≥3 drugs is required. Increasing resistance worldwide has led to four drugs being recommended as standard in many areas. Poor adherence to drug therapy is the main barrier to cure. Although directly observed therapy (DOTS) and intermittent therapy may improve the outcome, neither is a panacea. Co-operation and other strategies are required. Bacille Calmette-Guérin (BCG) vaccination remains the most widely used preventative strategy. Its efficacy is uncertain and its use needs to be targeted to neonates in high-risk areas who are most likely to benefit. The development of new vaccines against pulmonary TB is an important global challenge. <h3>Educational aims</h3> To describe the epidemiology and natural history of TB in children, focusing on pulmonary TB. To explore the challenges of diagnosis and provide an up-to-date overview of the methods available. To outline the management and prevention of pulmonary TB in children. <h3>Summary</h3> Despite advances in diagnosis, treatment and prevention, tuberculosis (TB) remains a major cause of mortality and morbidity worldwide. Diagnosis and treatment in children present a challenge, particularly in the face of growing drug resistance and coexistent disease such as HIV. New diagnostic methods have not yet been fully validated for use in children. No new drugs have become available in the past 30 years and many of the commercially available preparations are unsuitable for children. In 2006, a number of major documents and strategies were launched aimed at improving the care of children with TB, a previously neglected area.

Molecular epidemiology of tuberculosis: toy or tool? A review of the literature and examples from Central Europe

Genotyping has become an indispensable tool in medical microbiology and epidemiology. One of the first targets has been Mycobacterium tuberculosis. Over the past 15 years approximately 900 pertinent publications have substantiated the value of the genotyping approach for tuberculosis control. New insights into the understanding of the natural history of tuberculosis, especially regarding the frequencies of reactivation, reinfection or multiple infection entailed adaptations of pathophysiological concepts. However, assessment of recent transmission, outbreak analysis, and detection of laboratory contamination still form the genuine scope of genotyping. Detection of unsuspected clusters of cases can provide clues to search for further, undetected cases. Uncovering false positive cultures spares the risks and costs of unnecessary treatment and may reveal systematic laboratory weaknesses. Several European countries already profit from nationwide prospective fingerprinting. After providing genotyping results to public health officials, these were able to document epidemiological links for substantially more tuberculosis patients. On a global scale, strain families and particular strains have been identified, characterised and traced in their spread. The importation of Beijing-genotype multidrug-resistant M. tuberculosis into Central European countries will be described here as an example. The goal for further developments is the ability to compare isolates for epidemiological purposes in a single step that also comprises species determination, drug resistance testing and detection of pathogenicity factors.

Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis

Background: The diagnosis of childhood pulmonary tuberculosis presents a major challenge as symptoms traditionally associated with tuberculosis are extremely common in children from endemic areas. The natural history of tuberculosis...

Bacillarity at autopsy in pulmonary tuberculosis. Mycobacterium tuberculosis is often disseminated.

The aim of this investigation was to quantify dissemination of Mycobacterium tuberculosis infection in patients with pulmonary tuberculosis and to show the pattern of eradication during treatment. The study is based on 98 out of the 113 patients with pulmonary tuberculosis who died during their admission to hospital in the Municipality of Copenhagen from 1963 to 1971. These patients had cultures for M. tuberculosis performed from different organs at autopsy: 78% treated <=100 days had dissemination of bacteria, cultured with decreasing frequency in the lungs, spleen, liver, and kidneys, respectively. In comparison, 23% treated >100 days had dissemination of bacteria, among which 50% occurred in patients with records of poor treatment compliance, 14% in patients with good treatment compliance. 81% of all patients had at least one chest x-ray judged to be without a miliary pattern. This study emphasizes that M. tuberculosis is often disseminated to organs other than the lungs in severe pulmonary tuberculosis. Eradication of bacteria in these organs can take several months. This observation adds to our understanding of the natural history of tuberculosis: M. tuberculosis is a resilient organism that can adapt to a wide variety of environmental conditions.

Primary tuberculosis.

The natural history of tuberculosis is complex. Primary infection, the initial phase, occurs in people without specific immunity, generally normal children and young adults who have not previously been exposed to Mycobacterium tuberculosis. The initial infection can occur at any time during childhood, but adolescence is the peak time of risk. Primary disease develops within 5 years of the initial infection, which stimulates specific immunity, demonstrated by the development of a positive skin response to purified protein derivative of tuberculin. Although symptoms of primary disease may be few, early detection and treatment are important for both preventing the development of immediate complications, which carry a high risk of morbidity and mortality, and preventing spread of infection following later reactivation of disease. Our understanding of the host's immune response to the primary infection is increasing, and it is hoped this will lead to improved possibilities for vaccines in the future.

Epidemiological Model and Cost-Effectiveness Analysis of Tuberculosis Treatment Programmes in Indonesia

An epidemiological model of tuberculosis, based on the natural history of tuberculosis and the control programmes in Indonesia, was constructed. This model was used for estimating future tuberculosis-prevented cases and costs for three treatment strategies--the 100% standard course, the 100% short course, and the existing strategy (a combination of 65% standard course and 35% short course)--in accordance with the master plan of the Indonesian Government's tuberculosis control programme. A cost-effectiveness analysis of the three strategies confirmed that the short-course strategy was the most cost-effective. Sensitivity analysis, which applied a broad range of parameters, continued to confirm the short-course strategy as the most cost-effective. If the short-course strategy had been applied in 1980 instead of the existing strategy (using the most likely parameters), the short-course strategy would prevent 1.8 million sputum-positive cases and would save 61.0 million dollars by the year 2000.

The effects of the delayed type immune response upon the host

A consistent accumulation of experimental evidence, most of it published long ago, clearly shows that a constant consequence of the immune response elicited by the Koch bacillus is that the individual becomes susceptible to be injured or killed by the tuberculous antigen, which is totally innocuous to the virgin subject. This fact led Rich to conclude that throughout the natural history of tuberculosis, as soon as the immune reaction is activated, the tuberculo-protein poured out by the germ mass will exert its detrimental capabilities manifested as the constitutional symptoms of the disease (1). The pathogenicity of the specific antigen in the tuberculous-type immune reaction may be extrapolated to other states that elicit the same response, including cancer and tissue transplantation. Unexplained phenomena such as the general symptoms of many neoplasias, as well as the systemic manifestations of graft rejection, may then be attributed to the shedding of antigen from the foreign cell mass into the sensitized host.

The Natural History of Tuberculosis in the Human Body: X. Prognosis among Students with Tuberculin Reaction Conversion before, during and after School of Nursing

Of 3,192 graduates of three private hospital schools of nursing, 91.9 per cent were traced. The 68 who died from nontuberculous conditions and the 289 who were not located were followed medically for 1,374 and 8,734 person-years respectively before death or at the time of last contact. The 2,835 traced survivors were followed medically for 61,501 person-years. This study was devised not only to determine extent of a serious tuberculosis situation, but also to try to solve the problem. Prophylactic measures consisted of: a) examination of all hospital patient admissions and personnel; b) communicable disease technique wherever tuberculous patients were treated; c) the tuberculin test on all admissions to school with periodic retests on all non-reactors; d) periodic roentgenograms of chests of all tuberculin reactors; e) an educational program to provide information on all aspects of tuberculosis. When these prophylactic measures were well under way, the percentage of reactors on graduation began to decrease. These measures have been continued with the result that in school I in the class of 1965, 1966 and 1967, none had tuberculin conversion as students. In school II among the 602 students in the classes of 1966 and 1967, tuberculin conversion occurred in five. In school II among the 5,637 in the classes from 1954 through the spring of 1967, conversion occurred in three students. Among the 1,323 students who reacted to tuberculin on admission, or converted while in school, or after graduation, 35 (2.8 per cent) subsequently developed clinical pulmonary lesions, one had renal disease and ten pleurisy with effusion. No student developed tuberculous meningitis of miliary dissemination. Among the 14 who converted while in school, eleven did so before 1935, two in 1943 and one in 1944. This study exemplifies the fact that as long as one or a few react to tuberculin a tuberculosis problem exists. For example, in school I the only clinical cases since 1935 occurred in 1963. In school II the only such case since 1935 occurred in 1967. In school III the only one since 1939 was in 1956. It was the continuation of the routine protective measures which discovered these cases while they were minimal and required very little treatment. The methods employed in this study provide for no compromise with the tubercle bacillus. They protect nurses against invasions of tubercle bacilli so they maintain the same status of freedom with which they were born. To allow tubercle bacilli to invade human bodies is to lose many battles.